Paula North

Paula North
Medical College of Wisconsin | MCW · Department of Pathology

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135
Publications
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Publications

Publications (135)
Article
Background Donor specific cell-free DNA (cfDNA) shows promise as a non-invasive marker for allograft rejection, but as yet has not been validated in both adult and pediatric recipients Objectives To validate donor fraction (DF) cell-free DNA (cfDNA) as a non-invasive test to assess for risk of acute cellular rejection (ACR) and antibody mediated r...
Article
Background: Clinical rejection (CR) defined as decision to treat clinically suspected rejection with change in immunotherapy based on clinical presentation with or without diagnostic biopsy findings is an important part of care in heart transplantation. We sought to assess the utility of donor fraction cell-free DNA (DF cfDNA) in CR and the utilit...
Article
Full-text available
GNAQ is mutated in vascular and melanocytic lesions, including vascular malformations and nevi. No in vivo model of GNAQ activation in endothelial cells has previously been described. We introduce mutant GNAQ into a murine endothelial cell line, MS1. The resultant transduced cells exhibit a novel phenotype in vivo, with extensive vasoformative endo...
Article
Objectives Mortality rates following pediatric cardiac surgery with cardiopulmonary bypass (CPB) have declined over decades, but have plateaued in recent years. This is in part attributable to persistent issues with postoperative global inflammation and myocardial dysfunction, commonly manifested by systemic inflammatory response syndrome (SIRS) an...
Article
Background: Cell-free DNA is an emerging biomarker. While donor fraction may detect graft events in heart transplant recipients, the prognostic value of total nuclear cell-free DNA (ncfDNA) itself is largely unexplored. Objective: Explore the relationship between ncfDNA and clinical events in heart transplant recipients. Methods: We conducted...
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Vaccinations are widely credited with reducing death rates from COVID-19, but the underlying host-viral mechanisms/interactions for morbidity and mortality of SARS-CoV-2 infection remain poorly understood. Acute respiratory distress syndrome (ARDS) describes the severe lung injury, which is pathologically associated with alveolar damage, inflammati...
Article
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Infantile hemangioma is a vascular tumor characterized by the rapid growth of disorganized blood vessels followed by slow spontaneous involution. The underlying molecular mechanisms that regulate hemangioma proliferation and involution still are not well elucidated. Our previous studies reported that NOGOB receptor (NGBR), a transmembrane protein,...
Article
Background Elevated total cell-free DNA (TCF) has been associated with critical illness in adults while elevated donor fraction (DF), the ratio of donor specific cell-free DNA to TCF present in the recipient’s plasma, is associated with rejection following cardiac transplantation. This study investigates relationships between TCF and clinical outco...
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Cardiac disease is a frequent and significant adverse event associated with radiotherapy for cancer. Identifying the underlying mechanism responsible for radiation injury to the heart will allow interventions to be developed. In the present study, we tested if local kidney irradiation results in remodeling of the shielded, non‐targeted heart. One k...
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Lifelong noninvasive rejection monitoring in heart transplant patients is a critical clinical need historically poorly met in adults and unavailable for children and infants. Cell-free DNA (cfDNA) donor-specific fraction (DF), a direct marker of selective donor organ injury, is a promising analytical target. Methodological differences in sample pro...
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Propranolol is a widely used beta blocker that consists of a racemic mixture of R and S stereoisomers. Only the S stereoisomer has significant activity against the beta-adrenergic receptor. A fortuitous clinical observation was made in an infant who received propranolol for cardiac disease, and regression of a hemangioma of infancy was noted. This...
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Heart transplantation is a well‐established therapy for end‐stage heart failure in children and young adults. The highest risk of graft loss occurs in the first 60 days post‐transplant. Donor fraction of cell‐free DNA is a highly sensitive marker of graft injury. Changes in cell‐free DNA levels have not previously been studied in depth in patients...
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Combined germline and somatic second hit inactivating mutations of the RASA1 gene, which encodes a negative regulator of the Ras signaling pathway, cause blood and lymphatic vascular lesions in the human autosomal dominant vascular disorder capillary malformation-arteriovenous malformation (CM-AVM). How RASA1 mutations in endothelial cells (EC) res...
Article
Congenital hemangiomas are benign vascular tumors, categorized by their postnatal behavior as rapidly involuting, non‐involuting, or partially involuting. They are typically solitary, with a predilection for the head or limbs near a joint. We present two infants with small, multifocal congenital nonprogressive hemangiomas of the skin, one associate...
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To assess differences and trends in personal chemical exposure, volunteers from 14 communities in Africa (Senegal, South Africa), North America (United States (U.S.)) and South America (Peru) wore 262 silicone wristbands. We analysed wristband extracts for 1530 unique chemicals, resulting in 400 860 chemical data points. The number of chemical dete...
Article
Background and Rationale Sturge-Weber syndrome (SWS) is a neurocutaneous disorder associated with port wine birthmark, leptomeningeal capillary malformations, and glaucoma. It is associated with an unpredictable clinical course. Due to its rarity and complexity, many physicians are unaware of the disease and its complications. A major focus moving...
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ALK-positive histiocytosis is a recently described rare histiocytic proliferative disorder of early infancy. When infants present with anemia, thrombocytopenia, and hepatosplenomegaly, this entity should be included in the differential diagnosis along with hemophagocytic lymphohistiocytosis, metabolic/storage diseases, hematopoietic malignancies, a...
Article
Capillary malformation-arteriovenous malformation (CM-AVM) is an autosomal dominant vascular disorder that is associated with inherited inactivating mutations of the RASA1 gene in the majority of cases. Characteristically, patients exhibit one or more focal cutaneous CM that may occur alone or together with AVM, arteriovenous fistulas or lymphatic...
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Exposure monitoring with personal silicone wristband samplers was demonstrated in Peru in four agriculture and urban communities where logistic and practical constraints hinder use of more traditional approaches. Wristbands and associated methods enabled quantitation of 63 pesticides and screening for 1397 chemicals including environmental contamin...
Article
Renal vascular lesions (RVL) are rare and their morphological spectrum remains largely unknown, particularly in children. In this study, we characterize the clinicopathological features of RVL in a cohort of twelve children. Seven lesions were classified as previously recognized entities: vascular malformations (four), papillary endothelial hyperpl...
Article
Infantile hemangiomas (IHs) are the most common tumors of infancy and usually follow a typical course of growth and involution. We report four soft tissue tumors that were referred to the pediatric dermatology clinic as IHs and the process by which they were diagnosed and treated. Clinicians should be aware of presentations of these uncommon, but s...
Article
The localization of prenylated Ras at the plasma membrane promotes activation of Ras by receptor tyrosine kinases, such as VEGF and FGF receptors. Although Ras has been implicated in angiogenesis, the exact regulatory mechanisms controlling Ras translocation and activation are currently unclear because little is known regarding molecules that contr...
Article
A pilot program was initiated using whole genome sequencing (WGS) to diagnose suspected genetic disorders in the Genetics Clinic at Children's Hospital of Wisconsin. Twenty-two patients underwent WGS between 2010 and 2013. Initially, we obtained a 14% (3/22) diagnosis rate over 2 years; with subsequent reanalysis, this increased to 36% (8/22). Dise...
Article
Objective: This study examined vascular actions of angiotensin 1-7 (ANG 1-7) in human atrial and adipose arterioles. Approach and results: The endothelium-derived hyperpolarizing factor of flow-mediated dilation (FMD) switches from antiproliferative nitric oxide (NO) to proatherosclerotic hydrogen peroxide in arterioles from humans with coronary...
Article
Sturge-Weber syndrome (SWS) is a vascular neurocutaneous disorder that results from a somatic mosaic mutation in GNAQ, which is also responsible for isolated port-wine birthmarks. Infants with SWS are born with a cutaneous capillary malformation (port-wine birthmark) of the forehead or upper eyelid which can signal an increased risk of brain and/or...
Chapter
Accurate histopathological description combined with knowledgeable clinical and radiological evaluation is an absolute requisite for both study and meaningful diagnosis of vascular anomalies, both neoplastic and malformative. Unfortunately, traditional over-generic use of the hemangioma has caused inappropriate lumping of entities that we now know...
Book
This book comprehensively covers the classification, histopathology, pathogenesis, and molecular diagnosis of vascular tumors and malformations, correlating these with current approaches to clinical management. It offers a new multidisciplinary resource for clinicians, pathologists, molecular diagnosticians, and scientists in the field of vascular...
Article
Nogo-B receptor (NgBR) was identified as a receptor specific for Nogo-B. Our previous work has shown that Nogo-B and its receptor (NgBR) are essential for chemotaxis and morphogenesis of endothelial cells in vitro and intersomitic vessel formation via Akt pathway in zebrafish. Here, we further demonstrated the roles of NgBR in regulating vasculatur...
Article
Objectives The aim of this study was to present a rare case of a venous malformation that occupied the ethmoid and sphenoid sinuses. Prior to resection, it was believed to be a hemangioma. Methods This study includes a case report and review of the literature. Conclusion There is often confusion between “hemangiomas” and “vascular malformations,”...
Article
Protein kinase C has been implicated in the phosphorylation of the erythrocyte/brain glucose transporter, GLUT1, without a clear understanding of the site(s) of phosphorylation and the possible effects on glucose transport. Through in vitro kinase assays, mass spectrometry, and phosphospecific antibodies, we identify serine 226 in GLUT1 as a PKC ph...
Chapter
Pediatric vascular malformations are a histologically and clinically heterogeneous group of clinicopathologically distinct entities of diverse, still poorly understood etiology. Accurate histopathological diagnosis is frequently required to guide effective therapy as well as meaningful research, complementing clinical and radiological evaluation. R...
Article
The majority of causative variants in familial breast cancer remain unknown. Of the known risk variants, most are tumor cell autonomous and little attention has been paid yet to germline variants that may affect the tumor microenvironment. In this study, we developed a system called the Consomic Xenograft Model (CXM) to map germline variants that i...
Article
In kidney nephron, parietal epithelial cells line the Bowman's capsule and function as a permeability barrier for the glomerular filtrate. Bowman's capsule cells with proximal tubule epithelial morphology have been found. However, the effects of tubular metaplasia in Bowman's capsule on kidney function remain poorly understood. Sodium-glucose cotra...
Conference Paper
The endothelial cell-specific chemotaxis receptor (ECSCR) is a cell-surface protein selectively expressed by endothelial cells (ECs), with roles in EC migration, apoptosis and proliferation. Our previous study showed that loss of ECSCR in primary ECs reduced tyrosine phosphorylation of vascular endothelial growth factor (VEGF) receptor 2/kinase ins...
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NgBR is a type I receptor with a single transmembrane domain and was identified as a specific receptor for Nogo-B. Our recent findings demonstrated that NgBR binds farnesylated Ras and recruits Ras to the plasma membrane, which is a critical step required for the activation of Ras signaling in human breast cancer cells and tumorigenesis. Here, we f...
Article
PHACE syndrome represents the association of large infantile hemangiomas of the head and neck with brain, cerebrovascular, cardiac, ocular, and ventral or midline defects. Cardiac and cerebrovascular anomalies are the most common extracutaneous features of PHACE, and they also constitute the greatest source of potential morbidity. Congenital heart...
Article
Arteriovenous malformations (AVMs) are typically present at birth but may not become clinically significant till later in life. The rarity of AVMs leads to misdiagnosis, as they can be confused in young patients with infantile hemangioma (IH). Small vessel-rich AVM can be radiologically consistent with an IH, while the clinical presentation is that...
Article
The price of whole-genome and -exome sequencing has fallen to the point where these methods can be applied to clinical medicine. Here, we outline the lessons we have learned in converting a sequencing laboratory designed for research into a fully functional clinical program.
Article
Full-text available
Background: The Sturge-Weber syndrome is a sporadic congenital neurocutaneous disorder characterized by a port-wine stain affecting the skin in the distribution of the ophthalmic branch of the trigeminal nerve, abnormal capillary venous vessels in the leptomeninges of the brain and choroid, glaucoma, seizures, stroke, and intellectual disability....
Article
Background and objectives(3)-Deficient megakaryocytes were modified by human (3)-lentivirus transduction and transplantation to express sufficient levels of a C560R(3) amino acid substitution, for investigation of how an activated (IIb3) conformation affects platelets invivo in mice. Patient/Methods As in our previous report of an R560(3) mutation...
Article
Full-text available
The endothelial cell-specific chemotaxis receptor (ECSCR) is a cell-surface protein selectively expressed by endothelial cells (ECs), with roles in EC migration, apoptosis and proliferation. Our previous study (Verma, A., Bhattacharya, R., Remadevi, I., Li, K., Pramanik, K., Samant, G. V., Horswill, M., Chun, C. Z., Zhao, B., Wang, E., Miao, R. Q.,...
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Low molecular weight heparin (LMWH) is being tested as an experimental drug for improving pregnancy outcome in women with inherited thrombophilia and placenta-mediated pregnancy complications, such as recurrent pregnancy loss. The role of thrombotic processes in these disorders remains unproven, and the issue of antithrombotic prophylaxis is intens...
Article
Vascular anomalies may be appropriately classified into two broad categories, vascular tumors and vascular malformations, which are distinguished by the presence of cellular proliferation in contrast to aberrations in morphogenesis, respectively. This system of classification is based upon histological features that may in large part be differentia...
Article
Objective: A novel mouse model with a specific genetic mutation in a G protein coupled receptor (GPCR) encoded by the Oxgr1 gene results in a predisposition to spontaneous otitis media with effusion. As a primary component of interest in OME, mucin expression was examined in this model to assess expression as compared to wild type animals and suit...
Article
Selective inhibitors of sodium-glucose cotransporter 2 (SGLT2)-mediated reabsorption of glucose in the proximal tubule of the kidney are being developed for the treatment of diabetes. SGLT2 shares high degree of homology with SGLT3; however, very little is known about the expression and functional role of SGLT3 in the human kidney. Indeed, the SGLT...
Article
Full-text available
3-Bromopyruvate, an alkylating agent and a well-known inhibitor of energy metabolism, has been proposed as a specific anticancer agent. However, the chemopreventive effect of 3-bromopyruvate in lung tumorigenesis has not been tested. In this study, we investigated the chemopreventive activity of 3-bromopyruvate in a mouse lung tumor model. Benzo(a)...
Article
Full-text available
Tat-interactive protein 60 (Tip60) is a member of the MYST family of histone acetyltransferases. Studies using cultured cells have shown that Tip60 has various functions including DNA repair, apoptosis and cell-cycle regulation. We globally ablated the Tip60 gene (Htatip), observing that Tip60-null embryos die at the blastocyst stage (Hu et al. Dev...
Data
This file describes details of the Materials and Methods used for this study. These include animal identity, care and handling; plasmid descriptions; Tip60 antibody characterization; western blotting; antibodies employed & immunohistochemical protocols; semi-quantitative RT-PCR protocols; protocols for induction of cardiac hypertrophy by aortic ban...
Data
Specificity of the Anti-Tip60 Antibody. Western blots were used to determine specificity of the anti-Tip60 antibody. Panel A, western blot of total heart proteins electrophoretically separated in two-dimensions (iso-electric focusing then SDS/PAGE). The first-dimension (IEF) gel was loaded with 50 µg protein from three month-old adult mouse hearts....
Data
The Non-Cardiomyocyte:Cardiomyocyte Ratio Increases during Myocardial Development. The Tip60 Isoprotein Transition Occurs in non-Cardiomyocytes and in Cardiomyocytes. Panels A and B are Nkx2.5-immunostained (brown) sections from (A) embryonic and (B) adult mouse hearts. Nuclei were counter-stained with hematoxylin (blue). Scale bars = 20 µm. Panel...
Data
Expression of MycER Transgene and 4-OHT-Induced Hypertrophy in WT and Het Adult Hearts. Panel A shows expression of the MycER transgene in hearts of eight week-old adult wild type (WT) and Tip60-heterozygous (Het) mice, determined by semi-quantitative RT/PCR; the image is an autoradiograph of 32P-labeled PCR products. Panel B shows results of densi...
Data
Echocardiography of 4-OHT-induced Transgenic WT and Tip60-Heterozygous Mice. Left ventricular (LV) wall thickness and internal diameter were assessed during diastole in isoflurane-anesthestized three month-old mice, at baseline and after eight days' treatment with 4-OHT. Echocardiography using the parasternal long axis view was performed with a Vis...
Data
Trend Toward Reduced Tip60 Protein Levels in Aortic Banded and c-Myc Stressed Myocardium. Heart protein lysates were isolated and separated on 7.5% acrylamide/SDS gels. Panels A and B are western blots sequentially reacted with anti-Tip60 and anti-GAPDH antibodies. Panels C and D respectively show results from quantitative densitometry of bands in...
Article
Full-text available
Objective: A majority of vascular anomalies in children are infantile hemangiomas (IH). However, some children with an atypical growth pattern can be suggestive of an AVM. This case series discusses the clinical presentation, diagnosis, radiology, pathology, and treatment of small vessel AVMs at a multidisciplinary vascular anomalies center. Method...
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Objective: 1) Present outcomes of surgically treated infantile hemangioma, and describe changes in surgical management with the advent of changes in medical therapy. 2) Highlight the role of imaging in surgical planning. 3) Identify risk factors for surgical complications. Method: Retrospective chart review of patients in a multidisciplinary clinic...
Article
(1) Discuss indications for surgical treatment of infantile hemangioma (IH); (2) describe outcomes, management of complications and long term surveillance of surgically treated IH. Retrospective. The charts of children seen in a dedicated vascular anomalies center at a tertiary pediatric hospital were reviewed. Out of 1012 patients diagnosed with I...
Article
This study examined the effects of two new selective metalloprotease (MMP) inhibitors, XL081 and XL784, on the development of renal injury in rat models of hypertension, Dahl salt-sensitive (Dahl S) and type 2 diabetic nephropathy (T2DN). Protein excretion rose from 20 to 120 mg/day in Dahl S rats fed a high-salt diet (8.0% NaCl) for 4 wk to induce...
Article
The renin-angiotensin system plays an important role in the control of blood pressure (BP) and renal function. To illuminate the importance of renin in the context of a disease background in vivo, we used zinc-finger nucleases (ZFNs) designed to target the renin gene and create a renin knockout in the SS/JrHsdMcwi (SS) rat. ZFN against renin caused...
Article
Cutaneous angiosarcomas are rare tumors, which predominantly arise in the sun-exposed skin of the head and neck of adult and elderly patients. Rarely, these tumors can be seen in children. We identified cutaneous angiosarcomas in 10 children and assessed clinical (patient age, tumor site, tumor size, and tumor focality) and histologic features incl...
Article
Kaposiform hemangioendothelioma (KHE) and tufted angioma (TA) are rare tumors mainly occurring in early childhood. Our recent results showed that ectopic overexpression of human Prox1 gene, a lymphatic endothelial nuclear transcription factor, promoted an aggressive behavior in 2 murine models of KHE. This dramatic Prox1-induced phenotype prompted...
Article
Pediatric vascular tumors and malformations, comprising a broad category of lesions often referred to as vascular anomalies, are a heterogenous group of clinicopathologically distinct entities. Pathologists, clinicians, and radiologists have traditionally lumped these lesions under the generic term, hemangioma, sometimes qualified by modifiers, suc...
Article
Full-text available
Phospholipase Cgamma1 (PLCgamma1) is an important signaling effector of T cell receptor (TCR). To investigate the role of PLCgamma1 in T cell biology, we generated and examined mice with T cell-specific deletion of PLCgamma1. We demonstrate that PLCgamma1 deficiency affects positive and negative selection, significantly reduces single-positive thym...
Article
Unlabelled: There exists a worldwide shortage of donor livers available for orthotropic liver transplantation and hepatocyte transplantation therapies. In addition to their therapeutic potential, primary human hepatocytes facilitate the study of molecular and genetic aspects of human hepatic disease and development and provide a platform for drug...
Article
To reclassify facial nerve hemangiomas in the context of presently accepted vascular lesion nomenclature by examining histology and immunohistochemical markers. Cohort analysis of patients diagnosed with a facial nerve hemangioma between 1990 and 2008. Collaborative analysis at a specialty hospital and a major academic hospital. Seven su