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Margaret H Collins

Publications and source records attributed to Margaret H Collins.

At least 19 recordsLinked to original sources
PubMed2007

Homozygous K5Cre transgenic mice have wavy hair and accelerated malignant progression in a murine model of skin carcinogenesis.

Mice with conditional gene deletions have been extremely valuable in allowing investigators to study the genes of interest in a tissue-specific manner. The Cre-loxP recombination system provides a powerful tool to produce targeted rearrangements of particular genes. The keratin 5-Cre recombinase (K5Cre) transgenic mouse line has been used to generate skin specific gene deletions. We found that the K5Cre mice display a unique phenotype when bred to homozygosity. The K5Cre(+/+) mice have a wavy hair coat and curly whiskers. Histologically, the hair follicles appear disoriented. Over time, the K5Cre(+/+) mice develop patches of alopecia. These mice are also runted when compared to wild-type controls. Fostering the K5Cre(+/+) pups to wild-type mothers results in normal weight gain, suggesting a maternal defect in milk production. When the K5Cre(+/+) mammary glands were examined, we not only found a significant decrease in the number of mammary branches in the virgin females, but also a greater number of quiescent alveoli units in the lactating glands. When the K5Cre(+/+) mice were bred to v-Ha-ras (Tg . AC) transgenic mice, the resulting Tg . AC(+/-) K5Cre(+/+) offspring were utilized in a chemically induced skin carcinogenesis model. The mice were treated with 2.5 microg of 12-O-tetradecanoylphorbol-13-acetate (TPA) weekly for 10 wk. No difference was observed in the time to onset of papilloma formation, the number of papillomas and the average papilloma volume between the Tg . AC(+/-) K5Cre(+/+) mice and their corresponding controls. Surprisingly, however, the K5Cre(+/+) papillomas displayed an accelerated tendency to malignant progression; in addition, the frequency of malignant transformation of the papillomas is significantly enhanced. Although the K5Cre(+/+) mice resemble waved-1 and -2 mutants, the molecular basis for the K5Cre(+/+) phenotype is probably different. In conclusion, we discovered a unique phenotype associated with the K5Cre(+/+) transgenic line.

Alopecia↗
PubMed2007

Favorable histology, MYCN-amplified 4S neonatal neuroblastoma.

We report a neonate with 4S neuroblastoma and MYCN amplification, but favorable Shimada histology, successfully treated with chemotherapy and 13-cis-retinoic acid without stem cell transplantation. MYCN amplification in neuroblastoma is usually associated with unfavorable Shimada histology; the presence of these features in infants with 4S disease confers a poor prognosis. A small number of infants with 4S neuroblastoma and MYCN amplification have favorable Shimada histology. In this subgroup of infants, histopathology may be equally important in predicting outcome.

Adrenal Gland Neoplasms↗
PubMed2006

Mammary-specific Ron receptor overexpression induces highly metastatic mammary tumors associated with beta-catenin activation.

Activated growth factor receptor tyrosine kinases (RTK) play pivotal roles in a variety of human cancers, including breast cancer. Ron, a member of the Met RTK proto-oncogene family, is overexpressed or constitutively active in 50% of human breast cancers. To define the significance of Ron overexpression and activation in vivo, we generated transgenic mice that overexpress a wild-type or constitutively active Ron receptor in the mammary epithelium. In these animals, Ron expression is significantly elevated in mammary glands and leads to a hyperplastic phenotype by 12 weeks of age. Ron overexpression is sufficient to induce mammary transformation in all transgenic animals and is associated with a high degree of metastasis, with metastatic foci detected in liver and lungs of >86% of all transgenic animals. Furthermore, we show that Ron overexpression leads to receptor phosphorylation and is associated with elevated levels of tyrosine phosphorylated beta-catenin and the up-regulation of genes, including cyclin D1 and c-myc, which are associated with poor prognosis in patients with human breast cancers. These studies suggest that Ron overexpression may be a causative factor in breast tumorigenesis and provides a model to dissect the mechanism by which the Ron induces transformation and metastasis.

Animals↗
PubMed2006

Anti-IL-5 (mepolizumab) therapy for eosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EE) is characterized by high numbers of eosinophils in the esophagus and epithelial hyperplasia, and is being increasingly recognized. IL-5 promotes eosinophil trafficking to the esophagus, and positively regulates eosinophil growth, activation, survival, and tissue recruitment. OBJECTIVE: We hypothesized that the humanized monoclonal IgG(1) antibody against human IL-5 (mepolizumab) may be useful in the control of EE. METHODS: An open-label phase I/II safety and efficacy study of anti-IL-5 in 4 adult patients with EE and longstanding dysphagia and esophageal strictures was conducted. Patients received 3 infusions of anti-IL-5 (750 mg intravenously monthly) without change in their current therapy. The levels of plasma IL-5, peripheral blood eosinophils, and CCR3+ cells in blood, quality of life measurements, and histological analysis of esophageal biopsies were determined before and 1 month after treatment. RESULTS: Peripheral blood eosinophilia and percent of CCR3+ cells decreased by 6.4-fold and 7.9-fold (P < .05), respectively, after anti-IL-5 treatment. Notably, mean and maximal esophageal eosinophilia decreased from 46 to 6 and from 153 to 28 eosinophils/high-power field (x400; average, 8.9-fold, P < .001, and 6-fold, P < .05), respectively. Patients reported a better clinical outcome and improved quality of life (P = .03). Therapy was generally well tolerated, and responsiveness to anti-IL-5 therapy did not correlate with plasma IL-5 levels. CONCLUSION: Anti-IL-5 therapy is associated with marked decreases in peripheral blood and esophageal eosinophilia (including the number of CCR3+ blood cells) in patients with EE and improved clinical outcomes. CLINICAL IMPLICATIONS: Anti-IL-5 is a promising therapeutic intervention for EE.

Adolescent↗
PubMed2006

Deficient tracheal rings.

Deficient cartilaginous rings are an extremely rare intrinsic tracheal defect. To our knowledge, only two cases have previously been reported in the literature. We describe our experience with three patients presenting with this unusual defect causing severe tracheomalacia who were successfully managed with slide-tracheoplasty. With respect to correction of the stenotic tracheal segment, our clinical outcomes were excellent. Dissimilarities in medical history suggest that the origin of deficient tracheal rings can be either congenital or acquired.

Child, Preschool↗
PubMed2006

A randomized, double-blind, placebo-controlled trial of fluticasone propionate for pediatric eosinophilic esophagitis.

BACKGROUND & AIMS: Eosinophilic esophagitis is an increasingly recognized disorder with distinctive endoscopic, histologic, and allergic features. Although several therapies are advocated, no placebo-controlled trials have been conducted. We aimed to determine the efficacy of swallowed fluticasone propionate (FP) in the treatment of eosinophilic esophagitis. METHODS: We conducted a randomized, double-blind, placebo-controlled trial of swallowed FP in pediatric patients with active eosinophilic esophagitis. Thirty-six patients were randomly assigned to receive either 880 mug of FP (21 patients) or placebo (15 patients) divided twice daily for 3 months. The primary end point was histologic remission, defined by a peak eosinophil count of </=1 eosinophil in all 400x fields in both the proximal and distal esophagus. RESULTS: Fifty percent of FP-treated patients achieved histologic remission compared with 9% of patients receiving placebo (P = .047). FP decreased esophageal eosinophil levels, with a more pronounced effect in nonallergic individuals (65.9 +/- 25.3 vs 1.4 +/- 1.1 eosinophils/high-power field in the proximal esophagus [P = .03] and 84.6 +/- 19.7 vs 19.6 +/- 12.9 eosinophils/high-power field in the distal esophagus [P = .04]). Resolution of vomiting occurred more frequently with FP than placebo (67% vs 27%; P = .04). FP-induced resolution of mucosal eosinophilia was associated with resolution of endoscopic findings, epithelial hyperplasia, younger age (P = .0003), shorter height (P = .002), and lighter weight (P = .02). Effective treatment with FP decreased the number of CD8(+) T lymphocytes and mast cells in both the proximal and distal esophagus (P < .05). CONCLUSIONS: Swallowed FP is effective in inducing histologic remission in eosinophilic esophagitis, with a more pronounced effect in nonallergic and younger individuals, especially in the proximal esophagus.

Adolescent↗
PubMed2006

Aneurysmal bone cysts express vascular markers.

Recently, clonal chromosome abnormalities have been identified in the mural spindle cells in aneurysmal bone cysts (ABCs), but the nature of the cystic spaces is unclear. Endothelial injury has been suggested as a mechanism of aneurysmal formation in these lesions, but few studies have surveyed vascular markers in ABCs. We stained 25 primary aneurysmal bone cysts with a variety of antibodies that stain vessels. Antibody to factor 8 stained the edge of ABC cavities in almost all cases, and antibodies to VEGF-C, GLUT-1, and smooth muscle actin stained the edge of the cavities in approximately half the cases. Antibodies to D2-40 and CD34 also stained the edge of the cavities in some cases. These results suggest that the cavities in ABCs are related to vasculature and support the theory that vascular injury may be important in the pathogenesis of ABCs.

Actins↗
PubMed2006

Eotaxin-3 and a uniquely conserved gene-expression profile in eosinophilic esophagitis.

Eosinophilic esophagitis (EE) is an emerging disorder with a poorly understood pathogenesis. In order to define disease mechanisms, we took an empirical approach analyzing esophageal tissue by a genome-wide microarray expression analysis. EE patients had a striking transcript signature involving 1% of the human genome that was remarkably conserved across sex, age, and allergic status and was distinct from that associated with non-EE chronic esophagitis. Notably, the gene encoding the eosinophil-specific chemoattractant eotaxin-3 (also known as CCL26) was the most highly induced gene in EE patients compared with its expression level in healthy individuals. Esophageal eotaxin-3 mRNA and protein levels strongly correlated with tissue eosinophilia and mastocytosis. Furthermore, a single-nucleotide polymorphism in the human eotaxin-3 gene was associated with disease susceptibility. Finally, mice deficient in the eotaxin receptor (also known as CCR3) were protected from experimental EE. These results implicate eotaxin-3 as a critical effector molecule for EE and provide insight into disease pathogenesis.

Animals↗
PubMed2005

Prognostic value of MIB-1, E-cadherin, and CD44 in pediatric chordomas.

The prognosis of pediatric chordomas is difficult to predict based on histology. The objective of this study was to assess the expression of a proliferation marker and adhesion molecules in pediatric chordomas and relate the expressions to outcome. In 8 pediatric chordomas, we calculated the MIB-1 labeling index (LI) by counting the number of MIB-1-positive tumor cells in 100 tumor cells. The grade of expression of E-cadherin and CD44 was calculated by estimating the percentage of tumor cells expressing these markers. MIB-1 LI correlated with tumor recurrence (P = 0.007) and low survival rate (P = 0.007). The expression of E-cadherin correlated with disease-free survival (P = 0.009), tumor recurrence (P > 0.0007), and low survival rate (P > 0.0007). CD44 expression did not correlate with recurrence (P = 0.056) or survival rate (P = 0.056). Our results suggest that MIB-1 LI and expression of E-cadherin are helpful to predict outcome in pediatric chordomas.

Adolescent↗
PubMed2005

Ron receptor signaling augments mammary tumor formation and metastasis in a murine model of breast cancer.

The tyrosine kinase receptor Ron has been implicated in several types of cancer, including overexpression in human breast cancer. This is the first report describing the effect of Ron signaling on tumorigenesis and metastasis in a mouse model of breast cancer. Mice with a targeted deletion of the Ron tyrosine kinase signaling domain (TK-/-) were crossed to mice expressing the polyoma virus middle T antigen (pMT) under the control of the mouse mammary tumor virus promoter. Both pMT-expressing wild-type control (pMT+/- TK+/+) and pMT+/- TK-/- mice developed mammary tumors and lung metastases. However, a significant decrease in mammary tumor initiation and growth was found in the pMT+/- TK-/- mice compared with controls. An examination of mammary tumors showed that there was a significant decrease in microvessel density, significantly decreased cellular proliferation, and a significant increase in terminal deoxynucleotidyl transferase-mediated nick end labeling-positive staining in mammary tumor cells from the pMT+/- TK-/- mice compared with the pMT+/- TK+/+ mice. Biochemical analyses on mammary tumor lysates showed that whereas both the pMT-expressing TK+/+ and TK-/- tumors have increased Ron expression compared with normal mammary glands, the pMT-expressing TK-/- tumors have deficits in mitogen-activated protein kinase and AKT activation. These results indicate that Ron signaling synergizes with pMT signaling to induce mammary tumor formation, growth, and metastasis. This effect may be mediated in part through the regulation of angiogenesis and through proliferative and cell survival pathways regulated by mitogen-activated protein kinase and AKT.

Animals↗
PubMed2005

Ron tyrosine kinase receptor regulates papilloma growth and malignant conversion in a murine model of skin carcinogenesis.

Recent studies demonstrate that the receptor tyrosine kinase (TK) Ron is tumorigenic when overexpressed and plays a role in regulating skin homeostasis. We hypothesized that Ron signaling promotes skin carcinogenesis. To test this hypothesis, mice deficient in the TK domain of Ron (TK(-/-) mice) were crossed with v-Ha-ras (Tg.AC) transgenic mice; the resulting TK(-/-) Tg.AC(+/-) mice, and their controls, were utilized in a model of chemically induced Ras-mediated skin carcinogenesis. The mice were treated with 2.5 microg of 12-O-tetradecanoylphorbol-13-acetate applied weekly to the shaved back of 36 control (TK(+/+) Tg.AC(+/-)) and 35 experimental (TK(-/-) Tg.AC(+/-)) mice. In an analysis of the resulting papillomas, a reduction in cellular proliferation and papilloma volume was found in the TK(-/-) Tg.AC(+/-) mice compared to controls. Further, Ron protein expression was upregulated during papilloma formation. Ablation of Ron signaling resulted in partial defects in MAPK and Akt signaling that may account for the decreased papilloma growth in the TK(-/-) Tg.AC(+/-) mice. The papilloma-bearing mice were monitored for the occurrence of malignant skin tumors and other malignant tumor types for a period of 48 weeks. Loss of Ron receptor signaling significantly reduced the percent of papillomas that underwent malignant conversion as well as the number of mice developing other malignant tumor types. In conclusion, these studies demonstrate that Ron signaling augments papilloma growth and malignant conversion in vivo.

Animals↗
PubMed2005

Oncolytic herpes simplex virus mutants are more efficacious than wild-type adenovirus Type 5 for the treatment of high-risk neuroblastomas in preclinical models.

BACKGROUND: High-risk neuroblastoma (Nb) is incurable using current treatment regimens in the majority of patients. Oncolytic virotherapy is a novel approach being tested for several types of adult cancers. OBJECTIVES: To compare the susceptibility of Nb tumor models to oncolytic adenovirus and HSV mutants and delineate the mechanisms of resistance or sensitivity. METHODS: Human Nb cell lines were used to determine susceptibility to adenovirus type 5 wild-type and HSV1 mutant (NV1066) infection, adenovirus receptor expression, support of NV1066 replication, and induction of apoptosis. Human xenograft tumors in immunodeficient mice were evaluated for histological effects and tumor response to intratumoral injection of an oncolytic HSV mutant. RESULTS: All eight Nb cell lines tested in culture were relatively resistant to infection with wild type and attenuated adenoviruses. Cells expressed the cocksackie-adenovirus attachment receptor (CAR) but had low or absent expression of the internalization receptors (alphavbeta3, alphavbeta5 integrins). In contrast, all cells were uniformly sensitive to infection with the attenuated HSV mutant, NV1066. Productive virus replication and induction of apoptosis were observed in HSV-infected cells. CHLA-20 and LAN-5 xenograft tumors injected with a single dose of NV1066 showed a significant antitumor response, and the animals had a prolonged survival post infection in comparison to the PBS-treated control group. HSV injected tumors showed extensive areas of necrosis and morphologic evidence of apoptosis. CONCLUSIONS: Nb tumor models are resistant to adenovirus mediated oncolysis but highly sensitive to HSV mediated oncolysis. Further studies of HSV virotherapy as a novel treatment for Nb are warranted.

Adenoviruses, Human↗
PubMed2005

The rationale for nonsteroidal anti-inflammatory drug therapy for inflammatory myofibroblastic tumors: a Children's Oncology Group study.

BACKGROUND: Inflammatory myofibroblastic tumors (IMTs) are neoplasms that are highly vascularized, have an intermediate prognosis, and are associated with infiltration, obstruction, local recurrence, and rare metastasis. Resection of large IMTs can lead to substantial morbidity and even mortality. Anecdotal experience suggests that nonsteroidal anti-inflammatory drugs may eradicate large IMTs or shrink them to a more readily resectable size and configuration. To support the hypothesis that nonsteroidal anti-inflammatory drugs are antiangiogenic for IMTs by interfering with vascular endothelial growth factor (VEGF) signaling via cyclooxygenase 2 (COX-2) inhibition, IMT specimens were immunohistochemically examined for expression of COX-2 enzyme and VEGF. METHODS: The diagnosis of IMT was confirmed in all 18 cases comprising the study. Intensity of COX-2 and VEGF staining was graded, and staining uniformity was examined. ALK-1 protein expression, found in up to two thirds of IMTs, was also determined. RESULTS: COX-2 and VEGF expression were identified in all tissue examined, with staining intensity varying independently. ALK-1 protein expression was identified in 33% of specimens. Its presence was not related to the intensity of COX-2 or VEGF staining. CONCLUSIONS: Our data suggest that the mediators of angiogenesis, VEGF and COX-2, are present and may play an important role in the growth of IMTs.

Activin Receptors, Type II↗
PubMed2005

Renal carcinomas with the t(6;11)(p21;q12): clinicopathologic features and demonstration of the specific alpha-TFEB gene fusion by immunohistochemistry, RT-PCR, and DNA PCR.

A highly distinctive subset of renal neoplasms of children and young adults contains a t(6;11)(p21;q12), a translocation recently been shown to result in fusion of Alpha, a gene on 11q12, with the transcription factor gene TFEB on 6p21. To define the clinicopathologic spectrum of this nascent entity and to establish immunohistochemical (IHC) and molecular methods for the detection of the specific Alpha-TFEB fusion, we studied 7 renal neoplasms that showed the t(6;11) by cytogenetic or molecular analysis (patient age: range, 9-33 years; mean, 17 years). While all tumors were confined to the kidney, 3 tumors demonstrated vascular invasion. In limited follow-up, none has metastasized. We postulated that the Alpha-TFEB gene fusion may result in deregulated expression of TFEB protein that would be detectable by IHC. Using a polyclonal antibody to TFEB on formalin-fixed, paraffin-embedded tissue sections, we found that all 7 renal neoplasms with the t(6;11) demonstrated moderate (2 cases) or strong (5 cases) nuclear TFEB immunoreactivity. In contrast, none of 1089 other tumors (of 74 histologic types from 16 sites) labeled significantly for TFEB. Nuclear immunoreactivity for TFEB in normal tissues was extremely rare, limited to weak labeling of scattered benign lymphocytes. We also show that the Alpha-TFEB fusion RNAs are highly variable in size and structure, making detection by reverse-transcriptase polymerase chain reaction (RT-PCR) less reliable than for other gene fusions. Because Alpha is an intronless gene and therefore lacks splice signals, we hypothesized that DNA PCR and RT-PCR products would be identical, allowing for the use of more robust molecular assays based on genomic DNA. Indeed, in 2 cases with available frozen tissue, we showed the genomic Alpha-TFEB junction detected by DNA PCR to be identical to the Alpha-TFEB fusion mRNA detected by RT-PCR. In summary, renal neoplasms with the t(6;11) are a distinctive neoplastic entity with many similarities to the Xp11 translocation carcinomas, and together with the latter form a growing "MiTF/TFE family" of translocation carcinomas. Nuclear immunoreactivity for TFEB protein is a highly sensitive and specific diagnostic marker for these renal neoplasms. Finally, the special molecular features of the Alpha-TFEB gene fusion allow its molecular detection by DNA PCR as a robust alternative to RT-PCR in clinical tumor samples.

Adolescent↗
PubMed2004

Pediatric hepatic angiosarcoma: case report and review of the literature.

Pediatric hepatic angiosarcoma (PHAS) is a rare tumor, which usually presents as a rapid enlargement of the liver. To date, surgery, chemotherapy, and radiotherapy have not improved the poor prognosis of PHAS with only three survivors reported. The histology of PHAS is distinct from adult angiosarcoma, because PHAS displays hypercellular whorls of sarcomatous cells, or "kaposiform" spindle cells, in addition to the general features of angiosarcoma. We report a case of PHAS that was treated with vascular ablation, chemotherapy, and liver transplantation. Lung metastases occurred 14 months posttransplant.

Antineoplastic Agents↗
PubMed2004

Clinical and immunopathologic effects of swallowed fluticasone for eosinophilic esophagitis.

BACKGROUND & AIMS: Eosinophilic esophagitis (EE) is a recently recognized clinical disorder that is understood poorly. We aimed to determine the efficacy of swallowed fluticasone propionate on the immunopathologic features associated with EE. METHODS: A retrospective analysis was performed on 20 pediatric patients with EE. Inclusion criteria specified a peak eosinophil density of > or =24 cells per 400x field in the esophagus and treatment with swallowed fluticasone between 2 endoscopic assessments. Histologic specimens were examined for eosinophil and CD8(+) lymphocyte infiltration, papillary lengthening, and proliferation of the basal layer as determined by monoclonal anti-Ki-67 (MIB-1) antibody staining. RESULTS: The mean time interval between endoscopic assessments was 4.8 months. The patients were divided equally between allergic and nonallergic groups based on the results of skin-prick testing. All of the nonallergic patients responded to fluticasone propionate. The endoscopic appearance of the mucosa improved and microscopic evaluation showed markedly reduced eosinophil infiltration, reduced basal layer hyperplasia documented by a reduced number of MIB-1(+) cells, and a reduced number of CD8(+) lymphocytes. However, allergic patients were relatively refractory to therapy; 20% had a partial response, whereas 20% had no detectable improvement. Esophageal eosinophil levels before and after therapy in all patients strongly correlated with the level of epithelial cell proliferation as measured by MIB-1 staining. CONCLUSIONS: Collectively, these results suggest that patients treated with swallowed fluticasone have improved endoscopic, histologic, and immunologic parameters associated with EE. However, patients with identifiable allergies who fail dietary elimination may have a blunted response to treatment.

Administration, Oral↗
PubMed2004

Improving patient care: the use of a digital teaching file to enhance clinicians' access to the intellectual capital of interdepartmental conferences.

OBJECTIVE: We describe a simple method for creating teaching cases from clinical data, radiologic images, surgical images, and images from pathologic slides that are presented at tumor board conferences. CONCLUSION: The resulting interdisciplinary case files are of educational value both during and after conference presentations and can be used by clinicians to gather appropriate historical, laboratory, imaging, surgical, and pathologic data on their patients. This system improves the efficiency and accuracy in gathering patient histories when care is transferred among clinics, the emergency department, and wards.

Access to Information↗