Yanowitz J.,Magee Womens Research Institute
Current Opinion in Cell Biology | Year: 2010
The perpetuation of most eukaryotic species requires differentiation of pluripotent progenitors into egg and sperm and subsequent fusion of these gametes to form a new zygote. Meiosis is a distinguishing feature of gamete formation as it leads to the twofold reduction in chromosome number thereby maintaining ploidy across generations. This process increases offspring diversity through the random segregation of chromosomes and the exchange of genetic material between homologous parental chromosomes, known as meiotic crossover recombination. These exchanges require the establishment of unique and dynamic chromatin configurations that facilitate cohesion, homolog pairing, synapsis, double strand break formation and repair. The precise orchestration of these events is critical for gamete survival as demonstrated by the majority of human aneuploidies that can be traced to defects in the first meiotic division (Hassold T, Hall H, Hunt P: The origin of human aneuploidy: where we have been, where we are going. Hum Mol Genet 2007, 16 Spec No. 2:R203-R208.). This review will focus on recent advances in our understanding of key meiotic events and how coordination of these events is occurring. © 2010 Elsevier Ltd.
Weissgerber T.L.,Magee Womens Research Institute |
Davies G.A.L.,Queen's University |
Tschakovsky M.E.,Queen's University
Journal of Applied Physiology | Year: 2010
Radial artery diameter decreases when a wrist cuff is inflated to stop blood flow to distal tissue. This phenomenon, referred to as low flow-mediated vasoconstriction (L-FMC), was proposed as a vascular function test. Recommendations that L-FMC be measured concurrently with flow-mediated dilation (FMD) were based on radial artery data. However, cardiovascular disease prediction studies traditionally measure brachial artery FMD. Therefore, studies should determine whether L-FMC occurs in the brachial artery. The hypothesis that reduced shear causes L-FMC has not been tested. Brachial and radial artery L-FMC and FMD were assessed in active nonpregnant (n = 17), inactive nonpregnant (n = 10), active pregnant (n = 15, 34.1 ± 1.2 wk gestation), and inactive pregnant (n = 8, 34.2 ± 2.2 wk gestation) women. Radial artery diameter decreased significantly during occlusion in all groups (nonpregnant, -4.4 ± 4.2%; pregnant, -6.4 ± 3.2%). Brachial artery diameter did not change in active and inactive nonpregnant, and inactive pregnant women; however, the small decrease in active pregnant women was significant. Occlusion decreased shear rate in both arteries, yet L-FMC only occurred in the radial artery. Radial artery L-FMC was not correlated with the reduction in shear rate. L-FMC occurs in the radial but not the brachial artery and is not related to changes in shear rate. Positive correlations between L-FMC (negative values) and FMD (positive values) suggest that radial artery FMD may be reduced among women who experience greater L-FMC. Studies should clarify the underlying stimulus and mechanisms regulating L-FMC, and test the hypothesis that endothelial dysfunction is manifested as enhanced brachial artery L-FMC, but attenuated radial artery L-FMC. Copyright © 2010 the American Physiological Society.
Majumdar S.S.,National Institute of Immunology |
Sarda K.,National Institute of Immunology |
Bhattacharya I.,National Institute of Immunology |
Plant T.M.,Magee Womens Research Institute
Human Reproduction | Year: 2012
background: In humans, as well as in other higher primates, the infantile testis is exposed to an adult-like hormonal milieu, but spermatogenesis is not initiated at this stage of primate development. In the present study, we examined the molecular basis of this intriguing infertile state of the primate testis. methods: The integrity of androgen receptor (AR) and FSH receptor (FSHR) signaling pathways in primary cultures of Sertoli cells (Scs) harvested from azoospermic infant and spermatogenic pubertal monkey testes were investigated under identical in vitro hormonal conditions. In order to synchronously harvest Scs from early pubertal testis, the activation of testicular puberty was timed experimentally by prematurely initiating gonadotrophin secretion in juvenile animals with an intermittent infusion of gonadotrophin-releasing hormone. results: While qRT-PCR demonstrated that AR and FSHR mRNA expression in Scs from infant and pubertal testes were comparable, androgen-binding and FSH-mediated cAMP production by infant Scs was extremely low. Compromised AR and FSHR signaling in infant Scs was further supported by the finding that testosterone (T) and FSH failed to augment the expression of the T responsive gene, claudin 11, and the FSH responsive genes, inhibin-bB, stem cell factor (SCF) and glial cell line-derived neurotrophic factor (GDNF) in Scs harvested at this stage of development. conclusion: These results indicate that compromised AR and FSHR signaling pathways in Scs underlie the inability of the infant primate testis to respond to an endogenous hormonal milieu that later in development, at the time puberty, stimulates the initiation of spermatogenesis. This finding may have relevance to some forms of idiopathic infertility in men. © The Author 2012.
Lash T.L.,Emory University |
Abrams B.,University of California at Berkeley |
Bodnar L.M.,University of Pittsburgh |
Bodnar L.M.,Magee Womens Research Institute
Epidemiology | Year: 2014
BACKGROUND: Epidemiologic data sets continue to grow larger. Probabilistic-bias analyses, which simulate hundreds of thousands of replications of the original data set, may challenge desktop computational resources. METHODS: We implemented a probabilistic-bias analysis to evaluate the direction, magnitude, and uncertainty of the bias arising from misclassification of prepregnancy body mass index when studying its association with early preterm birth in a cohort of 773,625 singleton births. We compared 3 bias analysis strategies: (1) using the full cohort, (2) using a case-cohort design, and (3) weighting records by their frequency in the full cohort. RESULTS: Underweight and overweight mothers were more likely to deliver early preterm. A validation substudy demonstrated misclassification of prepregnancy body mass index derived from birth certificates. Probabilistic-bias analyses suggested that the association between underweight and early preterm birth was overestimated by the conventional approach, whereas the associations between overweight categories and early preterm birth were underestimated. The 3 bias analyses yielded equivalent results and challenged our typical desktop computing environment. Analyses applied to the full cohort, case cohort, and weighted full cohort required 7.75 days and 4 terabytes, 15.8 hours and 287 gigabytes, and 8.5 hours and 202 gigabytes, respectively. CONCLUSIONS: Large epidemiologic data sets often include variables that are imperfectly measured, often because data were collected for other purposes. Probabilistic-bias analysis allows quantification of errors but may be difficult in a desktop computing environment. Solutions that allow these analyses in this environment can be achieved without new hardware and within reasonable computational time frames. Copyright © 2014 by Lippincott Williams & Wilkins.
Burgener A.,Public Health Agency of Canada |
Burgener A.,University of Manitoba |
Burgener A.,Karolinska Institutet |
McGowan I.,University of Pittsburgh |
And 3 more authors.
Current Opinion in Immunology | Year: 2015
The mucosal barrier plays an integral function in human health as it is the primary defense against pathogens, and provides a critical transition between the external environment and the human internal body. In the context of HIV infection, the most relevant mucosal surfaces include those of the gastrointestinal (GI) and genital tract compartments. Several components help maintain the effectiveness of this mucosal surface, including the physical anatomy of the barrier, cellular immunity, soluble factors, and interactions between the epithelial barrier and the local microenvironment, including mucus and host microbiota. Any defects in barrier integrity or function can rapidly lead to an increase in acquisition risk, or with established infection may result in increased pathogenesis, morbidities, or mortality. Indeed, a key feature to all aspects of HIV infection from transmission to pathogenesis is disruption and/or dysfunction of mucosal barriers. Herein, we will detail the host-pathogen relationship of HIV and mucosal barriers in both of these scenarios. © 2015.
Roberts J.M.,Magee Womens Research Institute |
Roberts J.M.,University of Pittsburgh
Seminars in Perinatology | Year: 2014
The pregnancy disorders associated with placental ischemia share many similar pathological and pathophysiological features and are associated with the failure to deliver adequate nutrients and oxygen to the placenta. The origins of this deficiency are a subject of intense study. In this article, I review the genesis and consequences of this pathology addressing the similarities and the differences with the different disorders and addressing current gaps in our knowledge. © 2014 Elsevier Inc.
Wong J.L.,University of Pittsburgh |
Berk E.,University of Pittsburgh |
Edwards R.P.,Peritoneal Ovarian Cancer Specialty Care Center |
Edwards R.P.,University of Pittsburgh |
And 2 more authors.
Cancer Research | Year: 2013
Chemokine-driven interactions of immune cells are essential for effective antitumor immunity. Human natural killer (NK) cells can be primed by the interleukin (IL)-1-related proinflammatory cytokine IL-18 for unique helper activity, which promotes dendritic cell (DC) activation and DC-mediated induction of type-1 immune responses against cancer. Here, we show that such IL-18-primed "helper" NK cells produce high levels of the immature DC (iDC)-attracting chemokines CCL3 and CCL4 upon exposure to tumor cells or the additional inflammatory signals IFN-a, IL-15, IL-12, or IL-2. These "helper" NK cells potently attract iDCs in a CCR5-dependent mechanism and induce high DC production of CXCR3 and CCR5 ligands (CXCL9, CXCL10, and CCL5), facilitating the subsequent recruitment of type-1 effector CD8 + T (Teff) cells. Using cells isolated from the malignant ascites of patients with advanced ovarian cancer, we show that "helper" NK cell-inducing factors can be used to enhance local production of Teff cell-recruiting chemokines. Our findings reveal the unique chemokine expression profile of "helper"NK cells and highlight the potential for using two-signal-activated NKcells to promote homing of type- 1 immune effectors to the human tumor environment. © 2013 American Association for Cancer Research.
Steinman R.A.,University of Pittsburgh |
Steinman R.A.,Magee Womens Research Institute |
Brufsky A.M.,University of Pittsburgh |
Oesterreich S.,Magee Womens Research Institute
Breast Cancer Research | Year: 2012
Zoledronic acid (ZA) is an imidazole-containing bisphosphonate that has been extensively studied as an osteoclast inhibitor. ZA decreases bone turnover and has been effective in limiting osteolysis in metastatic cancers, including breast cancer. Recent clinical trials that demonstrated enhancement of disease-free survival by bisphosphonates have prompted interest in bisphosphonates as anti-cancer agents. ZA, for example, increased disease-free survival in postmenopausal and in premenopausal, hormone-suppressed breast cancer patients. Intriguingly, however, there was a lack of an anti-cancer effect of ZA in premenopausal women without ovarian suppression. These observations have prompted the conjecture that anti-cancer effects of ZA are limited to estrogen-poor environments. This review explores possible mechanisms compatible with differences in ZA activity in premenopausal women compared with postmenopausal (or hormone-suppressed) women. © 2012 BioMed Central Ltd.
Bodnar L.M.,University of Pittsburgh |
Simhan H.N.,University of Pittsburgh |
Simhan H.N.,Magee Womens Research Institute
Obstetrical and Gynecological Survey | Year: 2010
In the United States, significant, intractable disparities exist in rates of major pregnancy outcomes between non-Hispanic black and non-Hispanic white women. A previously unexplored candidate influence on the black-white disparity in adverse birth outcomes is maternal vitamin D status. This review summarizes the evidence relating maternal vitamin D to preeclampsia, spontaneous preterm birth, gestational diabetes, and fetal growth restriction, and addresses gaps in our understanding of the contribution of vitamin D to the intractable black-white disparity in these conditions. The literature reviewed highlights strong biologic plausibility of role for vitamin D in the pathophysiology of these poor pregnancy outcomes. Data also suggest that maternal vitamin D deficiency may increase the risk of preeclampsia and fetal growth restriction. Less research has been done in support of relations with spontaneous preterm birth and gestational diabetes, and fetal and infant survival have rarely been studied. Few trials of vitamin D supplementation have been conducted in pregnant women with adequate power to test effects on birth outcomes. Importantly, black pregnant women have rarely been studied in vitamin D-birth outcomes research. Although vitamin D is a promising candidate influence on black-white disparities in preeclampsia, spontaneous preterm birth, fetal growth restriction, and gestational diabetes, these associations require further study in large samples of black US women. Because vitamin D deficiency is widespread and black-white disparities in pregnancy outcomes and infant survival have been resistant to previous interventions, research to test vitamin D as a causal factor is of major public health significance. Target Audience: Obstetricians & Gynecologist, Family Physicians. Learning Objectives: After completion of this educational activity, the reader will be able to appreciate risk factors for inadequate vitamin D status. Understand the basic aspects of vitamin D metabolism. Become aware of recent literature linking inadequate vitamin D status and adverse pregnancy outcomes such as preeclampsia and preterm birth. © 2010 by Lippincott Williams & Wilkins.
Obermajer N.,University of Pittsburgh |
Muthuswamy R.,University of Pittsburgh |
Lesnock J.,Magee Womens Research Institute |
Edwards R.P.,Magee Womens Research Institute |
And 2 more authors.
Blood | Year: 2011
Dendritic cells (DCs) and myeloid-derived suppressor cells (MDSCs) show opposing roles in the immune system. In the present study, we report that the establishment of a positive feedback loop between prostaglandin E2 (PGE2) and cyclooxygenase 2 (COX2), the key regulator of PGE 2synthesis, represents the determining factor in redirecting the development of CD1a+ DCs to CD14+CD33+CD34 + monocytic MDSCs. Exogenous PGE2 and such diverse COX2 activators as lipopolysaccharide, IL-1β, and IFNγ all induce monocyte expression of COX2, blocking their differentiation into CD1a+ DCs and inducing endogenous PGE2, IDO1, IL-4Rα, NOS2, and IL-10, typical MDSC-associated suppressive factors. The addition of PGE2 to GM-CSF/IL-4-supplemented monocyte cultures is sufficient to induce the MDSC phenotype and cytotoxic T lymphocyte (CTL)-suppressive function. In accordance with the key role of PGE2 in the physiologic induction of human MDSCs, the frequencies of CD11b+CD33+ MDSCs in ovarian cancer are closely correlated with local PGE2 production, whereas the cancer-promoted induction of MDSCs is strictly COX2 dependent. The disruption of COX2-PGE2 feedback using COX2 inhibitors or EP2 and EP4 antagonists suppresses the production of MDSC-associated suppressive factors and the CTL-inhibitory function of fully developed MDSCs from cancer patients. The central role of COX2-PGE2 feedback in the induction and persistence of MDSCs highlights the potential for its manipulation to enhance or suppress immune responses in cancer, autoimmunity, or transplantation. © 2011 by The American Society of Hematology.