Publications by authors named "Hernan Correa"

71 Publications

Second Report of Fusion in Pediatric Spindle Cell Sarcoma With Infantile Fibrosarcoma-Like Morphology Suggesting Fusion Is a Recurrent Event.

Pediatr Dev Pathol 2021 Jun 13:10935266211012186. Epub 2021 Jun 13.

Division of Molecular Pathology, Translational Genomics Research Institute, Phoenix, Arizona.

Infantile/congenital fibrosarcoma (IFS) is the most common soft tissue tumor in children less than one year of age. The most common anatomic site of IFS is in the extremities or trunk, and rarely in the abdomen or retroperitoneum. Approximately 70-90% of cases are characterized by a distinct t(12;15)(p13;q25) translocation resulting in an gene fusion. As such, TRK inhibitors are considered frontline therapy in TRK-fusion positive IFS. The ETV6-NTRK3 fusion is also detected in congenital mesoblastic nephroma (CMN) and less frequently in myeloid leukemias, secretory breast carcinoma, and mammary-type secretory carcinoma of the skin and salivary glands. Infrequently, cases of tumors with IFS-like morphology without the characteristic ETV6-NTRK3 gene fusion have been identified. Herein, an ETV6-NTRK3 fusion negative spindle cell sarcoma with IFS-like morphology subjected to genomic profiling revealed a fusion, a fusion event that has been detected previously in an isolated case of undifferentiated infantile sarcoma.
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http://dx.doi.org/10.1177/10935266211012186DOI Listing
June 2021

Changes in FXR1 expression after Chemotherapy for Rhabdomyosarcoma.

J Pediatr Surg 2021 Jun 24;56(6):1148-1156. Epub 2021 Feb 24.

Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.

Background: Rhabdomyosarcoma (RMS) arises from abnormal muscle development. We reported previously that Fragile-X-Related 1 (FXR1), essential to normal myogenesis, was highly expressed in RMS relative to other embryonal tumors. This current study explored FXR1 expression across RMS disease characteristics and treatment response.

Methods: RMS patients ≤18 years (1980-2019; n = 152) were categorized according to tumor histology, PAX/FOXO1 translocation, and vital status. FXR1 protein expression was compared before and after chemotherapy. Impact of FXR1 expression on relapse-free (RFS) and overall survival (OS) was analyzed.

Results: FXR1 was most intensely expressed in the cytosol of undifferentiated rhabdomyoblasts. At diagnosis, FXR1 expression was ubiquitous and strong across all disease characteristics and foremost associated with worse RFS in translocation-positive patients (p = 0.0411). Among embryonal and translocation-negative RMS, survivors showed a significantly greater decrease in FXR1 expression after chemotherapy (p < 0.001) compared to decedents (p = 0.8). In contrast, alveolar and translocation-positive RMS specimens showed insignificant changes in FXR1 expression across therapy. As expected, alveolar histology, translocation presence, stage, and clinical group associated with worse survival.

Conclusions: FXR1 was expressed strongly across RMS specimens at diagnosis regardless of disease or patient characteristics, and particularly in undifferentiated cells. Reduction in FXR1 expression after chemotherapy associated with improved survival for embryonal and translocation-negative RMS patients.
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http://dx.doi.org/10.1016/j.jpedsurg.2021.02.038DOI Listing
June 2021

Key histopathologic features in idiopathic noncirrhotic portal hypertension: an interobserver agreement study and proposal for diagnostic criteria.

Mod Pathol 2021 03 21;34(3):592-602. Epub 2020 Sep 21.

Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.

Histologic features of idiopathic noncirrhotic portal hypertension (INCPH), loosely termed as obliterative portal venopathy (OPV), are heterogenous, often subtle, and overlap with other entities. To this date, no consensus histopathologic diagnostic criteria have been established for INCPH. For these reasons, rendering a reproducible consensus histologic diagnosis of OPV on a liver biopsy may often be challenging even for experienced hepatopathologists. We report herein a two-phase interobserver agreement study on the diagnosis of OPV and assessed the relative value of histologic features in 104 liver biopsies in distinguishing between INCPH and non-INCPH with the goal to obtain a consensus on specific practical diagnostic criteria. Six hepatopathologists blinded to clinical information and original pathologic diagnosis reviewed internet-based case study sets with high-resolution whole-slide images. The initial interobserver agreement on OPV was expectedly low, but significantly improved (moderate agreement in most categories) upon adopting a consensus view recognizing portal vein sclerosis as the only strong independent histologic predictor for INCPH, and that contrary to the conventional view, aberrant portal/periportal vessels does not significantly contribute to the positive assignment of OPV status. We propose a three-tiered classification with diagnostic criteria to facilitate the histologic assignment of OPV status for the evaluation of INCPH. Furthermore, we have validated the performance of the proposed criteria either based on histology alone or coupled with clinicopathologic correlation. This classification may aid in practical histologic assessment of liver biopsies with or without portal hypertension and help to improve diagnostic consistency and accuracy.
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http://dx.doi.org/10.1038/s41379-020-00676-8DOI Listing
March 2021

Novel Insights Into Tissue-Specific Biochemical Alterations in Pediatric Eosinophilic Esophagitis Using Raman Spectroscopy.

Clin Transl Gastroenterol 2020 07;11(7):e00195

Vanderbilt Biophotonics Center, Department of Biomedical Engineering, Vanderbilt University, Tennessee, USA.

Introduction: Elucidating esophageal biochemical composition in eosinophilic esophagitis (EoE) can offer novel insights into its pathogenesis, which remains unclear. Using Raman spectroscopy, we profiled and compared the biochemical composition of esophageal samples obtained from children with active (aEoE) and inactive EoE (iEoE) with non-EoE controls, examined the relationship between spectral markers and validated EoE activity indices.

Methods: In vitro Raman spectra from children with aEoE (n = 8; spectra = 51) and iEoE (n = 6; spectra = 48) and from non-EoE controls (n = 10; spectra = 75) were acquired. Mann-Whitney test was used to assess the differences in their Raman intensities (median [interquartile range]) and identify spectral markers. Spearman correlation was used to evaluate the relationship between spectral markers and endoscopic and histologic activity indices.

Results: Raman peaks attributable to glycogen content (936/1,449 cm) was lower in children with aEoE (0.20 [0.18-0.21]) compared with that in non-EoE controls (0.24 [0.23-0.29]). Raman intensity of proteins (1,660/1,209 cm) was higher in children with aEoE compared with that in non-EoE controls (3.20 [3.07-3.50] vs 2.91 [2.59-3.05]; P = 0.01), whereas that of lipids (1,301/1,260 cm) was higher in children with iEoE (1.56 [1.49-1.63]) compared with children with aEoE (1.40 [1.30-1.48]; P = 0.02). Raman peaks attributable to glycogen and lipid inversely correlated with eosinophilic inflammation and basal zone hyperplasia. Raman mapping substantiated our findings.

Discussion: This is the first study to identify spectral traits of the esophageal samples related to EoE activity and tissue pathology and to profile tissue-level biochemical composition associated with pediatric EoE. Future research to determine the role of these biochemical alterations in development and clinical course of EoE can advance our understanding of EoE pathobiology.
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http://dx.doi.org/10.14309/ctg.0000000000000195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386346PMC
July 2020

Factors Associated With Adequate Lamina Propria Sampling and Presence of Lamina Propria Fibrosis in Children with Eosinophilic Esophagitis.

Clin Gastroenterol Hepatol 2020 Jul 21. Epub 2020 Jul 21.

Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina.

Background & Aims: Esophageal biopsies in children with eosinophilic esophagitis (EoE) are often inadequate for assessment of lamina propria and lamina propria fibrosis (LPF). For children with EoE, little is known about the factors associated with adequate lamina propria (aLP) sampling or the relationship among epithelial features in esophageal biopsies with and without LPF. We aimed to evaluate aLP in esophageal biopsies from children with and without EoE, identify factors associated with aLP and LPF, and examine the relationship among epithelial features in biopsies with and without LPF in children with EoE.

Methods: In a retrospective study, we analyzed clinical, endoscopic, and histologic data from 217 children (124 with EoE and 94 without EoE [controls]) using descriptive statistics, logistic regression, Spearman's correlation, and receiver operating characteristic curve analysis. Active and inactive EoE were defined per the 2011 consensus guidelines.

Results: aLP was observed in biopsies from higher proportion of children with EoE (69%) than controls (31%) (P = .0001). Active EoE was independently associated with aLP (adjusted odds ratio [aOR], 4.23; 95% CI, 1.00-18.13; P = .05). Patient sex (aOR for boys, 8.37; 95% CI, 1.23-56.74; P = .03) and peak eosinophil count (aOR, 1.02; 95% CI, 1.01-1.04; P = .01) were independently associated with LPF. Epithelial features were strongly interrelated in biopsies with LPF, and the presence of specific epithelial features was associated with LPF.

Conclusions: aLP was observed in a higher proportion of esophageal biopsies from children with EoE than controls. EoE status, patient sex, and peak eosinophil count were associated with aLP sampling and LPF. Given the intricate relationship between epithelial features and LPF, computational models can be developed to identify children with esophageal biopsies without aLP who are at risk for LPF.
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http://dx.doi.org/10.1016/j.cgh.2020.07.035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033509PMC
July 2020

Health disparities among tennessee pediatric renal tumor patients.

J Pediatr Surg 2020 Jun 28;55(6):1081-1087. Epub 2020 Feb 28.

Surgical Outcomes Center for Kids, Vanderbilt University Medical Center, 2200 Children's Way, Nashville, TN; Department of Pediatric Surgery, Vanderbilt University Medical Center, 1211 Medical Center Drive, Nashville, TN.

Background/purpose: Wilms tumor (WT) poses a cancer health disparity to black children globally, which has not been evaluated thoroughly for other pediatric renal cancers. We aimed to characterize health disparities among Tennessee children treated for any renal cancer.

Methods: The Tennessee Cancer Registry (TCR) was queried for patients ≤18 years having any renal cancer (n = 160). To clarify treatment and outcomes, we performed a retrospective cohort study of pediatric renal cancer patients in our institutional cancer registry (ICR; n = 121). Diagnoses in both registries included WT, Sarcoma/Other, and Renal Cell Carcinoma. Wilcoxon/Pearson, Kaplan-Meier, and logistic regression were completed.

Results: In both registries, WT comprised the most common renal cancer and youngest median age. Sarcoma was intermediate in frequency and age, and RCC was least common, having the oldest age (p < 0.001). In the TCR, black patients comprised 26% of all patients, presented more commonly with distant disease than white patients (37% v. 16%; p = 0.021), and showed worse overall survival (73% v. 89%; p = 0.018), while the ICR showed similar survival between race groups (92% v. 93%, p = 0.868). Sarcoma and metastases were independent predictors of death in both registries (p ≤ 0.002).

Conclusions: Black children in Tennessee presented with more advanced disease and experienced worse survival when combining all renal cancer types, particularly RCC and Sarcoma. When treated at a comprehensive pediatric cancer center, these survival disparities appear diminished.

Type Of Study: Prognostic study.

Level Of Evidence: Level II (retrospective cohort).
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http://dx.doi.org/10.1016/j.jpedsurg.2020.02.029DOI Listing
June 2020

TCR Repertoire Characterization for T Cells Expanded in Response to hRSV Infection in Mice Immunized with a Recombinant BCG Vaccine.

Viruses 2020 02 20;12(2). Epub 2020 Feb 20.

Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago 8331010, Chile.

T cells play an essential role in the immune response against the human respiratory syncytial virus (hRSV). It has been described that both CD4 and CD8 T cells can contribute to the clearance of the virus during an infection. However, for some individuals, such an immune response can lead to an exacerbated and detrimental inflammatory response with high recruitment of neutrophils to the lungs. The receptor of most T cells is a heterodimer consisting of α and β chains (αβTCR) that upon antigen engagement induces the activation of these cells. The αβTCR molecule displays a broad sequence diversity that defines the T cell repertoire of an individual. In our laboratory, a recombinant Bacille Calmette-Guérin (BCG) vaccine expressing the nucleoprotein (N) of hRSV (rBCG-N-hRSV) was developed. Such a vaccine induces T cells with a Th1 polarized phenotype that promote the clearance of hRSV infection without causing inflammatory lung damage. Importantly, as part of this work, the T cell receptor (TCR) repertoire of T cells expanded after hRSV infection in naïve and rBCG-N-hRSV-immunized mice was characterized. A more diverse TCR repertoire was observed in the lungs from rBCG-N-hRSV-immunized as compared to unimmunized hRSV-infected mice, suggesting that vaccination with the recombinant rBCG-N-hRSV vaccine triggers the expansion of T cell populations that recognize more viral epitopes. Furthermore, differential expansion of certain TCRVβ chains was found for hRSV infection (TCRVβ8.3 and TCRVβ5.1,5.2) as compared to rBCG-N-hRSV vaccination (TCRVβ11 and TCRVβ12). Our findings contribute to better understanding the T cell response during hRSV infection, as well as the functioning of a vaccine that induces a protective T cell immunity against this virus.
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http://dx.doi.org/10.3390/v12020233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7077260PMC
February 2020

Correlation of endoscopic signs and mucosal alterations in children with eosinophilic esophagitis.

Gastrointest Endosc 2020 04 28;91(4):785-794.e1. Epub 2019 Nov 28.

Division of Gastroenterology and Hepatology, University of North Carolina, Chapel Hill, North Carolina, USA.

Background And Aims: In children with eosinophilic esophagitis (EoE), the relationship among the endoscopic reference score (EREFS), the histology scoring system (EoEHSS), and the peak eosinophil count (PEC) is incompletely described. Our aim was to determine the relationship among EREFS, EoEHSS, and PEC and develop a predictive model using components of EREFS and EoEHSS for EoE activity.

Methods: We analyzed 189 paired EREFSs, EoEHSSs, and PECs. Active EoE (aEoE; n = 98) was defined as ≥15 eosinophils per high-power field and inactive EoE (iEoE; n = 91) as <15 eosinophils per high-power field. Spearman correlation (r) with Bonferroni correction was used to assess the relationship between EREFS, EoEHSS and PEC, and a back-transformed average Fisher test was used to determine the statistical significance of the differences. Receiver operating characteristic analysis was used to develop the predictive model.

Results: The relationship between total EREFS and EoEHSS was modest (r = 0.61) but significantly stronger than the correlation between total EREFS and PEC (r = 0.55; P = .04). The relationship between total EREFS and EoEHSS tended to be stronger in aEoE compared with iEoE (r = 0.41 vs 0.24; P = .09). Compared with EREFS, EoEHSS had a significantly higher area under the curve (0.78 vs 0.92; P = .04) to predict aEoE. A combination of furrows, eosinophilic inflammation, basal cell hyperplasia, eosinophilic abscess, and dilated intercellular spaces had an area under the curve of 0.97, accuracy of 98%, sensitivity of 97%, and specificity of 98% to predict aEoE.

Conclusions: The endoscopy score modestly correlates with the histologic scoring system. Thus, the endoscopy score is not a reliable marker of tissue involvement in EoE. A panel of individual endoscopic and histologic signs hold promise to accurately predict EoE activity.
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http://dx.doi.org/10.1016/j.gie.2019.11.031DOI Listing
April 2020

Dual-Targeting AKT2 and ERK in cancer stem-like cells in neuroblastoma.

Oncotarget 2019 Sep 24;10(54):5645-5659. Epub 2019 Sep 24.

Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA.

Neuroblastoma remains one of the most difficult pediatric solid tumors to treat. In particular, the refractory and relapsing neuroblastomas are highly heterogeneous with diverse molecular profiles. We previously demonstrated that AKT2 plays critical roles in the regulation of neuroblastoma tumorigenesis. Here we hypothesize that targeting AKT2 could block the signal transduction pathways enhanced in chemo- and/or radiation-resistant neuroblastoma cancer stem-like cells. We found cell proliferation and survival signaling pathways AKT2/mTOR and MAPK were enhanced in cisplatin (CDDP)- and radiation-resistant neuroblastoma cells. Blocking these two pathways with specific inhibitors, CCT128930 (AKT2 inhibitor) and PD98059 (MEK inhibitor) decreased cell proliferation, angiogenesis, and cell migration in these resistant cells. We further demonstrated that the resistant cells had a higher sphere-forming capacity with increased expression of stem cell markers CD133, SOX2, ALDH, Nestin, Oct4, and Nanog. Importantly, the tumorsphere formation, which is a surrogate assay for self-renewal, was sensitive to the inhibitors of AKT2 and MAPK. Taken together, our findings suggest that CDDP- and radiation-resistant cancer stem-like neuroblastoma cells might serve as a useful tool to improve the understanding of molecular mechanisms of therapeutic resistance. This may aid in the development of more effective novel treatment strategies and better clinical outcomes in patients with neuroblastoma.
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http://dx.doi.org/10.18632/oncotarget.27210DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6771463PMC
September 2019

Identification of α-N-catenin as a novel tumor suppressor in neuroblastoma.

Oncotarget 2019 Aug 20;10(49):5028-5040. Epub 2019 Aug 20.

Department of Surgery, UT Southwestern Medical Center, Dallas, TX 75390, USA.

The lost expression of α-catenin has been found in cancers, and reinstalling α-catenin inhibits tumor growth. Here we hypothesized that the α-N-catenin, a homologous member of α-catenin and neural-specific expressed, functions as a novel tumor suppressor in neural crest-derived tumor, neuroblastoma. We correlated CTNNA2 (encodes α-N-catenin) expression to neuroblastoma disease relapse-free survival probability using publicly accessible human neuroblastoma datasets in R2 platform. The result showed that it negatively correlated to relapse-free survival probability significantly in patients with neuroblastoma with non-MYCN amplified tumor. Conversely, overexpressing CTNNA2 suppressed the neuroblastoma cell proliferation as measuring by the clonogenesis, inhibited anchorage-independent growth with soft agar colony formation assay. Forced expression of CTNNA2 decreased cell migration and invasion. Further, overexpression of CTNNA2 reduced the secretion of angiogenic factor IL-8 and HUVEC tubule formation. Our results show, for the first time, that α-N-catenin is a tumor suppressor in neuroblastoma cells. These findings were further corroborated with tumor xenograft study, in which α-N-catenin inhibited tumor growth and reduced tumor blood vessel formation. Interestingly, this is only observed in SK-N-AS xenografts lacking MYCN expression, and not in BE(2)-C xenografts with MYCN amplification. Mechanistically, α-N-catenin attenuated NF-κB responsive genes by inhibiting NF-κB transcriptional activity. In conclusion, these data demonstrate that α-N-catenin is a tumor suppressor in non-MYCN-amplified neuroblastomas and it inhibits NF-κB signaling pathway to suppress tumor growth in human neuroblastomas. Therefore, restoring the expression of α-N-catenin can be a novel therapeutic approach for neuroblastoma patients who have the deletion of CTNNA2 and lack of MYCN amplification.
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http://dx.doi.org/10.18632/oncotarget.27096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6707940PMC
August 2019

Noninvasive Follicular Thyroid Neoplasm With Papillary-Like Nuclear Features in Children: An Institutional Experience and Literature Review.

Pediatr Dev Pathol 2020 Mar-Apr;23(2):121-126. Epub 2019 Sep 4.

Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.

Background: Papillary thyroid carcinoma (PTC) in children has a distinctive set of clinicopathologic features and molecular signature compared to their adult counterparts. The recent recommendation to reclassify encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) without invasion as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is based on evidence derived almost exclusively from studies in adults. Clinicopathologic studies restricted to pediatric NIFTP are limited.

Methods: We retrospectively analyzed all pediatric PTC and NIFTP diagnosed and treated in our institution from 1999 to 2016 (n = 31).

Results: Using recently published consensus diagnostic criteria, we identified 3 NIFTP and 2 infiltrative follicular variants of papillary thyroid carcinoma (FVPTC) among 31 cases. Two of the NIFTP cases were initially diagnosed as EFVPTC. All 3 patients with NIFTP had unifocal tumors of lower American Joint Committee on Cancer (AJCC) classification (T2 or lower) and were free of lymph node or distant metastasis. Total (n = 1) or completion (n = 2) thyroidectomy was performed in all cases, and only 1 NIFTP patient received subsequent radioablative therapy. No residual or recurrent disease has been observed during follow-up (15-138 months) in patients with NIFTP.

Conclusions: Our experience with NIFTP in children is similar to outcomes reported in adult studies, suggesting that pediatric NIFTP behave indolently as evidenced by the absence of local recurrence in our cohort.
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http://dx.doi.org/10.1177/1093526619866584DOI Listing
January 2021

The Salivary Microbiome Is Altered in Children With Eosinophilic Esophagitis and Correlates With Disease Activity.

Clin Transl Gastroenterol 2019 06;10(6):e00039

Division of Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Objectives: Eosinophilic esophagitis (EoE) is an allergen-mediated inflammatory disease affecting the esophagus. Although microbial communities may affect the host immune responses, little is known about the role of the microbiome in EoE. We compared the composition of the salivary microbiome in children with EoE with that of non-EoE controls to test the hypotheses that the salivary microbiome is altered in children with EoE and is associated with disease activity.

Methods: Saliva samples were collected from 26 children with EoE and 19 non-EoE controls comparable for age and ethnicity. The salivary microbiome was profiled using 16S rRNA gene sequencing. Disease activity was assessed using the Eosinophilic Esophagitis Endoscopic Reference Score and the Eosinophilic Esophagitis Histologic Scoring System (EoEHSS).

Results: A trend toward lower microbial richness and alpha diversity was noted in children with EoE. Although the overall salivary microbiome composition was similar between children with and without EoE, specific taxa such as Streptococcus (q value = 0.06) tended to be abundant in children with active EoE compared with non-EoE controls. Haemophilus was significantly abundant in children with active EoE compared with inactive EoE (q value = 0.0008) and increased with the increasing EoEHSS and Eosinophilic Esophagitis Histology Scoring System (q value = 5e-10). In addition, 4 broad salivary microbial communities correlated with the EoEHSS.

Discussion: The composition of the salivary microbiome community structure can be altered in children with EoE. A relative abundance of Haemophilus positively correlates with the disease activity. These findings indicate that perturbations in the salivary microbiome may have a role in EoE pathobiology and could serve as a noninvasive marker of disease activity.
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http://dx.doi.org/10.14309/ctg.0000000000000039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613866PMC
June 2019

FXR1 expression domain in Wilms tumor.

J Pediatr Surg 2019 Jun 28;54(6):1198-1205. Epub 2019 Feb 28.

Vanderbilt University Medical Center, Department of Pediatric Surgery, Nashville, TN.

Background/purpose: Wilms tumor (WT) is the most common childhood kidney cancer globally. Our prior unbiased proteomic screen of WT disparities revealed increased expression of Fragile X-Related 1 (FXR1) in Kenyan specimens where survival is dismal. FXR1 is an RNA-binding protein that associates with poor outcomes in multiple adult cancers. The aim of this study therefore was to validate and characterize the FXR1 expression domain in WT.

Methods: Quantitative FXR1 gene expression was compared between WT, adjacent, adult, and fetal kidney specimens. The cellular and subcellular expression domain of FXR1 was characterized across these tissues using immunoperoxidase staining. RNA-sequencing of FXR1 was performed from WT and other pediatric malignancies to examine its broader target potential.

Results: FXR1 was detected in all clinical WT specimens evaluated (n = 82), and as a result appeared independent of demographic, histology, or adverse event. Specific cytosolic staining was strongest in blastema, intermediate and variable in epithelia, and weakest in stroma. When present, areas of skeletal muscle differentiation stained strongly for FXR1. qPCR revealed increased FXR1 expression in WT compared to adult and adjacent kidney (p < 0.0002) but was similar to fetal kidney (p = 0.648). RNA-sequencing revealed expression of FXR1 in multiple pediatric tumors, greatest in rhabdomyosarcoma and WT.

Conclusions: FXR1 was expressed consistently across this broad sampling of WT and most robustly in the primitive blastema. Notably, FXR1 labeled a specific self-renewing progenitor population of the fetal kidney.
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http://dx.doi.org/10.1016/j.jpedsurg.2019.02.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6545243PMC
June 2019

[Chilean guidelines for chronic urticaria].

Rev Med Chil 2018 Nov;146(11):1334-1342

Departamento de Dermatología, Facultad de Medicina, Universidad de Chile, Santiago, Chile.

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http://dx.doi.org/10.4067/S0034-98872018001101334DOI Listing
November 2018

Insight into the Etiology of Undifferentiated Soft Tissue Sarcomas from a Novel Mouse Model.

Mol Cancer Res 2019 05 25;17(5):1024-1035. Epub 2019 Jan 25.

Department of Cell and Developmental Biology, Vanderbilt University, Nashville, Tennessee.

Aberrant activation of the Hedgehog signaling pathway has been linked to the formation of numerous cancer types, including the myogenic soft tissue sarcoma, embryonal rhabdomyosarcoma (eRMS). Here, we report , a novel mouse model in which human GLI2A, a constitutive activator of Hedgehog signaling, induced undifferentiated sarcomas that were phenotypically divergent from eRMS. Rather, sarcomas arising in mice featured some characteristics that were reminiscent of Ewing sarcoma. Even though it is widely understood that Ewing sarcoma formation is driven by gene fusions, a genetically defined mouse model is not well-established. While gene fusions were not present in sarcomas, precluding their designation as Ewing sarcoma, we did find that GLI2A induced expression of known gene targets essential to Ewing pathogenesis, most notably, . Moreover, we found that naïve mesenchymal progenitors originate tumors in mice. Altogether, our work provides a novel genetic mouse model, which directly connects oncogenic Hedgehog activity to the etiology of undifferentiated soft tissue sarcomas for the first time. IMPLICATIONS: The finding that activation of Gli2 transcription factor is sufficient to induce Ewing-like sarcomas provides a direct transformative role of the Hedgehog signaling pathway in undifferentiated soft tissue sarcoma.
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http://dx.doi.org/10.1158/1541-7786.MCR-18-0117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6497566PMC
May 2019

The PathLink Acquired Gestational Tissue Bank: Feasibility of Project PLACENTA.

J Reprod Biotechnol Fertil 2018 ;7:14-27

Department of Medicine, Vanderbilt University Medical Center, Medical Center North, Nashville, Tennessee 37232.

Background: The Vanderbilt Institute for Clinical and Translational Research piloted the development of Project PLACENTA (PathLink Acquired gEstatioNal Tissue bAnk). This project investigated the feasibility of a fresh gestational tissue biobank, which provides tissue linked to electronic medical records for investigators interested in maternal-fetal health.

Methods: We developed a pipeline for collection of placental tissue from Labor and Delivery within approximately 30 minutes of delivery. An email alert was developed, to signal delivery, with the ability to specifically flag patients with certain phenotypic traits. Once collected, 4 to 8 mm punch biopsy cores were snap frozen and subsequently used for DNA, RNA and protein extraction. Tissue was also collected for Formalin Fixed Paraffin Embedded (FFPE) histology, flow cytometry, and quality control measures.

Results: Of 60 deliveries using the email notification system, 25 (42%) were sent to Pathology or assigned to other research protocols and were not available for collection, 10 (16%) were discarded prior to arrival at Labor and Delivery, and 25 (42%) were available for collection. Twenty placentas were collected and averaged 38 minutes per collection. DNA extraction yielded an average of 53 µg/µl per sample and RNA extraction yielded 679 ng/µl on average per sample. Proteomic studies showed no degradation of protein, abundant and similar quantities of protein across samples and differentiation between the amnion, decidua, and villi. Histological studies showed good quality for interpretation and occasional pathology including multifocal chronic villitis, meconium laden macrophages, and Stage 2 acute chorioamnionitis. Flow cytometry demonstrated good cell viability after isolation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326187PMC
January 2018

Distinct mucosal microbial communities in infants with surgical necrotizing enterocolitis correlate with age and antibiotic exposure.

PLoS One 2018 26;13(10):e0206366. Epub 2018 Oct 26.

Department of Pediatrics, Vanderbilt University, Nashville, Tennessee, United States of America.

Objective: Necrotizing enterocolitis (NEC) is the most common surgical emergency in preterm infants, and pathogenesis associates with changes in the fecal microbiome. As fecal samples incompletely represent microbial communities in intestinal mucosa, we sought to determine the NEC tissue-specific microbiome and assess its contribution to pathogenesis.

Design: We amplified and sequenced the V1-V3 hypervariable region of the bacterial 16S rRNA gene extracted from intestinal tissue and corresponding fecal samples from 12 surgical patients with NEC and 14 surgical patients without NEC. Low quality and non-bacterial sequences were removed, and taxonomic assignment was made with the Ribosomal Database Project. Operational taxonomic units were clustered at 97%. We tested for differences between NEC and non-NEC samples in microbiome alpha- and beta-diversity and differential abundance of specific taxa between NEC and non-NEC samples. Additional analyses were performed to assess the contribution of other demographic and environmental confounding factors on the infant tissue and fecal microbiome.

Results: The fecal and tissue microbial communities were different. NEC was associated with a distinct microbiome, which was characterized by low diversity, higher abundances of Staphylococcus and Clostridium_sensu_stricto, and lower abundances of Actinomyces and Corynebacterium. Infant age and vancomycin exposure correlated with shifts in the tissue microbiome.

Conclusion: The observed low diversity in NEC tissues suggests that NEC is associated with a bacterial bloom and a distinct mucosal bacterial community. The exact bacterial species that constitute the bloom varied by infant and were strongly influenced by age and exposure to vancomycin.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0206366PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6203398PMC
April 2019

Molecular and epidemiologic characterization of Wilms tumor from Baghdad, Iraq.

World J Pediatr 2018 12 28;14(6):585-593. Epub 2018 Aug 28.

Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, USA.

Background: Wilms tumor (WT) is the most common childhood kidney cancer worldwide, yet its incidence and clinical behavior vary according to race and access to adequate healthcare resources. To guide and streamline therapy in the war-torn and resource-constrained city of Baghdad, Iraq, we conducted a first-ever molecular analysis of 20 WT specimens to characterize the biological features of this lethal disease within this challenged population.

Methods: Next-generation sequencing of ten target genes associated with WT development and treatment resistance (WT1, CTNNB1, WTX, IGF2, CITED1, SIX2, p53, N-MYC, CRABP2, and TOP2A) was completed. Immunohistochemistry was performed for 6 marker proteins of WT (WT1, CTNNB1, NCAM, CITED1, SIX2, and p53). Patient outcomes were compiled.

Results: Mutations were detected in previously described WT "hot spots" (e.g., WT1 and CTNNB1) as well as novel loci that may be unique to the Iraqi population. Immunohistochemistry showed expression domains most typical of blastemal-predominant WT. Remarkably, despite the challenges facing families and care providers, only one child, with combined WT1 and CTNNB1 mutations, was confirmed dead from disease. Median clinical follow-up was 40.5 months (range 6-78 months).

Conclusions: These data suggest that WT biology within a population of Iraqi children manifests features both similar to and unique from disease variants in other regions of the world. These observations will help to risk stratify WT patients living in this difficult environment to more or less intensive therapies and to focus treatment on cell-specific targets.
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http://dx.doi.org/10.1007/s12519-018-0181-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6236303PMC
December 2018

Reversible deficits in apical transporter trafficking associated with deficiency in diacylglycerol acyltransferase.

Traffic 2018 11 21;19(11):879-892. Epub 2018 Sep 21.

Department of Surgery, Vanderbilt University School of Medicine, Nashville, Tennessee.

Deficiency in diacylglycerol acyltransferase (DGAT1) is a rare cause of neonatal diarrhea, without a known mechanism or in vitro model. A patient presenting at our institution at 7 weeks of life with failure to thrive and diarrhea was found by whole-exome sequencing to have a homozygous DGAT1 truncation mutation. Duodenal biopsies showed loss of DGAT1 and deficits in apical membrane transporters and junctional proteins in enterocytes. When placed on a very low-fat diet, the patient's diarrhea resolved with normalization of brush border transporter localization in endoscopic biopsies. DGAT1 knockdown in Caco2-BBe cells modeled the deficits in apical trafficking, with loss of apical DPPIV and junctional occludin. Elevation in cellular lipid levels, including diacylglycerol (DAG) and phospholipid metabolites of DAG, was documented by lipid analysis in DGAT1 knockdown cells. Culture of the DGAT1 knockdown cells in lipid-depleted media led to re-establishment of occludin and return of apical DPPIV. DGAT1 loss appears to elicit global changes in enterocyte polarized trafficking that could account for deficits in absorption seen in the patient. The in vitro modeling of this disease should allow for investigation of possible therapeutic targets.
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http://dx.doi.org/10.1111/tra.12608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191315PMC
November 2018

Gestational diabetes mellitus is associated with increased CD163 expression and iron storage in the placenta.

Am J Reprod Immunol 2018 10 9;80(4):e13020. Epub 2018 Jul 9.

Division of Infectious Diseases, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.

Problem: GDM has been associated with disturbances in iron homeostasis and exaggerated immune activation. We sought to investigate the extent to which placental iron storage and macrophage accumulations were altered in GDM.

Method Of Study: We conducted a retrospective, case-control study of archived placental tissues obtained from 22 pregnancies complicated by GDM and 22 unaffected controls. Controls were matched to cases based on maternal age, gestational age at birth, and method of delivery. Placental tissues were assessed for altered histology and CD68 and CD163 staining. Tissue iron was assessed using Prussian blue staining.

Results: Maternal hematocrit levels were higher in GDM participants compared to controls (P = 0.02). The presence of meconium-laden macrophages was significantly greater within the amnion of GDM cases (adjusted odds ratio (OR) 12.51). Although the total abundance of CD68-expressing macrophages was not significantly different between groups, we detected a significantly greater abundance of CD163 expression within the chorion and decidua of cases. The total area staining positive for iron was 24% (95% confidence intervals of 2%-46%) greater in GDM placentae versus controls.

Conclusion: GDM is associated with altered placental histology and increases in meconium-laden macrophages. Greater iron stores within the placentae of women with GDM is consistent with reports that iron excess is associated with an increased risk for GDM. The higher level of expression of CD163 on macrophage-like cells of the chorion and decidua in GDM suggests an increase in M2-like macrophages. Overall, our results add to growing evidence that GDM has direct effects on placental structure.
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http://dx.doi.org/10.1111/aji.13020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6193471PMC
October 2018

Mesangial cells, specialized renal pericytes and cytomegalovirus infectivity: Implications for HCMV pathology in the glomerular vascular unit and post-transplant renal disease.

J Transl Sci 2019 Feb 24;5(1). Epub 2018 May 24.

Meharry Medical College, School of Medicine, Centre for AIDS Health Disparities Research, 1005 Dr. D.B. Todd Jr. Blvd., Nashville, Tennessee 37208-3599, USA.

Background: Human Cytomegalovirus (HCMV) infection is problematic after kidney transplantation. Human mesangial cells along with human glomerular endothelial cells and podocytes constitute the renal glomerular vascular unit (GVU). HCMV infection of the GVU is poorly understood.

Methods: GVU cells infectivity was analysed by microscopy and immunofluorescence. Cytokines profiles were measured by Luminex assays. Renal tissue analysis for HCMV infection was performed by immunohistochemistry.

Results: Mesangial cells and glomerular endothelial cells but not podocytes were permissive for both lab adapted and clinical strains of HCMV. Luminex analysis of cytokines expressed by mesangial cells exposed to the SBCMV clinical strain was examined. A Tricell infection model of the GVU maintains >90% viability with a unique cytokine profile. Finally, we show αSMA stained mesangial cells permissive for HCMV in renal tissue from a transplant patient.

Conclusions: HCMV infection of mesangial cells induces angiogenic and proinflammatory cytokines that could contribute to glomerular inflammation.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6027753PMC
http://dx.doi.org/10.15761/JTS.1000248DOI Listing
February 2019

Mucosal Impedance Measurements Differentiate Pediatric Patients With Active Versus Inactive Eosinophilic Esophagitis.

J Pediatr Gastroenterol Nutr 2018 08;67(2):198-203

Division of Pediatric Gastroenterology, Hepatology and Nutrition.

Background And Aims: Eosinophilic esophagitis (EoE) is a chronic disorder in children that requires continued assessment of disease activity, involving repeated sedation, endoscopy, and biopsy analysis. We investigated whether mucosal impedance measurements can be used to monitor disease activity in pediatric patients with EoE.

Methods: We measured mucosal impedance at 3 locations in the esophagus in pediatric patients (1-18 years old; 32 with active EoE, 10 with inactive EoE, 32 with nonerosive reflux disease [NERD]) and 53 children with symptoms but normal findings from histologic analyses (controls) undergoing routine esophagogastroduodenoscopy at the Vanderbilt Pediatric Gastroenterology Clinic. Pathologists reviewed biopsies per routine protocol, determined eosinophilic density, and graded spongiosis on an ordinal visual scale. Mucosal impedance measurements were compared within patient groups. The primary outcome was correlation of mucosal impedance measurements with disease activity, based on severity of spongiosis and eosinophil counts.

Results: Mucosal impedance measurements were significantly lower in patients with active EoE at 2, 5, and 10 cm above the squamo-columnar junction (median values of 1069, 1368, and 1707, respectively) compared to patients with inactive EoE (median values of 3663, 3657, and 4494, respectively), NERD (median values of 2754, 3243, and 4387), and controls (median values of 3091, 3760, and 4509) (P < 0.001 for all comparisons to patients with active EoE). We found inverse correlations between mucosal impedance measurements and eosinophil count (P < 0.001), and spongiosis severity (P < 0.001).

Conclusions: Mucosal impedance measurements may provide immediate information about mucosal inflammation in children. Patients with active EoE have significantly lower mucosal impedance values than patients with inactive EoE, NERD, or controls; mucosal impedance measurements correlate inversely with eosinophil counts and spongiosis severity. Mucosal impedance is a promising rapid and less-invasive method to monitor EoE activity in pediatric patients with EoE; it could reduce costs and risks of disease monitoring.
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http://dx.doi.org/10.1097/MPG.0000000000001943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6060000PMC
August 2018

Isoxazole compound ML327 blocks MYC expression and tumor formation in neuroblastoma.

Oncotarget 2017 Oct 20;8(53):91040-91051. Epub 2017 Jul 20.

Section of Surgical Sciences, Department of Surgery, at Vanderbilt University Medical Center, TN 37232, Nashville, USA.

Neuroblastomas are the most common extracranial solid tumors in children and arise from the embryonic neural crest. -amplification is a feature of ∼30% of neuroblastoma tumors and portends a poor prognosis. Neural crest precursors undergo epithelial-to-mesenchymal transition (EMT) to gain migratory potential and populate the sympathoadrenal axis. Neuroblastomas are posited to arise due to a blockade of neural crest differentiation. We have recently reported effects of a novel MET inducing compound ML327 (-(3-(2-hydroxynicotinamido) propyl)-5-phenylisoxazole-3-carboxamide) in colon cancer cells. Herein, we hypothesized that forced epithelial differentiation using ML327 would promote neuroblastoma differentiation. In this study, we demonstrate that ML327 in neuroblastoma cells induces a gene signature consistent with both epithelial and neuronal differentiation features with adaptation of an elongated phenotype. These features accompany induction of cell death and G1 cell cycle arrest with blockage of anchorage-independent growth and neurosphere formation. Furthermore, pretreatment with ML327 results in persistent defects in proliferative potential and tumor-initiating capacity, validating the pro-differentiating effects of our compound. Intriguingly, we have identified destabilization of MYC signaling as an early and consistent feature of ML327 treatment that is observed in both -amplified and -single copy neuroblastoma cell lines. Moreover, ML327 blocked mRNA levels and tumor progression in established -amplified xenografts. As such, ML327 may have potential efficacy, alone or in conjunction with existing therapeutic strategies against neuroblastoma. Future identification of the specific intracellular target of ML327 may inform future drug discovery efforts and enhance our understanding of MYC regulation.
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http://dx.doi.org/10.18632/oncotarget.19406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5710904PMC
October 2017

Elevated TIMP-1 expression is associated with a prometastatic phenotype, disease relapse, and poor survival in neuroblastoma.

Oncotarget 2017 Oct 28;8(47):82609-82620. Epub 2017 Jul 28.

Section of Surgical Sciences, Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA.

Approximately two-thirds of patients with neuroblastoma are found to have metastatic disease at time of diagnosis with frequent skeletal, lymph node, central nervous system, and liver involvement. Using a serial splenic injection model, we have isolated an aggressive subclone (BE(2)-C/LM2) from -amplified neuroblastomas that demonstrate an enhanced propensity to develop metastatic liver lesions. BE(2)-C/LM2 subclone cells demonstrate increased adherent, soft agar colony and tumorsphere growth . Components of the tumor microenvironment regulate cancer progression, via networks of cytokines and growth factors. Cytokine array analysis identified increased TIMP-1 in the plasma of mice injected with BE(2)-C/LM2 subclone cells, leading us to hypothesize that TIMP-1 may play a role in our observed prometastatic phenotype. Immunoblotting and ELISA demonstrated enhanced endogenous TIMP-1 expression in our isolated neuroblastoma subclone. Silencing endogenous TIMP-1 successfully blocked proliferation, soft agar colony formation and tumorsphere formation by BE(2)-C/LM2 cells. Stable RNA interference of endogenous TIMP-1 failed to reverse the prometastatic phenotype of our BE(2)-C/LM2 subclone in our liver metastasis model, suggesting that endogenous TIMP-1 levels may not be an essential component of this behavior. Notably, tissue microarray analysis and Kaplan-Meier by gene expression demonstrates that elevated TIMP-1 expression is correlated with increased disease relapse and mortality in patients with neuroblastoma. Taken together, our study identifies TIMP-1 as a novel soluble factor that is associated with a prometastatic phenotype in our model and adverse outcomes in patients with neuroblastoma.
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http://dx.doi.org/10.18632/oncotarget.19664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5669914PMC
October 2017

Unique histologic features of tonsils from patients with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome.

Clin Rheumatol 2018 May 26;37(5):1309-1317. Epub 2017 Jul 26.

Division of Pediatric Infectious Diseases, Vanderbilt University School of Medicine, 1161 21st Avenue South, Nashville, TN, 37232, USA.

The objective of this study is to compare the histology and immune cell composition of tonsils from patients with periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome to those from patients with obstructive sleep apnea (OSA). Patients with PFAPA and age-matched controls with OSA who had undergone tonsillectomy at Vanderbilt Children's Hospital were recruited. After informed consent, archival paraffin-embedded, formalin-fixed tonsil tissues were obtained. Sizes of major histologic regions were measured. Cores of germinal centers, crypts, and squamous epithelium were assembled on a tissue microarray for immunohistochemical staining and digital image analysis. Features of tonsils from PFAPA and OSA patients were compared with Wilcoxon signed-rank test. Samples from 16 cases with PFAPA and 16 controls with OSA were evaluated. Tonsils from PFAPA cases had significantly smaller germinal centers (0.18 vs. 0.47 mm, p = 0.001) and wider squamous epithelia (176 vs. 138 μm, p = 0.008) than those of OSA patients. The percentages of B and T lymphocytes and myeloid cells were comparable in germinal centers, crypts, and squamous epithelia from PFAPA and OSA patients. Longer time from the last febrile episode in PFAPA cases was associated with larger germinal center area (Spearman's rho = 0.61, p = 0.02). We found differences in the sizes of germinal centers and squamous epithelia in tonsils of patients with PFAPA and OSA, but the cellular compositions within these areas were comparable. Our results suggest that tonsils from patients with PFAPA change histologically over time with enlarging germinal centers following a febrile episode. Additional studies are needed to understand the pathogenesis of PFAPA.
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http://dx.doi.org/10.1007/s10067-017-3773-8DOI Listing
May 2018

Placental pericytes and cytomegalovirus infectivity: Implications for HCMV placental pathology and congenital disease.

Am J Reprod Immunol 2017 Sep 25;78(3). Epub 2017 Jul 25.

Department of Microbiology and Immunology, Center for AIDS Health Disparities Research, Meharry Medical College, School of Medicine, Nashville, TN, USA.

Problem: Placental pericytes are essential for placental microvascular function, stability, and integrity. Mechanisms of human cytomegalovirus (HCMV) pathogenesis incorporating placental pericytes are unknown.

Method Of Study: HCMV-infected placental tissue was stained by dual-labeled immunohistochemistry. Primary placental pericytes, cytotrophoblasts, and villous fibroblasts were exposed to HCMV; and infectivity was analyzed by microscopy and immunofluorescence. Cytokine expression was examined by Luminex assay. A HCMV-GFP recombinant virus was used to examine replication kinetics.

Results: Immunohistochemistry showed HCMV in trophoblast and the villous core with T-cell and macrophage infiltration. Primary HCMV isolate from a patient (SBCMV)- infected pericytes showed dysregulation of proinflammatory and angiogenic cytokines when compared to control cells. A tri-cell model of the villous floor showed a unique expression profile. Finally, we show pericytes infected in vivo with HCMV in placental tissue from a congenitally infected child.

Conclusion: Placental pericytes support HCMV replication, inducing proinflammatory and angiogenic cytokines that likely contribute to viral dissemination, placenta inflammation, and dysregulation of placental angiogenesis.
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http://dx.doi.org/10.1111/aji.12728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5561471PMC
September 2017

Optimizing surgical resection of the bleeding Meckel diverticulum in children.

J Pediatr Surg 2017 Oct 23;52(10):1610-1615. Epub 2017 Mar 23.

Department of Pediatric Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.

Purpose: Meckel diverticula containing gastric heterotopia predispose to local hyperacidity, mucosal ulceration, and gastrointestinal bleeding in children. Eradication of acid-producing oxyntic cells is performed by either of two surgical methods: segmental enterectomy including the diverticulum or diverticulectomy only.

Methods: Retrospective review of all children having surgical resection of a Meckel diverticulum at a tertiary-referral children's hospital from 2002 to 2016 was performed. Demographic data, surgical method, pathological specimens, and outcomes were evaluated.

Results: 102 children underwent surgical resection of a Meckel diverticulum during the study period. 27 (26.5%) children presented with bleeding, of which 16 (59%) had diverticulectomy only, and 11 (41%) had segmental ileal resection. All Meckel diverticula in children presenting with bleeding contained gastric heterotopia, and resection margins were free of gastric mucosa. Histologically, 19 specimens showed microscopic features of ulceration, on average 2.95mm (SD 4.49) from the nearest gastric mucosa (range: 0-16mm). Mean length of hospitalization after ileal resection was 4.0days (SD 1.2) compared to 1.6days (SD 0.9) for diverticulectomy only (p<0.001), with no re-bleeding occurrences.

Conclusion: In the operative management of children having a bleeding Meckel diverticulum, diverticulectomy-only completely eradicates gastric heterotopia without increased risk of continued bleeding or complications and significantly shortens hospitalization.

Level Of Evidence: Treatment Study: Level III.
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http://dx.doi.org/10.1016/j.jpedsurg.2017.03.047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5610599PMC
October 2017

Functional KRAS mutations and a potential role for PI3K/AKT activation in Wilms tumors.

Mol Oncol 2017 04 15;11(4):405-421. Epub 2017 Mar 15.

Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.

Wilms tumor (WT) is the most common renal neoplasm of childhood and affects 1 in 10 000 children aged less than 15 years. These embryonal tumors are thought to arise from primitive nephrogenic rests that derive from the metanephric mesenchyme during kidney development and are characterized partly by increased Wnt/β-catenin signaling. We previously showed that coordinate activation of Ras and β-catenin accelerates the growth and metastatic progression of a murine WT model. Here, we show that activating KRAS mutations can be found in human WT. In addition, high levels of phosphorylated AKT are present in the majority of WT. We further show in a mouse model and in renal epithelial cells that Ras cooperates with β-catenin to drive metastatic disease progression and promotes in vitro tumor cell growth, migration, and colony formation in soft agar. Cellular transformation and metastatic disease progression of WT cells are in part dependent on PI3K/AKT activation and are inhibited via pharmacological inhibition of this pathway. Our studies suggest both KRAS mutations and AKT activation are present in WT and may represent novel therapeutic targets for this disease.
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http://dx.doi.org/10.1002/1878-0261.12044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5378659PMC
April 2017

A Subdermal Osteochondroma in a Young Girl.

Case Rep Orthop 2017 4;2017:8672816. Epub 2017 Jan 4.

Department of Orthopaedics and Rehabilitation, Vanderbilt University Medical Center, 4202 Doctors' Office Tower, 2200 Children's Way, Nashville, TN 37232-9565, USA; Department of Pathology, Vanderbilt University Medical Center, 4202 Doctors' Office Tower, 2200 Children's Way, Nashville, TN 37232-9565, USA; Department of Pediatrics, Vanderbilt University Medical Center, 4202 Doctors' Office Tower, 2200 Children's Way, Nashville, TN 37232-9565, USA; Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, 4202 Doctors' Office Tower, 2200 Children's Way, Nashville, TN 37232-9565, USA; Department of Pharmacology, Vanderbilt University Medical Center, 4202 Doctors' Office Tower, 2200 Children's Way, Nashville, TN 37232-9565, USA.

Osteochondromas are common benign tumors of cartilage and bone. They are usually found as contiguous bone with a cartilage cap at the end of the growth plate of long bones. Similar to structure are extraskeletal osteochondromas. However, unlike typical osteochondromas, extraskeletal osteochondromas are noncontinuous with bone. To our knowledge, all reported extraskeletal osteochondromas have been contained within fascial compartments. Here we present the case of a 5-year-old female who had a slow growing mass of the anterior distal right thigh. Imaging studies revealed an ossified mass extending from dermal layer of the subcutaneous tissue with no connection to the underlying deep fascia. An excisional biopsy was performed and proved to be a subdermal extraskeletal osteochondroma.
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http://dx.doi.org/10.1155/2017/8672816DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5241456PMC
January 2017

Li-Fraumeni Syndrome.

Authors:
Hernán Correa

J Pediatr Genet 2016 Jun 13;5(2):84-8. Epub 2016 Apr 13.

Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, United States.

Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome caused by a germline mutation of the TP53 gene on chromosome 17p13.1. It has an autosomal dominant pattern of inheritance with high penetrance. These patients have a very high lifetime cumulative risk of developing multiple malignancies and have a strong family history of early-onset malignancies. The protein p53, encoded by TP53, has a complex set of genome-preserving functions initiated during episodes of cellular stress and DNA damage. In LFS, TP53 gene mutations cause the loss of function of p53, leading to downstream events permissive for development of various malignancies throughout life. The LFS component tumors include soft tissue sarcomas, osteosarcoma, premenopausal breast cancer, brain tumors, and adrenal cortical carcinomas. Multiple types of sarcomas have been reported in association with LFS; this review article will focus on the most frequently encountered pediatric sarcomas associated with TP53 mutations.
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http://dx.doi.org/10.1055/s-0036-1579759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4918696PMC
June 2016
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