Person: Roberts, Drucilla
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Roberts
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Drucilla
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Roberts, Drucilla
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Publication Induced Human Decidual NK-Like Cells Improve Utero-Placental Perfusion in Mice(Public Library of Science, 2016) Cavalli, Ricardo C.; Cerdeira, Ana Sofia; Pernicone, Elizabeth; Korkes, Henri A.; Burke, Suzanne; Rajakumar, Augustine; Thadhani, Ravi; Roberts, Drucilla; Bhasin, Manoj; Karumanchi, Subbian; Kopcow, Hernan D.Decidual NK (dNK) cells, a distinct type of NK cell, are thought to regulate uterine spiral artery remodeling, a process that allows for increased blood delivery to the fetal-placental unit. Impairment of uterine spiral artery remodeling is associated with decreased placental perfusion, increased uterine artery resistance, and obstetric complications such as preeclampsia and intrauterine growth restriction. Ex vivo manipulation of human peripheral blood NK (pNK) cells by a combination of hypoxia, TGFß-1 and 5-aza-2’-deoxycytidine yields cells with phenotypic and in vitro functional similarities to dNK cells, called idNK cells. Here, gene expression profiling shows that CD56Bright idNK cells derived ex vivo from human pNK cells, and to a lesser extent CD56Dim idNK cells, are enriched in the gene expression signature that distinguishes dNK cells from pNK cells. When injected into immunocompromised pregnant mice with elevated uterine artery resistance, idNK cells homed to the uterus and reduced the uterine artery resistance index, suggesting improved placental perfusion.Publication Placental Pathology Associated with Household Air Pollution in a Cohort of Pregnant Women from Dar es Salaam, Tanzania(National Institute of Environmental Health Sciences, 2016) Wylie, Blair; Matechi, Emmanuel; Kishashu, Yahya; Fawzi, Wafaie; Premji, Zul; Coull, Brent; Hauser, Russ; Ezzati, Majid; Roberts, DrucillaBackground: Smoke from the burning of biomass fuels has been linked with adverse pregnancy outcomes such as low birth weight, stillbirth, and prematurity. Objective: To identify potential underlying mechanisms of adverse perinatal outcomes, we explored the association of placental pathology with household air pollution in pregnant women from urban/periurban Tanzania who cook predominantly with charcoal. Methods: Between 2011 and 2013, we measured personal exposures to fine particulate matter (PM2.5) and carbon monoxide (CO) over 72 hr among a cohort of Tanzanian pregnant women. Placentas were collected after delivery for examination. Placental pathologies of inflammatory, hypoxic, ischemic/hypertensive, infectious and thrombotic etiologies were diagnosed, blinded to exposure levels. Using multiple logistic regression, we explored the association of PM2.5 and CO exposure with placental pathology. Results: One hundred sixteen women had personal air exposure measurements and placental histopathology available for analysis. PM2.5 and CO exposures were moderate [geometric means (GSD) were 40.5 μg/m3 (17.3) and 2.21 ppm (1.47) respectively]; 88.6% of PM2.5 measurements exceeded World Health Organization air quality guidelines. We observed an increase in the odds (per 1-unit increase in exposure on the ln-scale) of fetal thrombotic vasculopathy (FTV) both with increasing PM2.5 [adjusted odds ratio (aOR) = 5.5; 95% CI: 1.1, 26.8] and CO measurements (aOR = 2.5; 95% CI: 1.0, 6.4) in adjusted models only. FTV also was more common among pregnancies complicated by stillbirth or low birth weight. Conclusions: Fetal thrombosis may contribute to the adverse outcomes associated with household air pollution from cook stoves during pregnancy. Larger studies are necessary for confirmation. Citation: Wylie BJ, Matechi E, Kishashu Y, Fawzi W, Premji Z, Coull BA, Hauser R, Ezzati M, Roberts D. 2017. Placental pathology associated with household air pollution in a cohort of pregnant women from Dar es Salaam, Tanzania. Environ Health Perspect 125:134–140; http://dx.doi.org/10.1289/EHP256Publication High Prevalence of Hypertension and Placental Insufficiency, but No In Utero HIV Transmission, among Women on HAART with Stillbirths in Botswana(Public Library of Science, 2012) Souda, Sajini; Parekh, Natasha; Binda, Kelebogile; Kayembe, Mukendi; Svab, Petr; Babitseng, Orphinah; Jimbo, William; Creek, Tracy; Essex, Max; Shapiro, Roger; Lockman, Shahin; Powis, Kathleen; Makhema, Joseph; Roberts, DrucillaBackground: Increased stillbirth rates occur among HIV-infected women, but no studies have evaluated the pathological basis for this increase, or whether highly active antiretroviral therapy (HAART) influences the etiology of stillbirths. It is also unknown whether HIV infection of the fetus is associated with stillbirth. Methods: HIV-infected women and a comparator group of HIV-uninfected women who delivered stillbirths were enrolled at the largest referral hospital in Botswana between January and November 2010. Obstetrical records, including antiretroviral use in pregnancy, were extracted at enrollment. Verbal autopsies; maternal HIV, CD4 and HIV RNA testing; stillbirth HIV PCR testing; and placental pathology (blinded to HIV and treatment status) were performed. Results: Ninety-nine stillbirths were evaluated, including 62 from HIV-infected women (34% on HAART from conception, 8% on HAART started in pregnancy, 23% on zidovudine started in pregnancy, and 35% on no antiretrovirals) and 37 from a comparator group of HIV-uninfected women. Only 2 (3.7%) of 53 tested stillbirths from HIV-infected women were HIV PCR positive, and both were born to women not receiving HAART. Placental insufficiency associated with hypertension accounted for most stillbirths. Placental findings consistent with chronic hypertension were common among HIV-infected women who received HAART and among HIV-uninfected women (65% vs. 54%, p = 0.37), but less common among HIV-infected women not receiving HAART (28%, p = 0.003 vs. women on HAART). Conclusions: In utero HIV infection was rarely associated with stillbirths, and did not occur among women receiving HAART. Hypertension and placental insufficiency were associated with most stillbirths in this tertiary care setting.Publication Acute Histologic Chorioamnionitis at Term: Nearly Always Noninfectious(Public Library of Science, 2012) Roberts, Drucilla; Celi, Ann; Riley, Laura; Onderdonk, Andrew; Boyd, Theonia; Johnson, Lise; Lieberman, ElliceBackground: The link between histologic acute chorioamnionitis and infection is well established in preterm deliveries, but less well-studied in term pregnancies, where infection is much less common. Methodology/Principal Findings We conducted a secondary analysis among 195 low-risk women with term pregnancies enrolled in a randomized trial. Histologic and microbiologic evaluation of placentas included anaerobic and aerobic cultures (including mycoplasma/ureaplasma species) as well as PCR. Infection was defined as ≥1,000 cfu of a single known pathogen or a ≥2 log difference in counts for a known pathogen versus other organisms in a mixed culture. Placental membranes were scored and categorized as: no chorioamnionitis, Grade 1 (subchorionitis and patchy acute chorioamnionitis), or Grade 2 (severe, confluent chorioamnionitis). Grade 1 or grade 2 histologic chorioamnionitis was present in 34% of placentas (67/195), but infection was present in only 4% (8/195). Histologic chorioamnionitis was strongly associated with intrapartum fever >38°C [69% (25/36) fever, 26% (42/159) afebrile, P<.0001]. Fever occurred in 18% (n = 36) of women. Most febrile women [92% (33/36)] had received epidural for pain relief, though the association with fever was present with and without epidural. The association remained significant in a logistic regression controlling for potential confounders (OR = 5.8, 95% CI = 2.2,15.0). Histologic chorioamnionitis was also associated with elevated serum levels of interleukin-8 (median = 1.3 pg/mL no histologic chorioamnionitis, 1.5 pg/mL Grade 1, 2.1 pg/mL Grade 2, P = 0.05) and interleukin-6 (median levels = 2.2 pg/mL no chorioamnionitis, 5.3 pg/mL Grade 1, 24.5 pg/mL Grade 2, P = 0.02) at admission for delivery as well as higher admission WBC counts (mean = 12,000cells/mm\(^3\) no chorioamnionitis, 13,400cells/mm\(^3\) Grade 1, 15,700cells/mm\(^3\) Grade 2, P = 0.0005). Conclusion/Significance: Our results suggest histologic chorioamnionitis at term most often results from a noninfectious inflammatory process. It was strongly associated with fever, most of which was related to epidural used for pain relief. A more ‘activated’ maternal immune system at admission was also associated with histologic chorioamnionitis.Publication Mammalian Target of Rapamycin Is a Therapeutic Target for Murine Ovarian Endometrioid Adenocarcinomas with Dysregulated Wnt/\(\beta\)-Catenin and PTEN(Public Library of Science, 2011) Tanwar, Pradeep; Zhang, LiHua; Kaneko-Tarui, Tomoko; Curley, Michael D.; Taketo, Makoto M.; Rani, Poonam; Roberts, Drucilla; Teixeira, JDespite the fact that epithelial ovarian cancers are the leading cause of death from gynecological cancer, very little is known about the pathophysiology of the disease. Mutations in the WNT and PI3K pathways are frequently observed in the human ovarian endometrioid adenocarcinomas (OEAs). However, the role of WNT/\(\beta\)-catenin and PTEN/AKT signaling in the etiology and/or progression of this disease is currently unclear. In this report we show that mice with a gain-of-function mutation in \(\beta\)-catenin that leads to dysregulated nuclear accumulation of \(\beta\)-catenin expression in the ovarian surface epithelium (OSE) cells develop indolent, undifferentiated tumors with both mesenchymal and epithelial characteristics. Combining dysregulated \(\beta\)-catenin with homozygous deletion of PTEN in the OSE resulted in development of significantly more aggressive tumors, which was correlated with inhibition of p53 expression and cellular senescence. Induced expression of both mTOR kinase, a master regulator of proliferation, and phosphorylation of its downstream target, S6Kinase was also observed in both the indolent and aggressive mouse tumors, as well as in human OEA with nuclear \(\beta\)-catenin accumulation. Ectopic allotransplants of the mouse ovarian tumor cells with a gain-of-function mutation in \(\beta\)-catenin and PTEN deletion developed into tumors with OEA histology, the growth of which were significantly inhibited by oral rapamycin treatment. These studies demonstrate that rapamycin might be an effective therapeutic for human ovarian endometrioid patients with dysregulated Wnt/\(\beta\)-catenin and Pten/PI3K signaling.