Publications by authors named "David Grynspan"

52 Publications

Fibrinogen-Like Protein 2-Associated Transcriptional and Histopathological Features of Immunological Preeclampsia.

Hypertension 2020 Sep 27;76(3):910-921. Epub 2020 Jul 27.

From the Department of Cellular and Molecular Medicine (P.R.-C., S.J.B, B.C.V., S.A.B.), University of Ottawa, ON, Canada.

Preeclampsia is a multifactorial hypertensive disorder of pregnancy, with variable presentation in both maternal and fetal factors, such that no treatment or marker is currently universal to all cases. Here, we demonstrate that the prothrombinase and immunomodulatory secreted factor FGL-2 (fibrinogen-like protein 2) is differentially expressed across previously characterized gene expression clusters containing clinically relevant disease subtypes. is low in a cluster consistent with the traditional paradigm of the pathology of preeclampsia (canonical preeclampsia) and high in a cluster exhibiting evidence of immune activation (immunological preeclampsia). We show that it is part of an immunoregulatory gene module integral to the transcriptional profile and placental pathology specific to immunological preeclampsia. We determine that associates positively with chronic inflammation lesions of the placenta while associating negatively with maternal vascular malperfusion lesions. The transcriptional profiles of maternal vascular malperfusion lesions show downregulation of and upregulation of previously investigated preeclampsia biomarkers, such as FLT1 (Fms Related Receptor Tyrosine Kinase 1) and ENG (endoglin). Conversely, the profiles of chronic inflammation lesions show an interesting downregulation of these genes, but an upregulation of and of -correlated immunoregulatory genes, suggesting it is upregulated downstream of major inflammatory mediators such as TNF (tumor necrosis factor)-α and IFN (interferon)-γ, hallmarks of the immunological preeclampsia subtype. This work, overall, demonstrates that FGL-2 expression levels in the term placenta reflect the unique pathophysiology that leads to immunological preeclampsia, leading to its potential as a subtype-specific biomarker.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.14807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418930PMC
September 2020

Neonatal necrotizing enterocolitis: a case series examining clinical diagnosis with discrepant versus concordant autopsy results.

J Perinatol 2020 06 17;40(6):928-934. Epub 2020 Feb 17.

Division of Neonatology, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.

Objective: The objective of this study is to determine whether rapidity of death in necrotizing enterocolitis (NEC) increased odds of discordance between clinical and pathological diagnosis.

Study Design: Retrospective case-series study including preterm infants admitted to the NICU.

Results: Twenty-two infants met the selection criteria. Gross pathologic evidence of NEC was present in 1/6 cases (17%) where demise occurred <12 h after onset of symptoms, 3/5 cases (60%) within 12-24 h, and 8/11 cases (73%) in >24 h. Histological evidence of necrosis was present in 4/6 (67%) cases when death occurred <12 h, 4/5 (80%) in 12-24 h, and 9/11 (82%) in >24 h. The percentage with gross pathologic evidence showed a monotonic trend (P = 0.031), while the trend was less clear for histologic findings (P = 0.496).

Conclusion: Pathologic features of cell death may not have had sufficient time to develop. This study could reassure both healthcare providers and families when pathologic and clinical diagnoses are not consistent.
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http://dx.doi.org/10.1038/s41372-020-0611-7DOI Listing
June 2020

Incorporating Transition-Affirming Language into Anatomical Pathology Reporting for Gender Affirmation Surgery.

Transgend Health 2019 21;4(1):335-338. Epub 2019 Nov 21.

Department of Pathology and Laboratory Medicine, Vernon Jubilee Hospital, Vernon, Canada.

The use of inclusive terminology in health records continues to be a challenge for transgender, gender-diverse, and nonbinary peoples. When patients access electronic health records, laboratory results, including pathology reports, are among the most frequently viewed items. There has been limited discussion of transgender care within laboratory medicine, despite its role in providing written pathology reports after gender-affirming surgery. This group proposes inclusive diagnostic terminology for pathology reporting and puts forward recommendations for procedural descriptions in the pathology report. Finally, we highlight pathological information that should be included in a report that has future cancer screening or diagnostic consequences.
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http://dx.doi.org/10.1089/trgh.2019.0026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868650PMC
November 2019

Gastroschisis Is Associated With Placental Delayed Villous Maturation.

Pediatr Dev Pathol 2020 May-Jun;23(3):197-203. Epub 2019 Sep 22.

Department of Pathology, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada.

Gastroschisis is a congenital abnormality characterized by visceral herniation through an abdominal wall defect. While the cause of gastroschisis is unknown, it has been linked to risk factors including young maternal age, smoking, and alcohol use during pregnancy. To date, the only established placental correlate is amniocyte vacuolization. Based on our clinical experience, we hypothesized that delayed villous maturation (DVM) is also associated with gastroschisis. We conducted a retrospective slide review of 23 placentas of neonates with gastroschisis. Additionally, we selected 2 control groups of placentas: 1 with a previous diagnosis of DVM and 1 with normal villous morphology. All placentas were randomized and reviewed by 2 perinatal pathologists, who were blinded to the group; DVM and amniocyte vacuolization were assessed. Gastroschisis was associated with increased placental DVM in 65.2% of cases (vs 13.6% of controls;  = .0007) and increased amniocyte vacuolization in 52.2% of cases (vs 9.1% of controls;  = .003) compared to the control group. Based on the normal and DVM groups, kappa agreement between current slide review and initial pathology diagnosis was 0.419, indicating moderate agreement. Our study shows that gastroschisis is associated with placental DVM. This association may be due to (1) a common upstream factor contributing to both gastroschisis and DVM or (2) DVM may be a consequence of the altered placental and amniotic environment in the context of gastroschisis.
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http://dx.doi.org/10.1177/1093526619875877DOI Listing
March 2021

Both "canonical" and "immunological" preeclampsia subtypes demonstrate changes in placental immune cell composition.

Placenta 2019 08 27;83:53-56. Epub 2019 Jun 27.

Department of Physiology, University of Toronto, Ontario, Canada; Department of Obstetrics and Gynaecology, University of Toronto, Ontario, Canada. Electronic address:

Our prior work investigating the heterogeneity of preeclampsia identified multiple placental subtypes of this disorder, including a "canonical" group with maternal vascular malperfusion and an "immunological" group with signs of allograft rejection. Here, we perform a pilot immunohistochemistry study to investigate if an increase in infiltrating maternal immune cells is contributing to the "immunological" pathology subtype. This revealed an enrichment of monocytes and/or neutrophils (CD68  and MPO cells) in the intervillous space of these placentas. Surprisingly, "canonical" samples also demonstrated a significant result, with decreased CD68 staining. As such, further immunohistochemistry to assess immune contributions in preeclampsia subtypes is warranted.
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http://dx.doi.org/10.1016/j.placenta.2019.06.384DOI Listing
August 2019

Pilomatrixoma of the ocular adnexa: report of 3 cases with variations in the histopathological findings.

Can J Ophthalmol 2019 08 16;54(4):413-416. Epub 2019 Jan 16.

Departments of Ophthalmology, The Ottawa Hospital and University of Ottawa, Ottawa, Ont.; Departments of Ophthalmology, The Children's Hospital of Eastern Ontario and University of Ottawa, Ottawa, Ont.

Objective: To report the clinical and variations in the histopathological features of pilomatrixoma of the ocular adnexa in 3 young individuals.

Design: A retrospective case series was performed with clinical, histological, and immunohistochemical analysis.

Participants: Case 1 is an 18-year-old male who presented with a reddish-blue swelling under the left eyebrow. The lesion measured 2 × 1 cm. Case 2 is a 2-year-old female who presented with a reddish-blue nodule inferior to the right eyebrow with telangiectatic vessels. The lesion measured 6 × 4 × 4 mm. Case 3 is a 14-year-old female who presented with a subcutaneous lesion under the right upper eyebrow with fluctuating inflammation. The lesion measured 12 × 3 × 2 mm. Histopathological examination of case 1 disclosed peripheral basaloid cells and central shadow cells containing calcific foci, separated by a transition zone. In case 2, histopathological analysis revealed central calcific foci in islands of shadow cells with more peripheral basaloid cells. In case 3, we observed numerous clusters of shadow cells with focal calcifications, as well as basaloid cells in a disorganized configuration.

Conclusion: Pilomatrixoma is an uncommon benign skin neoplasm originating from the matrix of the hair root. We describe a spectrum of histopathological findings in pilomatrixoma of the ocular adnexal in 3 young individuals.
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http://dx.doi.org/10.1016/j.jcjo.2018.10.015DOI Listing
August 2019

Recurrent Placental Transcriptional Profile With a Different Histological and Clinical Presentation: A Case Report.

Pediatr Dev Pathol 2019 Nov-Dec;22(6):584-589. Epub 2019 Jun 7.

Department of Pathology and Laboratory Medicine, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada.

Statistically, patients with severe pregnancy complications are at risk of recurrent complications, but it is less understood if patients present with similar or different placental pathologies in subsequent pregnancies. In this case report, we describe 2 consecutive adverse pregnancies in the same woman 4 years apart. The first pregnancy was diagnosed as early-onset preeclampsia and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome, with placental maternal vascular malperfusion features, such as syncytial knots and accelerated villous maturity. In contrast, the second pregnancy was associated with normotensive fetal growth restriction and placental "immunological" lesions, such as massive perivillous fibrin deposition and chronic intervillositis. However, based on the expression of FLT1, LIMCH1, and TAP1 by quantitative polymerase chain reaction, the placentas from both pregnancies were found to exhibit an "immunological" transcriptional signature. This suggests that this small panel of gene expression markers may be able to predict the future reoccurrence of an immunological placental pathology despite no histological evidence within the first pregnancy. These results call for more studies looking at paired pregnancies of individuals with recurrent obstetric complications and confirm the importance of assessing matched transcriptional and histopathological placental information.
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http://dx.doi.org/10.1177/1093526619852871DOI Listing
April 2020

Neu-Laxova syndrome presenting prenatally with increased nuchal translucency and cystic hygroma: The utility of exome sequencing in deciphering the diagnosis.

Am J Med Genet A 2019 05 5;179(5):813-816. Epub 2019 Mar 5.

Regional Genetics Program, CHEO, University of Ottawa, Ottawa, Ontario, Canada.

Neu-Laxova syndrome (NLS) is a lethal autosomal recessive microcephaly syndrome associated with intrauterine growth restriction (IUGR) and multiple congenital anomalies. Clinical features include central nervous system malformations, joint contractures, ichthyosis, edema, and dysmorphic facial features. Biallelic pathogenic variants in either the PHGDH or PSAT1 genes have been shown to cause NLS. Using exome sequencing, we aimed to identify the underlying genetic diagnosis in three fetuses (from one family) with prenatal skin edema, severe IUGR, micrognathia, renal anomalies, and arthrogryposis and identified a homozygous c.1A>C (p.Met1?, NM_006623.3) variant in the PHGDH gene. Loss of the translation start codon is a novel genetic mechanism for the development of NLS. Prenatal diagnosis of NLS is challenging and few reports describe the fetal pathology. Fetal neuropathologic examination revealed: delayed brain development, congenital agenesis of the corticospinal tracts, and hypoplasia of the hippocampus, cerebellum and brainstem. Each pregnancy also showed increased nuchal translucency (NT) or cystic hygroma. While NLS is rare, it may be a cause of recurrent increased NT/cystic hygroma. This finding provides further support that cystic hygroma has many different genetic causes and that exome sequencing may shed light on the underlying genetic diagnoses in this group of prenatal patients.
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http://dx.doi.org/10.1002/ajmg.a.61076DOI Listing
May 2019

A synoptic framework and future directions for placental pathology reporting.

Placenta 2019 02 11;77:46-57. Epub 2019 Jan 11.

Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Canada; Interdisciplinary School of Health Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, Canada. Electronic address:

Placental pathology is a key modality for determining placental health during pregnancy, especially in the event of adverse pregnancy outcomes. However, issues with standardization in placental diagnosis, reporting practices and clinical translation prevent this modality from being used to its full potential. This article will highlight these standardization issues and summarize ongoing work in this field to overcome them. Additionally, we propose a synoptic reporting framework for placental pathology based on current consensus guidelines, aimed at enhancing the comprehensiveness and quality of reporting placental findings. We believe this approach will improve our understanding of the placenta in adverse pregnancy outcomes and, importantly, offer the opportunity to increase knowledge translation to key stakeholder groups including patients.
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http://dx.doi.org/10.1016/j.placenta.2019.01.009DOI Listing
February 2019

Placental villous hypermaturation is associated with improved neonatal outcomes.

Placenta 2019 01 14;76:1-5. Epub 2019 Jan 14.

Department of Pathology and Laboratory Medicine, University of Ottawa, Ottawa, Canada. Electronic address:

Introduction: Accelerated placental maturation is considered a sign of maternal vascular malperfusion, and is often interpreted as an adaptive, compensatory response by the placenta. We tested this interpretation by comparing outcomes in pregnancies with and without accelerated maturation.

Methods: Using data from the National Collaborative Perinatal Project, we categorized preterm placentas (24-34 weeks, inclusive; 2525 births) by whether they showed placental villous hypermaturation (PVH), i.e., had the appearance of a placenta of 37 weeks or over upon microscopic examination. We assessed whether PVH was associated with maternal race, maternal BMI, fetal sex, type of preterm birth, preeclampsia, signs of infection or inflammation or placental abruption. We also assessed whether placentas showing PVH were associated with improved outcomes in terms of survival, Apgar score, or oxygen use.

Results: PVH was more common in preeclamptic pregnancies and less common in pregnancies complicated by placental abruption or showing signs of placental infection or inflammation. Adjusting for potentially confounding factors, PVH was associated with reduced odds of fetal death, death between birth and 120 days of age, low Apgar scores and oxygen use. PVH was also associated with higher birthweights for gestational age. When correcting for the effect of birthweight, the association between PVH and reduced fetal and neonatal death remained significant.

Discussion: Accelerated placental maturation, as manifested by PVH, is associated with improved outcomes. Our work therefore supports the hypothesis that accelerated maturation is a compensatory response by the placenta to improve its transport capacity in specific pregnancy complications.
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http://dx.doi.org/10.1016/j.placenta.2019.01.012DOI Listing
January 2019

The Density of Cell Nuclei at the Materno-Fetal Exchange Barrier is Sexually Dimorphic in Normal Placentas, but not in IUGR.

Sci Rep 2019 02 20;9(1):2359. Epub 2019 Feb 20.

LMU Munich, Faculty of Medicine, Institute of Anatomy, Chair of Neuroanatomy, Munich, Germany.

Placental sexual dimorphism is of special interest in prenatal programming. Various postnatal diseases with gender dependent incidence, especially neuropsychiatric disorders like schizophrenia and autism spectrum disorders, have prenatal risk factors established. However, the functional relevance of placental microarchitecture in prenatal programming is poorly investigated, mainly due to a lack of statistically efficient methods. We hypothesized that the recently established 3D microscopic analysis of villous trees would be able to identify microscopic structural correlates of human placental sexual dimorphism. We analyzed the density of cell nuclei of villous trophoblast, i.e. the materno-fetal exchange barrier, in placentas from term pregnancies. The cell nuclei were grouped into proliferative and non-proliferative nuclei by detection of a proliferation marker (PCNA). Normal female placentas showed a higher density of non-proliferating nuclei (PCNA-negative) in villous trophoblast than normal male placentas. The density of PCNA-negative cell nuclei was higher in placentas of pregnancies with intrauterine growth retardation (IUGR) than in control placentas. The data of the present study shows that the density of non-proliferative cell nuclei in the syncytial layer of villous trophoblast is influenced by fetal sex and by IUGR, while proliferation remains unchanged. A novel concept of post-fusion regulation of syncytial structure and function is proposed.
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http://dx.doi.org/10.1038/s41598-019-38739-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382753PMC
February 2019

A Case of Fulminant Lung Necrosis in a Preterm Neonate.

Pediatr Dev Pathol 2019 Oct 13;22(5):461-464. Epub 2019 Feb 13.

Department of Pathology and Laboratory Medicine, The Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.

is a ubiquitous Gram-positive rod seldom considered pathogenic in clinical isolates. However, it possesses multiple virulence factors explaining why it has been linked to fulminant and pyogenic infections in vulnerable hosts. Its recovery from sterile samples in immunocompromised patients cannot be disregarded. Premature infants would fall into this category. We describe the case of a neonate born at 26 weeks of gestational age, who died of a rapidly progressive necrotizing pneumonia following suspected nosocomial acquisition. The rapidity of his course and the autopsy findings of necrosis with minimal inflammation suggest a toxin-mediated process. Pathologists should be aware of this pathogen and obtain proper microbiological samples in the presence of such autopsy findings, as the diagnosis may have infection-prevention implications in health-care settings.
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http://dx.doi.org/10.1177/1093526619825895DOI Listing
October 2019

Fractal Dimension Does Not Correlate As Well With Models of Neonatal Chronic Lung Injury as It Does With Placental Distal Villous Hypoplasia.

Pediatr Dev Pathol 2019 Mar-Apr;22(2):171-174. Epub 2019 Feb 2.

3 Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada.

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http://dx.doi.org/10.1177/1093526618782499DOI Listing
March 2019

Pannexin 1 inhibits rhabdomyosarcoma progression through a mechanism independent of its canonical channel function.

Oncogenesis 2018 Nov 21;7(11):89. Epub 2018 Nov 21.

Molecular Biomedicine Program, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.

Rhabdomyosarcoma (RMS) is an aggressive soft tissue sarcoma of childhood thought to arise from impaired differentiation of skeletal muscle progenitors. We have recently identified Pannexin 1 (PANX1) channels as a novel regulator of skeletal myogenesis. In the present study, we determined that PANX1 transcript and protein levels are down-regulated in embryonal (eRMS) and alveolar RMS (aRMS) patient-derived cell lines and primary tumor specimens as compared to differentiated skeletal muscle myoblasts and tissue, respectively. While not sufficient to overcome the inability of RMS to reach terminal differentiation, ectopic expression of PANX1 in eRMS (Rh18) and aRMS (Rh30) cells significantly decreased their proliferative and migratory potential. Furthermore, ectopic PANX1 abolished 3D spheroid formation in eRMS and aRMS cells and induced regression of established spheroids through induction of apoptosis. Notably, PANX1 expression also significantly reduced the growth of human eRMS and aRMS tumor xenografts in vivo. Interestingly, PANX1 does not form active channels when expressed in eRMS (Rh18) and aRMS (Rh30) cells and the addition of PANX1 channel inhibitors did not alter or reverse the PANX1-mediated reduction of cell proliferation and migration. Moreover, expression of channel-defective PANX1 mutants not only disrupted eRMS and aRMS 3D spheroids, but also inhibited in vivo RMS tumor growth. Altogether our findings suggest that PANX1 alleviates RMS malignant properties in vitro and in vivo through a process that is independent of its canonical channel function.
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http://dx.doi.org/10.1038/s41389-018-0100-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6246549PMC
November 2018

Biallelic Mutations in LRRC56, Encoding a Protein Associated with Intraflagellar Transport, Cause Mucociliary Clearance and Laterality Defects.

Am J Hum Genet 2018 11;103(5):727-739

Yorkshire Regional Genetics Service, St. James's University Hospital, Leeds LS9 7TF, UK; School of Medicine, University of Leeds, St. James's University Hospital, Leeds LS9 7TF, UK. Electronic address:

Primary defects in motile cilia result in dysfunction of the apparatus responsible for generating fluid flows. Defects in these mechanisms underlie disorders characterized by poor mucus clearance, resulting in susceptibility to chronic recurrent respiratory infections, often associated with infertility; laterality defects occur in about 50% of such individuals. Here we report biallelic variants in LRRC56 (known as oda8 in Chlamydomonas) identified in three unrelated families. The phenotype comprises laterality defects and chronic pulmonary infections. High-speed video microscopy of cultured epithelial cells from an affected individual showed severely dyskinetic cilia but no obvious ultra-structural abnormalities on routine transmission electron microscopy (TEM). Further investigation revealed that LRRC56 interacts with the intraflagellar transport (IFT) protein IFT88. The link with IFT was interrogated in Trypanosoma brucei. In this protist, LRRC56 is recruited to the cilium during axoneme construction, where it co-localizes with IFT trains and is required for the addition of dynein arms to the distal end of the flagellum. In T. brucei carrying LRRC56-null mutations, or a variant resulting in the p.Leu259Pro substitution corresponding to the p.Leu140Pro variant seen in one of the affected families, we observed abnormal ciliary beat patterns and an absence of outer dynein arms restricted to the distal portion of the axoneme. Together, our findings confirm that deleterious variants in LRRC56 result in a human disease and suggest that this protein has a likely role in dynein transport during cilia assembly that is evolutionarily important for cilia motility.
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http://dx.doi.org/10.1016/j.ajhg.2018.10.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218757PMC
November 2018

Impaired antimicrobial response and mucosal protection induced by ibuprofen in the immature human intestine.

Pediatr Res 2018 12 16;84(6):813-820. Epub 2018 Oct 16.

Laboratory of Intestinal Physiopathology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, QC, Canada.

Background: The use of nonsteroidal anti-inflammatory drugs (NSAIDs) such as indomethacin (INDO) and ibuprofen (IBU) has been shown to be an effective therapy for the closure of patent ductus arteriosus (PDA). However, this treatment has been associated with an increased risk of developing enteropathies in neonates. Whether the use of IBU is safer than INDO for the immature intestine remains to be elucidated.

Methods: The direct impact of IBU on the human immature intestinal transcriptome was investigated using serum-free organ culture. Differentially expressed genes were analyzed with Ingenuity Pathway Analysis software and compared with those previously reported with INDO. Validation of differentially expressed genes was confirmed by qPCR.

Results: We identified several biological processes that were significantly modulated by IBU at similar levels to what had previously been observed with INDO, while the expression of genes involved in "antimicrobial response" and "mucus production" was significantly decreased exclusively by IBU in the immature intestine.

Conclusions: Our findings indicate that IBU has a harmful influence on the immature intestine. In addition to exerting many of the INDO observed deleterious effects, IBU alters pathways regulating microbial colonization and intestinal epithelial defense.
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http://dx.doi.org/10.1038/s41390-018-0201-yDOI Listing
December 2018

Placental transcriptional and histologic subtypes of normotensive fetal growth restriction are comparable to preeclampsia.

Am J Obstet Gynecol 2019 01 9;220(1):110.e1-110.e21. Epub 2018 Oct 9.

Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Background: Infants born small for gestational age because of pathologic placenta-mediated fetal growth restriction can be difficult to distinguish from those who are constitutionally small. Additionally, even among fetal growth-restricted pregnancies with evident placental disease, considerable heterogeneity in clinical outcomes and long-term consequences has been observed. Gene expression studies of fetal growth-restricted placentas also have limited consistency in their findings, which is likely due to the presence of different molecular subtypes of disease. In our previous study on preeclampsia, another heterogeneous placenta-centric disorder of pregnancy, we found that, by clustering placentas based only on their gene expression profiles, multiple subtypes of preeclampsia, including several with co-occurring suspected fetal growth restriction, could be identified.

Objective: The purpose of this study was to discover placental subtypes of normotensive small-for-gestational-age pregnancies with suspected fetal growth restriction through the use of unsupervised clustering of placental gene expression data and to investigate their relationships with hypertensive suspected fetal growth-restricted placental subtypes.

Study Design: A new dataset of 20 placentas from normotensive small-for-gestational-age pregnancies (birthweight <10th percentile for gestational age and sex) with suspected fetal growth restriction (ultrasound features of placental insufficiency) underwent genome-wide messenger RNA expression assessment and blinded detailed histopathologic evaluation. These samples were then combined with a subset of samples from our previously published preeclampsia cohort (n=77) to form an aggregate fetal growth-focused cohort (n=97) of placentas from normotensive small-for-gestational-age, hypertensive (preeclampsia and chronic hypertensive) small-for-gestational-age, and normotensive average-for-gestational-age pregnancies. Gene expression data were subjected to unsupervised clustering, and clinical and histopathologic features were correlated to the identified sample clusters.

Results: Clustering of the aggregate dataset revealed 3 transcriptional subtypes of placentas from normotensive small-for-gestational-age/suspected fetal growth-restricted pregnancies, with differential enrichment of clinical and histopathologic findings. The first subtype exhibited either no placental disease or mild maternal vascular malperfusion lesions, and, co-clustered with the healthy average-for-gestational-age control subjects; the second subtype showed more severe evidence of hypoxic damage and lesions of maternal vascular malperfusion, and the third subtype demonstrated an immune/inflammatory response and histologic features of a maternal-fetal interface disturbance. Furthermore, all 3 of these normotensive small-for-gestational-age subtypes co-clustered with a group of placentas from hypertensive small-for-gestational-age pregnancies with more severe clinical outcomes, but very comparable transcriptional and histologic placental profiles.

Conclusion: Overall, this study provides evidence for at least 2 pathologic placental causes of normotensive small-for-gestational-age, likely representing true fetal growth restriction. These subtypes also show considerable similarity in gene expression and histopathology to our previously identified "canonical" and "immunologic" preeclampsia placental subtypes. Furthermore, we discovered a subtype of normotensive small-for-gestational-age (with suspected fetal growth restriction) with minimal placental disease that may represent both constitutionally small infants and mild fetal growth restriction, although these cannot be distinguished with the currently available data. Future work that focuses on the identification of etiology-driven biomarkers and therapeutic interventions for each subtype of fetal growth restriction is warranted.
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http://dx.doi.org/10.1016/j.ajog.2018.10.003DOI Listing
January 2019

The clinical heterogeneity of preeclampsia is related to both placental gene expression and placental histopathology.

Am J Obstet Gynecol 2018 12 29;219(6):604.e1-604.e25. Epub 2018 Sep 29.

Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Interdisciplinary School of Health Sciences, Faculty of Health Sciences, University of Ottawa, Ottawa, Ontario, Canada. Electronic address:

Background: Preeclampsia is a life-threatening disorder of pregnancy, demonstrating a high degree of heterogeneity in clinical features such as presentation, disease severity, and outcomes. This heterogeneity suggests distinct pathophysiological mechanisms may be driving the placental disease underlying this disorder. Our group recently reported distinct clusters of placental gene expression in preeclampsia and control pregnancies, allowing for the identification of at least 3 clinically relevant gene expression-based subtypes of preeclampsia. Histopathological examination of a small number of samples from 2 of the gene expression-based subtypes revealed placental lesions consistent with their gene expression phenotype, suggesting that detailed placental histopathology may provide further insight into the pathophysiology underlying these distinct gene expression-based subtypes.

Objectives: The objective of the study was to assess histopathological lesions in the placentas of patients belonging to each identified gene expression-based subtype of preeclampsia, characterized in our previous study. Our goal was to further understand the pathophysiologies defining these gene expression-based subtypes by integrating gene expression with histopathological findings, possibly identifying additional subgroups of preeclampsia patients.

Study Design: Paraffin-embedded placental biopsies from patients included in the gene expression profiling study (n = 142 of 157, 90.4%) were sectioned, hematoxylin and eosin stained, and imaged. An experienced perinatal pathologist, blinded to gene expression findings and clinical information, assessed the presence and severity of histological lesions using a comprehensive, standardized data collection form. The frequency and severity scores of observed histopathological lesions were compared among gene expression-based subtypes as well as within each subtype using using Fisher exact tests, Kruskal-Wallis tests, and hierarchical clustering. The histological findings of the placental samples were visualized using t-distributed stochastic neighbor embedding and phylogenetic trees. Concordance and discordance between gene expression findings and histopathology were also investigated and visualized using principal component analysis.

Results: Several histological lesions were found to be characteristic of each gene expression-based preeclampsia subtype. The overall concordance between gene expression and histopathology for all samples was 65% (93 of 142), with characteristic placental lesions for each gene expression-based subtype complementing prior gene enrichment findings (ie, placentas with enrichment of hypoxia-associated genes showed severe lesions of maternal vascular malperfusion). Concordant samples were located in the central area of each gene expression-based cluster when viewed on a principal component analysis plot. Interestingly, discordant samples (gene expression and histopathology not reflective of one another) were generally found to lie at the periphery of the gene expression-based clusters and tended to border the group of patients with phenotypically similar histopathology.

Conclusion: Our findings demonstrates a high degree of concordance between placental lesions and gene expression across subtypes of preeclampsia. Additionally, novel integrative analysis of scored placental histopathology severity and gene expression findings allowed for the identification of patients with intermediate phenotypes of preeclampsia not apparent through gene expression profiling alone. Future investigations should examine the temporal relationship between these 2 modalities as well as consider the maternal and fetal contributions to these subtypes of disease.
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http://dx.doi.org/10.1016/j.ajog.2018.09.036DOI Listing
December 2018

The problem with using the birthweight:placental weight ratio as a measure of placental efficiency.

Placenta 2018 08 3;68:52-58. Epub 2018 Jul 3.

Maternal and Fetal Health Research Centre, Institute of Human Development, University of Manchester, Manchester, UK; Maternal and Fetal Health Research Centre, Manchester Academic Health Science Centre, St.Mary's Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK. Electronic address:

Introduction: The ratio of birthweight to placental weight (BW:PW) is often used as a measure of placental efficiency in humans and animals. However, ratios have properties that are known to lead to spurious results. An alternative approach is the use of residuals from regression, which reflect whether birthweight is higher or lower than expected for a given placental weight, given the population pattern. We hypothesized that biologically meaningful measures of placental efficiency would differ between placentas with and without pathology, and between adverse and normal perinatal and postnatal outcomes.

Methods: We examined associations between measures of placental efficiency (BW:PW ratio or residuals) and placental pathology, Apgar scores and infant death using National Collaborative Perinatal Project data (4645 preterm births and 28497 term births).

Results: BW:PW ratios and residuals were significantly lower in placentas showing pathologies including signs of large infarcts or hemorrhage, although many of these differences were small. Low BW:PW ratios and residuals were also associated with low Apgar scores and increased risk of postnatal death. Whereas residuals were lower in term placentas that appeared immature by microscopic examination, the opposite was true for BW:PW ratios.

Conclusion: The BW:PW ratio produced an artefact whereby histologically less mature placentas at term appeared to be more "efficient" than mature placentas, illustrating a known problem with the use of ratios. For other traits, residuals generally showed differences between placentas with and without pathology that were as great as those seen with BW:PW ratios, and often showed stronger associations with adverse outcomes.
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http://dx.doi.org/10.1016/j.placenta.2018.06.311DOI Listing
August 2018

Apparent Diffusion Coefficient of the Placenta in Twin versus Singleton Pregnancies.

Fetal Diagn Ther 2018 8;44(2):129-134. Epub 2018 Mar 8.

Medical Imaging Department, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.

Previous studies in singleton pregnancies reported conflicting trends in apparent diffusion coefficient (ADC) values with gestational age (GA) and stable relative ADC (rADC; ADC placenta divided by ADC globe) throughout pregnancy. The purpose of our study was to compare the ADC and rADC of placentas of twin and singleton pregnancies.

Materials And Methods: Fetal MRI of 11 twin and 23 singleton pregnancies were retrospectively analyzed. Each group was further divided by GA (≤24 and >24 weeks). On ADC, 3 regions of interest were selected in the placenta and 1 in the globe. ADC and rADC measurements were compared between different GA and between singleton and twin placentas.

Results: No significant difference was shown between ADC and rADC values of singleton and twin placentas as well as between ADC and rADC values of singleton and twin placentas at different GA. No significant difference was shown when accounting for both GA and number of fetuses.

Conclusion: The diffusion characteristics of twin placentas are similar to those of singleton placentas. ADC and rADC remain stable throughout pregnancy in twin and singleton placentas, reflecting stable extracellular water diffusion, despite changes associated with placental maturation.
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http://dx.doi.org/10.1159/000479686DOI Listing
December 2018

Growth Restriction, Osteopenia, Placental Massive Perivillous Fibrin Deposition With (or Without) Intervillous Histiocytes and Renal Tubular Dysgenesis-An Emerging Complex.

Pediatr Dev Pathol 2018 Jan-Feb;21(1):91-94. Epub 2017 Mar 15.

6 Department of Pathology and Laboratory Medicine, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Canada.

We describe a case of a pregnancy complicated by early onset asymmetric growth restriction with anhydramnios with termination occurring at 21 weeks. Fetal autopsy showed demineralization of bones and renal tubular dysgenesis. Placental pathology showed features of massive perivillous fibrin deposition and chronic histiocytic intervillositis. We review prior documentation of this association and briefly discuss potential pathogenesis.
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http://dx.doi.org/10.1177/1093526617697061DOI Listing
May 2019

Gene markers of normal villous maturation and their expression in placentas with maturational pathology.

Placenta 2017 Oct 12;58:52-59. Epub 2017 Aug 12.

Department of Physiology, University of Toronto, Ontario, Canada; Department of Obstetrics and Gynaecology, University of Toronto, Ontario, Canada. Electronic address:

Introduction: The placenta demonstrates a recognized sequence of histomorphologic maturation throughout pregnancy, and in some cases, shows abnormally advanced (AVM) or delayed (DVM) villous maturation. While AVM and DVM have important clinical implications, it is unknown whether they truly represent a state of accelerated/delayed normal maturation or a state of pathological maldevelopment. The purpose of our study is, therefore, to address this challenge via a genome-wide search for expression markers of normal villous maturation (NM) and the assessment of these genes in cases of maturational pathology.

Methods: A total of 142 placentas, previously evaluated by gene expression microarray, were reviewed histologically and classified as NM, AVM, or DVM. Expression data from healthy NM placentas underwent Pearson correlations with gestational age (GA) and network/pathway analysis to identify candidate gene markers. Candidates were then validated in an independent microarray dataset and used to calculate "molecular GAs" of placentas with maturational pathology.

Results: Analysis of NM placentas yielded 17 candidate markers of normal villous maturation, of which 11 were independently validated. Genes with expression increasing across gestation were associated with transcription and metabolism, while those demonstrating decreasing expression were involved in cell cycle and division. Molecular GA was 5.3 weeks older than true GA among AVM placentas (p < 0.001), and 1.1 weeks younger among DVM placentas (p = 0.149).

Discussion: We have found evidence of advanced molecular GA in AVM placentas, while molecular alterations in DVM placentas were merely suggestive of delayed maturation. In the future, these findings will need to be validated with additional techniques such as in situ hybridization or immunohistochemistry.
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http://dx.doi.org/10.1016/j.placenta.2017.08.005DOI Listing
October 2017

Prenatally Diagnosed Infant AML.

J Pediatr Hematol Oncol 2018 04;40(3):238-239

Division of Hematology/Oncology.

We report the first case of a fetus with acute myeloid leukemia, without Down syndrome, diagnosed in utero. A cordocentesis sample prepared to investigate hepatomegaly led to further evaluations revealing acute myeloid leukemia, monocytic type, in the fetus. Cytogenetic analysis showed mixed lineage leukemia duplication, no gene disruption or trisomy. Planned treatment included intrauterine exchange transfusion to extend gestation, low-dose chemotherapy at birth, and full chemotherapy once stable. Before any intervention, the child was delivered emergently for maternal condition and died 2 hours later. Although it is now possible to diagnose hematologic malignancy in a fetus, there is little information to direct management.
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http://dx.doi.org/10.1097/MPH.0000000000000893DOI Listing
April 2018

H3.1 K36M mutation in a congenital-onset soft tissue neoplasm.

Pediatr Blood Cancer 2017 Dec 16;64(12). Epub 2017 May 16.

Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.

We describe a patient who presented with a congenital soft tissue lesion initially diagnosed as infantile fibromatosis at 15 days of age. Unusually, the mass demonstrated malignant progression leading to death at 20 months of age. Biological progression to malignancy is not known to occur in fibromatosis, and fibrosarcoma is not known to progress from a benign lesion. Whole-exome sequencing of the tumor identified a driver mutation in histone H3.1 at lysine (K)36. Our findings support the link between oncohistones and infantile soft tissue tumors and provide additional evidence for the oncogenic effects of p.K36M in H3 variants.
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http://dx.doi.org/10.1002/pbc.26633DOI Listing
December 2017

Recurrent Massive Perivillous Fibrin Deposition and Chronic Intervillositis Treated With Heparin and Intravenous Immunoglobulin: A Case Report.

J Obstet Gynaecol Can 2017 Aug 26;39(8):676-681. Epub 2017 Apr 26.

Department of Pathology and Laboratory Medicine, Children's Hospital of Eastern Ontario and University of Ottawa, Ottawa, ON. Electronic address:

Background: Massive perivillous fibrin deposition (MPVFD) and chronic intervillositis (CI) are related rare pathological correlates of severe intrauterine growth restriction (IUGR) and fetal loss with high recurrence rates. No standard management has been established.

Case: A patient underwent termination of pregnancy at 21 weeks for severe early onset IUGR. Placental histology showed mixed CI with MPVFD. Several months later, the patient became pregnant and was managed with prednisone and aspirin (ASA) but miscarried at 16 weeks. Placental pathology showed MPVFD and focal CI. For two subsequent pregnancies, she was treated with intravenous immunoglobulin (IVIG), heparin, and ASA. Both pregnancies resulted in healthy near-term deliveries with normal placentas.

Conclusion: IVIG, heparin, and ASA can be an option in patients with recurrent pregnancy loss due to MPVFD and CI.
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http://dx.doi.org/10.1016/j.jogc.2017.03.089DOI Listing
August 2017

The nitric oxide synthase 2 pathway is targeted by both pro- and anti-inflammatory treatments in the immature human intestine.

Nitric Oxide 2017 Jun 14;66:53-61. Epub 2017 Mar 14.

Research Consortium on Child Intestinal Inflammation, Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Canada. Electronic address:

Background And Aim: NO synthase 2 (NOS2) was recently identified as one the most overexpressed genes in intestinal samples of premature infants with necrotizing enterocolitis (NEC). NOS2 is widely implicated in the processes of epithelial cell injury/apoptosis and host immune defense but its specific role in inflammation of the immature human intestinal mucosa remains unclear. Interestingly, factors that prevent NEC such as epidermal growth factor (EGF) attenuate the inflammatory response in the mid-gestation human small intestine using serum-free organ culture while drugs that are associated with NEC occurrence such as the non-steroidal anti-inflammatory drug, indomethacin (INDO), exert multiple detrimental effects on the immature human intestine. In this study we investigate the potential role of NOS2 in modulating the gut inflammatory response under protective and stressful conditions by determining the expression profile of NOS2 and its downstream pathways in the immature intestine.

Methods: Gene expression profiles of cultured mid-gestation human intestinal explants were investigated in the absence or presence of a physiological concentration of EGF (50 ng/ml) or 1 μM INDO for 48 h using Illumina whole genome microarrays, Ingenuity Pathway Analysis software and quantitative PCR to investigate the expression of NOS2 and NOS2-pathway related genes.

Results: In the immature intestine, NOS2 expression was found to be increased by EGF and repressed by INDO. Bioinformatic analysis identified differentially regulated pathways where NOS2 is known to play an important role including citrulline/arginine metabolism, epithelial cell junctions and oxidative stress. At the individual gene level, we identified many differentially expressed genes of the citrulline/arginine metabolism pathway such as ARG1, ARG2, GLS, OAT and OTC in response to EGF and INDO. Gene expression of tight junction components such as CLDN1, CLDN2, CLDN7 and OCN and of antioxidant markers such as DUOX2, GPX2, SOD2 were also found to be differentially modulated by EGF and INDO.

Conclusion: These results suggest that the protective effect of EGF and the deleterious influence of INDO on the immature intestine could be mediated via regulation of NOS2. Pathways downstream of NOS2 involved with these effects include metabolism linked to NO production, epithelial barrier permeability and antioxidant expression. These results suggest that NOS2 is a likely regulator of the inflammatory response in the immature human gut and may provide a mechanistic basis for the protective effect of EGF and the deleterious effects of INDO.
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http://dx.doi.org/10.1016/j.niox.2017.03.003DOI Listing
June 2017

Engaging Cell Death Pathways for the Treatment of Rhabdomyosarcoma.

Crit Rev Oncog 2016 ;21(3-4):221-239

Molecular Biomedicine Program, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada; Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada.

Rhabdomyosarcoma (RMS), a malignant neoplasm of presumed mesenchymal origin, is the most common soft tissue cancer of childhood. Despite aggressive treatment, resistance to current therapies remains a challenge. The success of most cytotoxic chemotherapies requires intact programmed cell death (apoptosis) pathways. Defects in the cellular apoptotic program play a key role in the pathogenesis of RMS and contribute to chemotherapeutic resistance to current treatments. Targeting and engaging apoptotic pathways using small-molecule IAP antagonists, death-inducing ligands, reestablishing pannexin channel expression and activity, immunotherapies, or a combination of these approaches is expected to improve outcomes in RMS patients. There is a clear need to better understand the molecular basis of apoptotic resistance in RMS, which may provide an opportunity to identify the patients most likely to benefit from targeted treatments, and for the discovery of novel therapies.
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http://dx.doi.org/10.1615/CritRevOncog.2016016996DOI Listing
October 2017

Placental growth factor as a marker of fetal growth restriction caused by placental dysfunction.

Placenta 2016 06 23;42:1-8. Epub 2016 Mar 23.

Department of Obstetrics and Gynaecology, Faculty of Medicine, University of British Columbia, 4500 Oak Street, Vancouver, British Columbia, V6H 3N1, Canada. Electronic address:

Introduction: Discriminating between placentally-mediated fetal growth restriction and constitutionally-small fetuses is a challenge in obstetric practice. Placental growth factor (PlGF), measurable in the maternal circulation, may have this discriminatory capacity.

Methods: Plasma PlGF was measured in women presenting with suspected fetal growth restriction (FGR; ultrasound fetal abdominal circumference <10th percentile for gestational age) at sites in Canada, New Zealand and the United Kingdom. When available, placenta tissue underwent histopathological examination for lesions indicating placental dysfunction, blinded to PlGF and clinical outcome. Lesions were evaluated according to pre-specified severity criteria and an overall severity grade was assigned (0-3, absent to severe). Low PlGF (concentration <5th percentile for gestational age) to identify placental FGR (severity grade≥2) was assessed and compared with routine parameters for fetal assessment. For all cases, the relationship between PlGF and the sampling-to-delivery interval was determined.

Results: Low PlGF identified placental FGR with an area under the receiver-operator characteristic curve of 0.96 [95% CI 0.93-0.98], 98.2% [95% CI 90.5-99.9] sensitivity and 75.1% [95% CI 67.6-81.7] specificity. Negative and positive predictive values were 99.2% [95% CI 95.4-99.9] and 58.5% [95% CI 47.9-68.6], respectively. Low PlGF outperformed gestational age, abdominal circumference and umbilical artery resistance index in predicting placental FGR. Very low PlGF (<12 pg/mL) was associated with shorter sampling-to-delivery intervals than normal PlGF (13 vs. 29.5 days, P < 0.0001).

Discussion: Low PlGF identifies small fetuses with significant underlying placental pathology and is a promising tool for antenatal discrimination of FGR from fetuses who are constitutionally-small.
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http://dx.doi.org/10.1016/j.placenta.2016.03.010DOI Listing
June 2016

Histone H3K36 mutations promote sarcomagenesis through altered histone methylation landscape.

Science 2016 May;352(6287):844-9

Epigenetics Theme, Wisconsin Institute for Discovery, University of Wisconsin, Madison, WI 53715, USA. Department of Biomolecular Chemistry, School of Medicine and Public Health, University of Wisconsin, Madison, WI 53715, USA.

Several types of pediatric cancers reportedly contain high-frequency missense mutations in histone H3, yet the underlying oncogenic mechanism remains poorly characterized. Here we report that the H3 lysine 36-to-methionine (H3K36M) mutation impairs the differentiation of mesenchymal progenitor cells and generates undifferentiated sarcoma in vivo. H3K36M mutant nucleosomes inhibit the enzymatic activities of several H3K36 methyltransferases. Depleting H3K36 methyltransferases, or expressing an H3K36I mutant that similarly inhibits H3K36 methylation, is sufficient to phenocopy the H3K36M mutation. After the loss of H3K36 methylation, a genome-wide gain in H3K27 methylation leads to a redistribution of polycomb repressive complex 1 and de-repression of its target genes known to block mesenchymal differentiation. Our findings are mirrored in human undifferentiated sarcomas in which novel K36M/I mutations in H3.1 are identified.
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http://dx.doi.org/10.1126/science.aac7272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4928577PMC
May 2016

Unsupervised Placental Gene Expression Profiling Identifies Clinically Relevant Subclasses of Human Preeclampsia.

Hypertension 2016 07 9;68(1):137-47. Epub 2016 May 9.

From the Department of Physiology (K.L., J.C.K., B.J.C.) and Department of Obstetrics and Gynaecology, (J.C.K., B.J.C.), University of Toronto, Toronto, Ontario, Canada; and Department of Cellular and Molecular Medicine (S.J.B., S.A.B.), Department of Pathology and Laboratory Medicine (D.G.), and Interdisciplinary School of Health Sciences (S.A.B.), University of Ottawa, Ottawa, Ontario, Canada.

Preeclampsia (PE) is a complex, hypertensive disorder of pregnancy, demonstrating considerable variability in maternal symptoms and fetal outcomes. Unfortunately, prior research has not accounted for this variability, resulting in a lack of robust biomarkers and effective treatments for PE. Here, we created a large (N=330) clinically relevant human placental microarray data set, consisting of 7 previously published studies and 157 highly annotated new samples from a single BioBank. Applying unsupervised clustering to this combined data set identified 3 clinically significant probable etiologies of PE: "maternal", with healthy placentas and term deliveries; "canonical", exhibiting expected clinical, ontological, and histopathologic features of PE; and "immunologic" with severe fetal growth restriction and evidence of maternal antifetal rejection. Moreover, these groups could be distinguished using a small quantitative polymerase chain reaction panel and demonstrated varying influence of maternal factors on PE development. An additional subclass of PE placentas was also revealed to form because of chromosomal abnormalities in these samples, supported by array-based comparative genomic hybridization analysis. Overall, our findings represent a new paradigm in our understanding of the origins and maternal-placental contributions to the pathology of PE. The study of PE represents a unique opportunity to access human tissue associated with a complex hypertensive disorder, and our novel approach could be applied to other hypertensive and heterogeneous human diseases.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.116.07293DOI Listing
July 2016