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1.
Am Surg ; : 31348241248788, 2024 Apr 22.
Article in English | MEDLINE | ID: mdl-38648035

ABSTRACT

BACKGROUND: The minimum weight for enterostomy closure (EC) in infants remains debated with the current acceptable cut-off of >2 kg. As enterostomy-related complications or high enterostomy output (>30cc/kg/d) may prohibit a premature infant from reaching 2 kg, additional data is needed to evaluate the safety of EC in infants <2 kg. The objective of this study was to evaluate postoperative outcomes in low body weight (<2 kg) infants undergoing EC compared to larger infants. METHODS: We performed a multi-center retrospective analysis from 1/1/2012-12/31/2022 of all infants (age <1 year) who were <4 kg at time of EC. Primary outcomes included postoperative complications and 30-day mortality. Non-parametric analysis was performed using the Kruskal-Wallis one-way analysis of variance and chi-square tests. Univariable logistic regression was performed to identify factors associated with postoperative complications. RESULTS: Of 92 infants, 15 infants (16.3%) underwent EC at <2 kg, 16 (17.4%) at 2-2.49 kg, 31 (33.7%) at 2.5-2.99 kg, and 30 (32.6%) at ≥3 kg. Infants <2 kg at time of EC exhibited higher rates of hyperbilirubinemia (P = .030), neurologic comorbidities (P = .030), and high enterostomy output (P = .041). There was no difference in postoperative complications (P = .460) or 30-day mortality (P = .460) between the <2 kg group and larger weight groups. Low body weight was not associated with an increased risk for developing a postoperative complication (OR: 1.001, 95% CI: 1.001-1.001; P = .032). CONCLUSION: Our findings suggest that EC in infants <2 kg may be safe with comparable postoperative outcomes to larger weight infants. Thus, the timing of EC should be based on the infant's physiologic status, in contrast to a predetermined minimum weight cut-off.

2.
Pediatr Surg Int ; 38(2): 193-199, 2022 Feb.
Article in English | MEDLINE | ID: mdl-34854975

ABSTRACT

PURPOSE: The purpose of this study was to investigate factors impacting transplant-free survival among infants with biliary atresia. METHODS: A multi-institutional, retrospective cohort study was performed at nine tertiary-level children's hospitals in the United States. Infants who underwent Kasai portoenterostomy (KP) from January 2009 to May 2017 were identified. Clinical characteristics included age at time of KP, steroid use, surgical approach, liver pathology, and surgeon experience. Likelihood of transplant-free survival (TFS) was evaluated using logistic regression, adjusting for patient and surgeon-level factors. Secondary outcomes at 1 year included readmission, cholangitis, reoperation, mortality, and biliary clearance. RESULTS: Overall, 223 infants underwent KP, and 91 (40.8%) survived with their native liver. Mean age at surgery was 63.9 days (± 24.7 days). At 1 year, 78.5% experienced readmission, 56.9% developed cholangitis, 3.8% had a surgical revision, and 5 died. Biliary clearance at 3 months was achieved in 76.6%. Controlling for patient and surgeon-level factors, each additional day of age toward operation was associated with a 2% decrease in likelihood of TFS (OR 0.98, 95% CI 0.97-0.99). CONCLUSION: Earlier surgical intervention by Kasai portoenterostomy at tertiary-level centers significantly increases likelihood for TFS. Policy-level interventions to facilitate early screening and surgical referral for infants with biliary atresia are warranted to improve outcomes.


Subject(s)
Biliary Atresia , Liver Transplantation , Biliary Atresia/surgery , Humans , Infant , Portoenterostomy, Hepatic , Retrospective Studies , Treatment Outcome
3.
J Pediatr Surg ; 50(5): 771-4, 2015 May.
Article in English | MEDLINE | ID: mdl-25783370

ABSTRACT

INTRODUCTION: Attempts at defining predictors of poor outcome in fetal sacrococcygeal teratoma (SCT) have been hampered by small patient numbers. We sought to validate the utility of tumor volume to fetal weight ratio (TFR) as a predictor of poor prognosis and to identify other morphological outcome predictors in a multicenter series. METHODS: Records of prenatally diagnosed SCT at three fetal centers from 1986 to 2011 were reviewed. Prenatal imaging characteristics including TFR, morphology, hydrops, and placentomegaly were assessed. Poor prognosis was defined as fetal demise, need for fetal intervention, or perinatal death. Receiver operating characteristic (ROC) analysis was used to select a TFR cutoff value. RESULTS: Seventy-nine fetuses with SCT were evaluated. Eleven pregnancies ending in elective termination were excluded. ROC analysis revealed that TFR >0.12 prior to 24 weeks gestation was predictive of poor prognosis (AUC=0.913; Sensitivity=91.7%, Specificity=76.2%, PPV=86.8%; NPV=84.2%). Solid tumor morphology and presence of hydrops were found to be predictors of poor prognosis. None of the factors associated with poor prognosis were independent predictors on multivariate analysis. CONCLUSION: This study validates TFR >0.12 prior to 24 weeks gestation as an objective predictor of outcomes in fetuses with SCT that can be easily applied in most clinical settings.


Subject(s)
Spinal Cord Neoplasms/diagnosis , Teratoma/diagnosis , Ultrasonography, Prenatal/methods , Female , Fetal Death , Gestational Age , Humans , Pregnancy , Prognosis , Sacrococcygeal Region , Spinal Cord Neoplasms/mortality , Teratoma/mortality , United States/epidemiology
4.
J Pediatr Surg ; 49(1): 39-45; discussion 45, 2014 Jan.
Article in English | MEDLINE | ID: mdl-24439578

ABSTRACT

PURPOSE: Pulmonary hypertension (pHTN), a main determinant of survival in congenital diaphragmatic hernia (CDH), results from in utero vascular remodeling. Phosphodiesterase type 5 (PDE5) inhibitors have never been used antenatally to treat pHTN. The purpose of this study is to determine if antenatal PDE5 inhibitors can prevent pHTN in the fetal lamb model of CDH. METHODS: CDH was created in pregnant ewes. Postoperatively, pregnant ewes received oral placebo or tadalafil, a PDE5 inhibitor, until delivery. Near term gestation, lambs underwent resuscitations, and lung tissue was snap frozen for protein analysis. RESULTS: Mean cGMP levels were 0.53±0.11 in placebo-treated fetal lambs and 1.73±0.21 in tadalafil-treated fetal lambs (p=0.002). Normalized expression of eNOS was 82%±12% in Normal-Placebo, 61%±5% in CDH-Placebo, 116%±6% in Normal-Tadalafil, and 86%±8% in CDH-Tadalafil lambs. Normalized expression of ß-sGC was 105%±15% in Normal-Placebo, 82%±3% in CDH-Placebo, 158%±16% in Normal-Tadalafil, and 86%±8% in CDH-Tadalafil lambs. Endothelial NOS and ß-sGC were significantly decreased in CDH (p=0.0007 and 0.01 for eNOS and ß-sGC, respectively), and tadalafil significantly increased eNOS expression (p=0.0002). CONCLUSIONS: PDE5 inhibitors can cross the placental barrier. ß-sGC and eNOS are downregulated in fetal lambs with CDH. Antenatal PDE5 inhibitors normalize eNOS and may prevent in utero vascular remodeling in CDH.


Subject(s)
Carbolines/therapeutic use , Fetal Diseases/drug therapy , Fetal Therapies , Hernias, Diaphragmatic, Congenital , Nitric Oxide Synthase Type III/biosynthesis , Phosphodiesterase 5 Inhibitors/therapeutic use , Animals , Carbolines/administration & dosage , Carbolines/pharmacology , Cyclic GMP/analysis , Disease Models, Animal , Drug Evaluation, Preclinical , Enzyme Induction/drug effects , Female , Hernia, Diaphragmatic/complications , Hernia, Diaphragmatic/embryology , Hernia, Diaphragmatic/enzymology , Hernia, Diaphragmatic/prevention & control , Hypertension, Pulmonary/embryology , Hypertension, Pulmonary/enzymology , Hypertension, Pulmonary/etiology , Hypertension, Pulmonary/prevention & control , Hypertrophy, Right Ventricular/embryology , Hypertrophy, Right Ventricular/enzymology , Hypertrophy, Right Ventricular/etiology , Lung/chemistry , Lung/drug effects , Lung/embryology , Lung/pathology , Maternal-Fetal Exchange , Nitric Oxide Synthase Type III/genetics , Organ Size/drug effects , Phosphodiesterase 5 Inhibitors/administration & dosage , Phosphodiesterase 5 Inhibitors/pharmacology , Pregnancy , Random Allocation , Second Messenger Systems/drug effects , Sheep , Tadalafil
5.
J Pediatr Surg ; 48(6): 1198-204, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23845607

ABSTRACT

PURPOSE: Many infants develop a postsurgical chylothorax after diaphragmatic hernia repair. The pathogenesis remains elusive but may be owing to dysfunctional lymphatic development. This study characterizes pulmonary lymphatic development in the nitrofen mouse model of CDH. METHODS: CD1 pregnant mice were fed nitrofen/bisdiamine (N/B) or olive oil at E8.5. At E14.5 and E15.5, lung buds were categorized by phenotype: normal, N/B without CDH (N/B - CDH), or N/B with CDH (N/B+CDH). Anti-CD31 was used to localize all endothelial cells, while anti-LYVE-1 was used to identify lymphatic endothelial cells in lung buds using immunofluorescence. Differential protein expression of lymphatic-specific markers was analyzed. RESULTS: Lymphatic endothelial cells localized to the mesenchyme surrounding the airway epithelium at E15.5. CD31 and LYVE-1 colocalization identified lymphatic endothelial cells. LYVE-1 expression was upregulated in N/B+CDH lung buds in comparison to N/B - CDH and normal lung buds by immunofluorescence. Western blotting shows that VEGF-D, LYVE-1, Prox-1, and VEGFR-3 expression was upregulated in N/B+CDH lung buds in comparison to N/B - CDH or control lung buds at E14.5. CONCLUSIONS: Lung lymphatics are hyperplastic in N/B+CDH. Upregulation of lymphatic-specific genes suggests that lymphatic hyperplasia plays an important role in dysfunctional lung lymphatic development in the nitrofen mouse model of CDH.


Subject(s)
Endothelial Cells/pathology , Hernias, Diaphragmatic, Congenital , Lung/embryology , Lymphoid Tissue/abnormalities , Animals , Biomarkers/metabolism , Blotting, Western , Endothelial Cells/metabolism , Female , Fluorescent Antibody Technique , Glycoproteins/metabolism , Hernia, Diaphragmatic/chemically induced , Hernia, Diaphragmatic/embryology , Hernia, Diaphragmatic/metabolism , Hernia, Diaphragmatic/pathology , Hyperplasia/metabolism , Lung/metabolism , Lung/pathology , Lymphoid Tissue/embryology , Lymphoid Tissue/metabolism , Lymphoid Tissue/pathology , Membrane Transport Proteins , Mice , Phenyl Ethers , Platelet Endothelial Cell Adhesion Molecule-1/metabolism , Pregnancy , Up-Regulation , Vascular Endothelial Growth Factor D/metabolism , Vascular Endothelial Growth Factor Receptor-3/metabolism
6.
J Pediatr Surg ; 48(6): 1225-31, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23845611

ABSTRACT

PURPOSE: Some fetuses with sacrococcygeal teratoma (SCT) develop hydrops, but there is no consensus on an appropriate prognostic marker for poor prognosis. The purpose of this study is to establish predictors of poor prognosis in fetuses with SCT. METHODS: A retrospective review of patients with prenatally diagnosed SCT from 1986 to 2011 was performed. Patients with outcome data and ultrasound exams before 32 weeks gestational age (GA) were included (n=37). Tumor volume-to-fetal weight ratio (TFR) and tumor morphology were assessed as sonographic predictors of poor prognosis. RESULTS: Twelve patients (32%) had good prognosis, and twenty-five patients (68%) had poor prognosis. All patients with poor prognosis had a morphology score ≥ 3, which is a significant predictor of poor prognosis (p <0.0001). TFR was assessed, and a receiver operating characteristic (ROC) analysis identified a cutoff value of 0.12 before 24 weeks GA and 0.11 before 32 weeks GA as predictors for poor prognosis. TFR is a significant predictor of poor prognosis (p<0.0001). CONCLUSIONS: Patients with cystic SCT all had good prognosis. TFR >0.12 was validated as a sonographic predictor of poor prognosis. TFR and tumor morphology can be used to counsel expectant families with prenatally diagnosed SCT regarding prognosis.


Subject(s)
Teratoma/pathology , Tumor Burden , Ultrasonography, Prenatal , Female , Fetal Development , Follow-Up Studies , Humans , Hydrops Fetalis/etiology , Infant, Newborn , Pregnancy , Prognosis , ROC Curve , Retrospective Studies , Sacrococcygeal Region , Survival Rate , Teratoma/complications , Teratoma/diagnostic imaging , Teratoma/mortality
7.
J Pediatr Surg ; 47(10): 1938-42, 2012 Oct.
Article in English | MEDLINE | ID: mdl-23084212

ABSTRACT

We describe a rare case of multiple intestinal atresias, congenital bilateral perisylvian polymicrogyria, and chronic pulmonary hypertension in a surviving monochorionic twin with co-twin demise. This constellation of congenital anomalies represents a multiple vascular disruption syndrome due to intrauterine vascular compromise in the setting of possible twin-to-twin transfusion syndrome.


Subject(s)
Diseases in Twins/complications , Hypertension, Pulmonary/etiology , Intellectual Disability/complications , Intestinal Atresia/complications , Malformations of Cortical Development/complications , Vascular Diseases/complications , Abnormalities, Multiple , Chorion , Chronic Disease , Humans , Infant, Newborn , Intestinal Atresia/classification , Male , Syndrome
8.
IEEE Trans Inf Technol Biomed ; 16(6): 1208-15, 2012 Nov.
Article in English | MEDLINE | ID: mdl-22801521

ABSTRACT

Congenital pulmonary hypoplasia is a devastating condition affecting fetal and newborn pulmonary physiology, resulting in great morbidity and mortality. The fetal lung develops in a fluid-filled environment. In this work, we describe a novel, implantable pressure sensing and recording device which we use to study the pressures present in the fetal pulmonary tree throughout gestation. The system achieves 0.18 cm H2O resolution and can record for twenty one days continuously at 256 Hz. Sample tracings of in vivo fetal lamb recordings are shown.


Subject(s)
Fetal Monitoring/instrumentation , Fetus/surgery , Lung/embryology , Prostheses and Implants , Transducers, Pressure , Animals , Biomedical Engineering/instrumentation , Sheep
9.
Clin Perinatol ; 39(2): 269-78, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22682378

ABSTRACT

This article reviews fetal intervention for congenital anomalies, which has evolved from a mere concept to a medical specialty over the past 3 decades. Advances in surgical techniques have paralleled developments in fetal imaging, fetal diagnosis, and the advent of maternal tocolysis to prevent preterm labor. Fetal intervention has become an important option for fetuses who would otherwise not survive gestation or who would endure significant morbidity and mortality after birth. However, there were many trials and tribulations as fetal surgery developed into a medical specialty.


Subject(s)
Congenital Abnormalities/surgery , Fetus/surgery , Congenital Abnormalities/diagnosis , General Surgery/trends , Humans , Prenatal Diagnosis
10.
Clin Perinatol ; 39(2): 289-300, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22682380

ABSTRACT

Congenital diaphragmatic hernia (CDH) is a common birth anomaly. Absence or presence of liver herniation and determination of lung-to-head ratio are the most accurate predictors of prognosis for fetuses with CDH. Though open fetal CDH repair has been abandoned, fetal endoscopic balloon tracheal occlusion promotes lung growth in fetuses with severe CDH. Although significant improvements in lung function have not yet been shown in humans, reversible or dynamic tracheal occlusion is promising for select fetuses with severe CDH. This article reviews advances in prenatal diagnosis of CDH, the experimental basis for tracheal occlusion, and its translation into human clinical trials.


Subject(s)
Balloon Occlusion/methods , Fetoscopy/methods , Hernias, Diaphragmatic, Congenital , Lung/diagnostic imaging , Trachea/diagnostic imaging , Female , Hernia, Diaphragmatic/diagnosis , Hernia, Diaphragmatic/therapy , Humans , Lung/physiopathology , Pregnancy , Prenatal Diagnosis , Prognosis , Trachea/surgery , Ultrasonography, Prenatal
11.
J Cutan Pathol ; 38(10): 801-7, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21883364

ABSTRACT

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine carcinoma of the skin. Disease progression usually occurs via lymphatic spread to regional lymphatic draining basins, followed by distant metastasis. We report the clinical course, histopathology and genetic analysis of a 69-year-old woman with likely hematogenous spread of cutaneous neuroendocrine carcinoma manifesting as a single metastatic lesion to a distant cutaneous site. Although the possibility of two cutaneous primary MCCs was considered, array comparative genomic hybridization (aCGH) identified identical distal amplification of a region of chromosome 12p, and synchronous loss of chromosomes 8p and 17p, effectively ruling out the possibility of independent primaries. We propose that this represents a primary cheek MCC with rapid, isolated cutaneous metastasis to the contralateral ankle via hematogenous spread. The distinction between a second primary MCC and a distant cutaneous metastasis clearly has important implications with regard to staging, treatment and prognosis. To our knowledge, this represents the first report of the use of aCGH to clarify the relationship of multiple synchronous cutaneous MCCs and the first report of a single distant cutaneous focus of hematogenous spread. Our data calls into question prior reports alleging multiple cutaneous primaries of this very rare tumor.


Subject(s)
Carcinoma, Merkel Cell/pathology , Neoplasms, Second Primary/etiology , Skin Neoplasms/pathology , Aged , Carcinoma, Merkel Cell/genetics , Carcinoma, Merkel Cell/therapy , Combined Modality Therapy , Comparative Genomic Hybridization , DNA, Neoplasm/analysis , Diagnosis, Differential , Female , Humans , Skin Neoplasms/genetics , Skin Neoplasms/therapy
12.
J Gastrointest Surg ; 13(4): 713-21, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19057967

ABSTRACT

INTRODUCTION: Fibroinflammatory biliary stricture (FIBS) is a rare benign tumor-like process of the extrahepatic bile duct that masquerades as cholangiocarcinoma. METHODS: In order to distinguish this unusual entity from cancer, we performed a systematic analysis of 11 patients with FIBS. All patients presented with jaundice; six patients had coexisting autoimmune disease. Preoperative evaluation included computed tomography scan and endoscopic retrograde cholangiopancreatography with benign brush cytology. Surgical treatment included nine bile duct resections with five concurrent liver resections and two incisional biopsies. Light microscopy demonstrated fibrous lesions admixed with chronic inflammation. RESULTS AND DISCUSSION: Immunohistochemistry demonstrated smooth muscle actin expression in all lesions except one; five tumors exhibited IgG4 positive plasma cells. The lesions were negative for cytokeratin, ALK1, CD21, S100, Ki67, and p53. Six patients received postoperative immunosuppression. At 41 month median follow-up (range 15-58 months), there was no evidence of recurrent FIBS in ten patients, while one was lost to follow-up. CONCLUSION: FIBS is a rare myofibroblastic lesion with an immunohistochemical profile distinct from other epithelial and stromal neoplasms of the extrahepatic bile duct. A subset of these cases appear to represent IgG4-related sclerosing cholangitis. Because preoperative cytology is not diagnostic of FIBS, surgical resection remains the mainstay of diagnosis and treatment, while immunosuppression may reduce the risk of recurrence.


Subject(s)
Bile Duct Neoplasms/diagnosis , Bile Ducts, Extrahepatic/pathology , Bile Ducts, Intrahepatic , Cholangiocarcinoma/diagnosis , Actins/metabolism , Adult , Aged , Cholangiopancreatography, Endoscopic Retrograde , Constriction, Pathologic , Female , Humans , Immunohistochemistry , Inflammation/pathology , Male , Middle Aged , Muscle, Smooth/metabolism , Portal Vein/diagnostic imaging , Retrospective Studies , Tomography, X-Ray Computed
13.
BMC Neurosci ; 9: 29, 2008 Feb 26.
Article in English | MEDLINE | ID: mdl-18302779

ABSTRACT

BACKGROUND: Plasmalemmal vesicle associated protein-1 (PV-1) is selectively expressed in human brain microvascular endothelial cells derived from clinical specimens of primary and secondary malignant brain tumors, cerebral ischemia, and other central nervous system (CNS) diseases associated with blood-brain barrier breakdown. In this study, we characterize the murine CNS expression pattern of PV-1 to determine whether localized PV-1 induction is conserved across species and disease state. RESULTS: We demonstrate that PV-1 is selectively upregulated in mouse blood vessels recruited by brain tumor xenografts at the RNA and protein levels, but is not detected in non-neoplastic brain. Additionally, PV-1 is induced in a mouse model of acute ischemia. Expression is confined to the cerebovasculature within the region of infarct and is temporally regulated. CONCLUSION: Our results confirm that PV-1 is preferentially induced in the endothelium of mouse brain tumors and acute ischemic brain tissue and corresponds to blood-brain barrier disruption in a fashion analogous to human patients. Characterization of PV-1 expression in mouse brain is the first step towards development of rodent models for testing anti-edema and anti-angiogenesis therapeutic strategies based on this molecule.


Subject(s)
Blood-Brain Barrier/metabolism , Brain Ischemia/metabolism , Brain Neoplasms/metabolism , Carrier Proteins/analysis , Endothelium, Vascular/metabolism , Membrane Proteins/analysis , Animals , Biomarkers/analysis , Disease Models, Animal , Male , Mice , Mice, Inbred C57BL , Reverse Transcriptase Polymerase Chain Reaction , Species Specificity , Up-Regulation
14.
Biol Psychol ; 74(3): 396-404, 2007 Mar.
Article in English | MEDLINE | ID: mdl-17126984

ABSTRACT

UNLABELLED: The aim of the present study was to compare two protocols and two information types on detection of concealed knowledge. Four independent groups of subjects were run. Two were tested on probe stimuli of a self-referring (AUTO) nature and two were tested on incidentally acquired details of a mock crime (MOCK). Each pair of groups was run either in a one-probe (1PB) or multiple probe (6PB) block. In the single probe block, which was repeated three times with a different probe on each block, one probe item was randomly repeated multiple times in a Bernoulli series with frequently presented, meaningless or irrelevant items. There was also a rare target item designed to force attention to the stimulus screen. All stimulus types were of the same category within each block. In contrast, in the multiple probe (and category) block, rare probes, rare targets and frequent irrelevant items were repeatedly presented in a Bernoulli series within one block. MAJOR RESULTS: There was a difference in task demand as measured by reaction time between the two protocols (the multiple probe protocol was more demanding), and a difference trend in P300 detection sensitivity between protocols for both information types combined in favor of the 1PB (p<.07). With both protocols combined, there was a trend (p<.07) favoring detection of familiar versus incidentally learned information. In terms of P300 amplitudes, both protocols showed the usual result that P300 to probes was greater than that to irrelevants. Also, as with detection rates, self-referring information was better detected in terms of Probe-Irrelevant P300 amplitude differences than mock crime information, regardless of protocol. There was no effect of time passage across the repeated blocks of the one-probe protocol. Methodological problems with the multiple probe protocol as utilized in most recent publications are discussed.


Subject(s)
Arousal/physiology , Attention/physiology , Cerebral Cortex/physiology , Criminal Psychology , Event-Related Potentials, P300/physiology , Guilt , Lie Detection , Mental Recall/physiology , Adolescent , Adult , Dominance, Cerebral/physiology , Electroencephalography , Female , Humans , Male , Practice, Psychological , Reaction Time/physiology , Signal Processing, Computer-Assisted
15.
Clin Cancer Res ; 11(21): 7643-50, 2005 Nov 01.
Article in English | MEDLINE | ID: mdl-16278383

ABSTRACT

PURPOSE: Plasmalemmal vesicle associated protein-1 (PV-1) is up-regulated in the endothelium of human glioblastoma. We sought to further characterize the expression pattern of PV-1 in human brain tumors and interrogate its role in brain tumor angiogenesis. EXPERIMENTAL DESIGN: Quantitative reverse transcription-PCR and in situ hybridization were used to measure PV-1 expression in a panel of 46 human brain tumors and related pathologic states. Matrigel tubulogenesis assays and cell migration assays were used to show function of PV-1 in primary human endothelial cells (HMVEC) under gene knockdown conditions. RESULTS: PV-1 is selectively up-regulated in a variety of high-grade human brain tumors, including glioblastoma and metastatic carcinoma, as well as other cerebral disorders associated with blood-brain barrier disruption, such as acute ischemia. Expression levels were reduced in low-grade neoplasia; however, tumors associated with the ependyma and choroid plexus, known sites of PV-1 expression, also exhibited robust expression. Cerebral expression of PV-1 mRNA was confined to endothelial cells in all cases. PV-1 expression was induced in HMVEC cells in vitro by exposure to medium conditioned by U87MG and U251MG human brain tumor cell lines and by medium supplemented with exogenous vascular endothelial growth factor or scatter factor/hepatocyte growth factor. RNA interference-mediated inhibition of PV-1 induction in HMVEC cells blocked Matrigel-induced tubulogenesis and inhibited cell migration induced by conditioned medium or angiogenic growth factors. CONCLUSIONS: Our results confirm that PV-1 is preferentially induced in the endothelium of high-grade human brain tumors. Inhibition of PV-1 expression is associated with failure of endothelial differentiation in vitro. PV-1 represents a novel marker of brain tumor angiogenesis and integrity of the blood-brain barrier and is a potential therapeutic target.


Subject(s)
Biomarkers, Tumor , Brain Neoplasms/pathology , Carrier Proteins/biosynthesis , Gene Expression Regulation, Neoplastic , Membrane Proteins/biosynthesis , Neovascularization, Pathologic , Blood-Brain Barrier , Blotting, Western , Cell Line, Tumor , Cell Movement , Cells, Cultured , Collagen/chemistry , Culture Media, Conditioned/pharmacology , Drug Combinations , Endothelium, Vascular/cytology , Endothelium, Vascular/pathology , Humans , In Situ Hybridization , Ischemia , Laminin/chemistry , Microcirculation , Neoplasm Metastasis , Proteoglycans/chemistry , RNA/metabolism , RNA Interference , RNA, Messenger/metabolism , RNA, Small Interfering/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Transcription, Genetic , Up-Regulation , Vascular Endothelial Growth Factor A/metabolism
16.
Nucleic Acids Res ; 32(2): 719-27, 2004.
Article in English | MEDLINE | ID: mdl-14757836

ABSTRACT

Two forms of human tryptophanyl-tRNA synthetase (TrpRS) are produced in vivo through alternative mRNA splicing. The two forms, full-length TrpRS and mini TrpRS, are catalytically active, but are distinguished by the striking anti-proliferative and anti-angiogenic activity specific to mini TrpRS. Here we describe two new splice variants of human TrpRS mRNA. Their production was strongly regulated by gamma-interferon (IFN-gamma), an anti-proliferative cytokine known to stimulate the expression of other anti-angiogenic factors. A new IFN-gamma-sensitive promoter was demonstrated to drive production of these splice variants. In human endothelial cells, both the newly discovered and a previously reported promoter were shown to respond specifically to IFN-gamma and not to other cytokines such as tumor necrosis factor-alpha, transforming growth factor-beta, interleukin-4 or erythropoietin. In addition, both promoters were stimulated by the 'downstream' interferon regulatory factor 1 that, in turn, is known to be regulated by the 'upstream' signal transducer and activator of transcription 1alpha subunit. Thus, the tandem promoters provide a dual system to regulate expression and alternative splicing of human TrpRS in vivo.


Subject(s)
Alternative Splicing/drug effects , Angiogenesis Inhibitors/genetics , Gene Expression Regulation, Enzymologic/drug effects , Interferon-gamma/pharmacology , Promoter Regions, Genetic/drug effects , Tryptophan-tRNA Ligase/genetics , 5' Untranslated Regions/genetics , Alternative Splicing/genetics , Base Sequence , Cells, Cultured , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Endothelial Cells/drug effects , Endothelial Cells/metabolism , HeLa Cells , Humans , Interferon Regulatory Factor-1 , Isoenzymes/genetics , Phosphoproteins/genetics , Phosphoproteins/metabolism , Promoter Regions, Genetic/genetics , RNA, Messenger/genetics , RNA, Messenger/metabolism
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