Scholars@Duke
Stephen Xavier Skapek

Stephen Xavier Skapek

Instructor in the Department of Pediatrics
Pediatrics, Transplant and Cellular Therapy

Selected Publications

An imbalance between proliferation and differentiation underlies the development of microRNA-defective pineoblastoma.

Journal Article Genes Dev · June 2, 2025 Mutations in the microRNA processing genes DROSHA and DICER1 drive several cancers that resemble embryonic progenitors. To understand how microRNAs regulate tumorigenesis, we ablated Drosha or Dicer1 in the developing pineal gland to emulate the pathogenes ... Full text Link to item Cite

A Novel Approach to Harnessing Acoustic A-Lines to Detect Circulating Tumor Cells in Flowing Blood.

Journal Article Nano Lett · December 11, 2024 Circulating tumor cells (CTCs) are associated with tumor burden and treatment response and, as hallmarks of the initiation of tumor dissemination, can predict the likelihood of metastatic progression before widespread tumors can be detected by standard ana ... Full text Link to item Cite

Germline Genetic Testing and Survival Outcomes Among Children With Rhabdomyosarcoma: A Report From the Children's Oncology Group.

Journal Article JAMA Netw Open · March 4, 2024 IMPORTANCE: Determining the impact of germline cancer-predisposition variants (CPVs) on outcomes could inform novel approaches to testing and treating children with rhabdomyosarcoma. OBJECTIVE: To assess whether CPVs are associated with outcome among child ... Full text Link to item Cite

Genomic profiling of subcutaneous patient-derived xenografts reveals immune constraints on tumor evolution in childhood solid cancer.

Journal Article Nat Commun · November 22, 2023 Subcutaneous patient-derived xenografts (PDXs) are an important tool for childhood cancer research. Here, we describe a resource of 68 early passage PDXs established from 65 pediatric solid tumor patients. Through genomic profiling of paired PDXs and patie ... Full text Link to item Cite

Comprehensive characterization of patient-derived xenograft models of pediatric leukemia

Journal Article Iscience · November 17, 2023 Patient-derived xenografts (PDX) remain valuable models for understanding the biology and for developing novel therapeutics. To expand current PDX models of childhood leukemia, we have developed new PDX models from Hispanic patients, a subgroup with a poor ... Full text Cite

Osteosarcoma Explorer: A Data Commons With Clinical, Genomic, Protein, and Tissue Imaging Data for Osteosarcoma Research.

Journal Article JCO Clin Cancer Inform · September 2023 PURPOSE: Osteosarcoma research advancement requires enhanced data integration across different modalities and sources. Current osteosarcoma research, encompassing clinical, genomic, protein, and tissue imaging data, is hindered by the siloed landscape of d ... Full text Link to item Cite

Germline genetic variants and pediatric rhabdomyosarcoma outcomes: a report from the Children's Oncology Group.

Journal Article J Natl Cancer Inst · June 8, 2023 BACKGROUND: Relative to other pediatric cancers, survival for rhabdomyosarcoma (RMS) has not improved in recent decades, suggesting the need to enhance risk stratification. Therefore, we conducted a genome-wide association study for event-free survival (EF ... Full text Link to item Cite

A pilot study evaluating the use of sirolimus in children and young adults with desmoid-type fibromatosis.

Journal Article Pediatr Blood Cancer · June 7, 2023 Deregulation of the mTOR pathway may play an important role in tumor biology when the APC/β-catenin pathway is disrupted in desmoid-type fibromatosis (DT). A pilot study was conducted to determine whether sirolimus can block the mTOR pathway (primary aim) ... Full text Link to item Cite

Predicting Molecular Subtype and Survival of Rhabdomyosarcoma Patients Using Deep Learning of H&E Images: A Report from the Children's Oncology Group.

Journal Article Clin Cancer Res · January 17, 2023 PURPOSE: Rhabdomyosarcoma (RMS) is an aggressive soft-tissue sarcoma, which primarily occurs in children and young adults. We previously reported specific genomic alterations in RMS, which strongly correlated with survival; however, predicting these mutati ... Full text Link to item Cite

Methyltransferase Inhibition Enables Tgfβ Driven Induction of CDKN2A and B in Cancer Cells.

Journal Article Mol Cell Biol · 2023 CDKN2A/B deletion or silencing is common across human cancer, reinforcing the general importance of bypassing its tumor suppression in cancer formation or progression. In rhabdomyosarcoma (RMS) and neuroblastoma, two common childhood cancers, the three CDK ... Full text Link to item Cite

Exon skipping in genes encoding lineage-defining myogenic transcription factors in rhabdomyosarcoma.

Journal Article Cold Spring Harb Mol Case Stud · August 6, 2022 Rhabdomyosarcoma (RMS) is a childhood sarcoma composed of myoblast-like cells, which suggests a defect in terminal skeletal muscle differentiation. To explore potential defects in the differentiation program, we searched for mRNA splicing variants in genes ... Full text Link to item Cite

Genomic Classification and Clinical Outcome in Rhabdomyosarcoma: A Report From an International Consortium.

Journal Article J Clin Oncol · September 10, 2021 PURPOSE: Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. Despite aggressive therapy, the 5-year survival rate for patients with metastatic or recurrent disease remains poor, and beyond PAX-FOXO1 fusion status, no genomic markers are a ... Full text Link to item Cite

Germline Cancer Predisposition Variants in Pediatric Rhabdomyosarcoma: A Report From the Children's Oncology Group.

Journal Article J Natl Cancer Inst · July 1, 2021 BACKGROUND: Several cancer-susceptibility syndromes are reported to underlie pediatric rhabdomyosarcoma (RMS); however, to our knowledge there have been no systematic efforts to characterize the heterogeneous genetic etiologies of this often-fatal malignan ... Full text Link to item Cite

Rationale for the use of tyrosine kinase inhibitors in the treatment of paediatric desmoid-type fibromatosis.

Journal Article Br J Cancer · May 2021 In children with desmoid-type fibromatosis (DTF) in whom disease progression occurs after an initial watch-and-wait strategy, prolonged low-dose chemotherapy using vinblastine and methotrexate (VBL-MTX) is currently the standard of care. These conventional ... Full text Link to item Cite

Prioritization of Novel Agents for Patients with Rhabdomyosarcoma: A Report from the Children's Oncology Group (COG) New Agents for Rhabdomyosarcoma Task Force.

Journal Article J Clin Med · April 1, 2021 Rhabdomyosarcoma is the most common soft tissue sarcoma diagnosed in children and adolescents. Patients that are diagnosed with advanced or relapsed disease have exceptionally poor outcomes. The Children's Oncology Group (COG) convened a rhabdomyosarcoma n ... Full text Link to item Cite

Pathogenic germline variants in cancer susceptibility genes in children and young adults with rhabdomyosarcoma

Journal Article JCO Precision Oncology · January 1, 2021 PURPOSE Rhabdomyosarcoma (RMS) is the most common pediatric soft-tissue sarcoma and accounts for 3% of all pediatric cancer. In this study, we investigated germline sequence and structural variation in a broad set of genes in two large, independent RMS coh ... Full text Cite

HDAC6 promotes growth, migration/invasion, and self-renewal of rhabdomyosarcoma.

Journal Article Oncogene · January 2021 Rhabdomyosarcoma (RMS) is a devastating pediatric sarcoma. The survival outcomes remain poor for patients with relapsed or metastatic disease. Effective targeted therapy is lacking due to our limited knowledge of the underlying cellular and molecular mecha ... Full text Link to item Cite

Functional imaging of RAS pathway targeting in malignant peripheral nerve sheath tumor cells and xenografts.

Journal Article Pediatr Blood Cancer · December 2020 BACKGROUND: Malignant peripheral nerve sheath tumor (MPNST) is an aggressive form of soft-tissue sarcoma (STS) in children. Despite intensive therapy, relatively few children with metastatic and unresectable disease survive beyond three years. RAS pathway ... Full text Link to item Cite

Transcriptome analysis of desmoplastic small round cell tumors identifies actionable therapeutic targets: a report from the Children's Oncology Group.

Journal Article Sci Rep · July 23, 2020 To further understand the molecular pathogenesis of desmoplastic small round cell tumor (DSRCT), a fatal malignancy occurring primarily in adolescent/young adult males, we used next-generation RNA sequencing to investigate the gene expression profiles intr ... Full text Link to item Cite

Development of a Data Model and Data Commons for Germ Cell Tumors.

Journal Article JCO Clin Cancer Inform · June 2020 Germ cell tumors (GCTs) are considered a rare disease but are the most common solid tumors in adolescents and young adults, accounting for 15% of all malignancies in this age group. The rarity of GCTs in some groups, particularly children, has impeded prog ... Full text Link to item Cite

Bayesian Modeling Identifies PLAG1 as a Key Regulator of Proliferation and Survival in Rhabdomyosarcoma Cells.

Journal Article Mol Cancer Res · March 2020 We recently developed a novel computational algorithm that incorporates Bayesian methodology to identify rhabdomyosarcoma disease genes whose expression level correlates with copy-number variations, and we identified PLAG1 as a candidate oncogenic driver. ... Full text Link to item Cite

A risk-based treatment strategy for non-rhabdomyosarcoma soft-tissue sarcomas in patients younger than 30 years (ARST0332): a Children's Oncology Group prospective study.

Journal Article Lancet Oncol · January 2020 BACKGROUND: Tumour grade, tumour size, resection potential, and extent of disease affect outcome in paediatric non-rhabdomyosarcoma soft-tissue sarcoma (NRSTS), but no risk stratification systems exist and the standard of care is poorly defined. We develop ... Full text Link to item Cite

Testis-specific Arf promoter expression in a transposase-aided BAC transgenic mouse model.

Journal Article Mol Biol Rep · December 2019 CDKN2A is an evolutionarily conserved gene encoding proteins implicated in tumor suppression, ocular development, aging, and metabolic diseases. Like the human form, mouse Cdkn2a encodes two distinct proteins-p16Ink4a, which blocks cyclin-dependent kinase ... Full text Link to item Cite

Novel PDGFRB rearrangement in multifocal infantile myofibromatosis is tumorigenic and sensitive to imatinib.

Journal Article Cold Spring Harb Mol Case Stud · October 2019 Infantile myofibromatosis (IM) is an aggressive neoplasm composed of myofibroblast-like cells in children. Although typically localized, it can also present as multifocal disease, which represents a challenge for effective treatment. IM has previously been ... Full text Link to item Cite

Refinement of risk stratification for childhood rhabdomyosarcoma using FOXO1 fusion status in addition to established clinical outcome predictors: A report from the Children's Oncology Group.

Journal Article Cancer Med · October 2019 BACKGROUND: Previous studies of the prognostic importance of FOXO1 fusion status in patients with rhabdomyosarcoma (RMS) have had conflicting results. We re-examined risk stratification by adding FOXO1 status to traditional clinical prognostic factors in c ... Full text Link to item Cite

Identification of De Novo Enhancers Activated by TGFβ to Drive Expression of CDKN2A and B in HeLa Cells.

Journal Article Molecular cancer research : MCR · September 2019 Disruption of the CDKN2A (INK4A/ARF) and B (INK4B) genes, which encode three function-independent tumor suppressors, is one of the most common events in human cancer. Because their relative importance in tumor prevention appears ... Full text Cite

Twist2 amplification in rhabdomyosarcoma represses myogenesis and promotes oncogenesis by redirecting MyoD DNA binding.

Journal Article Genes Dev · June 1, 2019 Rhabdomyosarcoma (RMS) is an aggressive pediatric cancer composed of myoblast-like cells. Recently, we discovered a unique muscle progenitor marked by the expression of the Twist2 transcription factor. Genomic analyses of 258 RMS patient tumors uncovered p ... Full text Link to item Cite

Rhabdomyosarcoma.

Journal Article Nat Rev Dis Primers · January 7, 2019 Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and represents a high-grade neoplasm of skeletal myoblast-like cells. Decades of clinical and basic research have gradually improved our understanding of the pathophysiology of RMS a ... Full text Link to item Cite

Addition of Vincristine and Irinotecan to Vincristine, Dactinomycin, and Cyclophosphamide Does Not Improve Outcome for Intermediate-Risk Rhabdomyosarcoma: A Report From the Children's Oncology Group.

Conference J Clin Oncol · September 20, 2018 Purpose Intermediate-risk rhabdomyosarcoma (RMS) includes patients with either nonmetastatic, unresected embryonal RMS (ERMS) with an unfavorable primary site or nonmetastatic alveolar RMS (ARMS). The primary aim of this study was to improve the outcome of ... Full text Link to item Cite

Undifferentiated Sarcomas in Children Harbor Clinically Relevant Oncogenic Fusions and Gene Copy-Number Alterations: A Report from the Children's Oncology Group.

Journal Article Clinical cancer research : an official journal of the American Association for Cancer Research · August 2018 Purpose: A comprehensive analysis of the genomics of undifferentiated sarcomas (UDS) is lacking. We analyzed copy-number alterations and fusion status in patients with UDS prospectively treated on Children's Oncology Group protocol ARST0332.Exper ... Full text Cite

Integrative Bayesian Analysis Identifies Rhabdomyosarcoma Disease Genes.

Journal Article Cell Rep · July 3, 2018 Identifying oncogenic drivers and tumor suppressors remains a challenge in many forms of cancer, including rhabdomyosarcoma. Anticipating gene expression alterations resulting from DNA copy-number variants to be particularly important, we developed a compu ... Full text Link to item Cite

PAX3-FOXO1 transgenic zebrafish models identify HES3 as a mediator of rhabdomyosarcoma tumorigenesis.

Journal Article Elife · June 5, 2018 Alveolar rhabdomyosarcoma is a pediatric soft-tissue sarcoma caused by PAX3/7-FOXO1 fusion oncogenes and is characterized by impaired skeletal muscle development. We developed human PAX3-FOXO1 -driven zebrafish models of tumorigenesis and found that PAX3-F ... Full text Link to item Cite

Clinical and mutational spectrum of highly differentiated, paired box 3:forkhead box protein o1 fusion-negative rhabdomyosarcoma: A report from the Children's Oncology Group.

Journal Article Cancer · May 1, 2018 BACKGROUND: Pediatric paired box 3:forkhead box protein O1 fusion-negative (PF-) rhabdomyosarcoma (RMS) represents a diverse spectrum of tumors with marked differences in histology, myogenic differentiation, and clinical behavior. METHODS: This study sough ... Full text Link to item Cite

Histology, fusion status, and outcome in metastatic rhabdomyosarcoma: A report from the Children's Oncology Group.

Journal Article Pediatr Blood Cancer · December 2017 BACKGROUND: Distinguishing alveolar rhabdomyosarcoma (ARMS) from embryonal rhabdomyosarcoma (ERMS) has historically been of prognostic and therapeutic importance. However, classification has been complicated by shifting histologic criteria required for an ... Full text Link to item Cite

Potential pitfalls of mass spectrometry to uncover mutations in childhood soft tissue sarcoma: A report from the Children's Oncology Group.

Journal Article Sci Rep · September 19, 2016 Mass spectrometry-based methods have been widely applied - often as the sole method - to detect mutations in human cancer specimens. We applied this approach to 52 childhood soft tissue sarcoma specimens in an attempt to identify potentially actionable mut ... Full text Link to item Cite

The Role of Childhood Infections and Immunizations on Childhood Rhabdomyosarcoma: A Report From the Children's Oncology Group.

Journal Article Pediatr Blood Cancer · September 2016 BACKGROUND: Rhabdomyosarcoma (RMS) is a rare, highly malignant tumor arising from primitive mesenchymal cells that differentiate into skeletal muscle. Relatively little is known about RMS susceptibility. Based on growing evidence regarding the role of earl ... Full text Link to item Cite

Current state of pediatric sarcoma biology and opportunities for future discovery: A report from the sarcoma translational research workshop.

Journal Article Cancer Genet · May 2016 Sarcomas are a rare subgroup of pediatric cancers comprised of a variety of bone and soft-tissue tumors. While significant advances have been made in improving outcomes of patients with localized pediatric sarcomas since the addition of systemic chemothera ... Full text Link to item Cite

Histology, Fusion Status, and Outcome in Alveolar Rhabdomyosarcoma With Low-Risk Clinical Features: A Report From the Children's Oncology Group.

Journal Article Pediatr Blood Cancer · April 2016 BACKGROUND: Distinguishing alveolar rhabdomyosarcoma (ARMS) from embryonal rhabdomyosarcoma (ERMS) is of prognostic and therapeutic importance. Criteria for classifying these entities evolved significantly from 1995 to 2013. ARMS is associated with inferio ... Full text Link to item Cite

p19(Arf) limits primary vitreous cell proliferation driven by PDGF-B.

Journal Article Exp Eye Res · April 2016 Arf encodes an important tumor suppressor, p19(Arf), which also plays a critical role to control hyperplasia in the primary vitreous during mouse eye development. In the absence of Arf, mice are born blind and display a phenotype closely mimicking severe f ... Full text Link to item Cite

Negative regulation of initial steps in skeletal myogenesis by mTOR and other kinases.

Journal Article Sci Rep · February 5, 2016 The transition from a committed progenitor cell to one that is actively differentiating represents a process that is fundamentally important in skeletal myogenesis. Although the expression and functional activation of myogenic regulatory transcription fact ... Full text Link to item Cite

Whole slide images stitching for osteosarcoma detection

Conference 2015 IEEE 5th International Conference on Computational Advances in Bio and Medical Sciences Iccabs 2015 · December 2, 2015 Whole slide imaging (WSI), the conversion of conventional glass-slide histopathology to a digital image, is at the heart of telepathology, which will allow disease diagnosis and the practice of pathology from a distance. Scanning systems that generate WSIs ... Full text Cite

Recurrent internal tandem duplications of BCOR in clear cell sarcoma of the kidney.

Journal Article Nat Commun · November 17, 2015 The X-linked BCL-6 co-repressor (BCOR) gene encodes a key constituent of a variant polycomb repressive complex (PRC) that is mutated or translocated in human cancers. Here we report on the identification of somatic internal tandem duplications (ITDs) clust ... Full text Link to item Cite

Clinical Application of Prognostic Gene Expression Signature in Fusion Gene-Negative Rhabdomyosarcoma: A Report from the Children's Oncology Group.

Journal Article Clin Cancer Res · October 15, 2015 PURPOSE: Pediatric rhabdomyosarcoma (RMS) has two common histologic subtypes: embryonal (ERMS) and alveolar (ARMS). PAX-FOXO1 fusion gene status is a more reliable prognostic marker than alveolar histology, whereas fusion gene-negative (FN) ARMS patients a ... Full text Link to item Cite

The World Health Organization Classification of Skeletal Muscle Tumors in Pediatric Rhabdomyosarcoma: A Report From the Children's Oncology Group.

Journal Article Arch Pathol Lab Med · October 2015 CONTEXT: The World Health Organization Classification Since 1995, the International Classification of Rhabdomyosarcoma has provided prognostically relevant classification for rhabdomyosarcoma (RMS) and allowed risk stratification for children with RMS. The ... Full text Link to item Cite

Family history of cancer and childhood rhabdomyosarcoma: a report from the Children's Oncology Group and the Utah Population Database.

Journal Article Cancer Med · May 2015 Relatively little is known about the epidemiology and factors underlying susceptibility to childhood rhabdomyosarcoma (RMS). To better characterize genetic susceptibility to childhood RMS, we evaluated the role of family history of cancer using data from t ... Full text Link to item Cite

Clonality and evolutionary history of rhabdomyosarcoma.

Journal Article PLoS Genet · March 2015 To infer the subclonality of rhabdomyosarcoma (RMS) and predict the temporal order of genetic events for the tumorigenic process, and to identify novel drivers, we applied a systematic method that takes into account germline and somatic alterations in 44 t ... Full text Link to item Cite

Sarcomas.

Journal Article Pediatr Clin North Am · February 2015 Malignant bone tumors (osteosarcoma, Ewing sarcoma) and soft-tissue sarcomas (rhabdomyosarcoma, nonrhabdomyosarcoma) account for approximately 14% of childhood malignancies. Successful treatment of patients with sarcoma depends on a multidisciplinary appro ... Full text Link to item Cite

Odontogenic myxoma of the face: mimicry of cherubism.

Journal Article J Oral Maxillofac Surg · November 2014 The present study is a case report of a 3-year-old girl who was referred to our clinic with the clinical features of cherubism. A locally aggressive tumor was diffusely infiltrating the maxilla and mandible. At 4 years after resection, our patient has not ... Full text Link to item Cite

Maternal and birth characteristics and childhood rhabdomyosarcoma: a report from the Children's Oncology Group.

Journal Article Cancer Causes Control · July 2014 PURPOSE: Previous assessments of childhood rhabdomyosarcoma have indicated maternal and birth characteristics may be associated with tumor development; however, much work remains to identify novel and confirm suspected risk factors. Our objective was to ev ... Full text Link to item Cite

Isolation and characterization of mammalian cells expressing the Arf promoter during eye development.

Journal Article Biotechniques · May 2014 Although many researchers have successfully uncovered novel functions of the tumor suppressor p19(Arf) utilizing various types of cultured cancer cells and immortalized fibroblasts, these systems do not accurately reflect the endogenous environment in whic ... Full text Link to item Cite

Myogenin, AP2β, NOS-1, and HMGA2 are surrogate markers of fusion status in rhabdomyosarcoma: a report from the soft tissue sarcoma committee of the children's oncology group.

Journal Article Am J Surg Pathol · May 2014 Pediatric rhabdomyosarcoma (RMS) is traditionally classified on the basis of the histologic appearance into alveolar (ARMS) and embryonal (ERMS) subtypes. The majority of ARMS contain a PAX3-FOXO1 or PAX7-FOXO1 gene fusion, but about 20% do not. Intergroup ... Full text Link to item Cite

Comprehensive genomic analysis of rhabdomyosarcoma reveals a landscape of alterations affecting a common genetic axis in fusion-positive and fusion-negative tumors.

Journal Article Cancer Discov · February 2014 UNLABELLED: Despite gains in survival, outcomes for patients with metastatic or recurrent rhabdomyosarcoma remain dismal. In a collaboration between the National Cancer Institute, Children's Oncology Group, and Broad Institute, we performed whole-genome, w ... Full text Link to item Cite

miR-34a is essential for p19(Arf)-driven cell cycle arrest.

Journal Article Cell Cycle · 2014 The Arf tumor suppressor gene product, p19(Arf), regulates cell proliferation in incipient cancer cells and during embryo development. Beyond its commonly accepted p53-dependent actions, p19(Arf) also acts independently of p53 in both contexts. One such p5 ... Full text Link to item Cite

Varied manifestations of persistent hyperplastic primary vitreous with graded somatic mosaic deletion of a single gene.

Journal Article Mol Vis · 2014 PURPOSE: Persistent hyperplastic primary vitreous (PHPV) represents a developmental eye disease known to have diverse manifestations ranging from a trivial remnant of hyaloid vessels to a dense fibrovascular mass causing lens opacity and retinal detachment ... Link to item Cite

Allergies, atopy, immune-related factors and childhood rhabdomyosarcoma: a report from the Children's Oncology Group.

Journal Article International journal of cancer · January 2014 Rhabdomyosarcoma (RMS) is a highly malignant tumor of developing muscle that can occur anywhere in the body. Due to its rarity, relatively little is known about the epidemiology of RMS. Atopic disease is hypothesized to be protective against several malign ... Full text Cite

Targeting oxidative stress in embryonal rhabdomyosarcoma.

Journal Article Cancer Cell · December 9, 2013 Rhabdomyosarcoma is a soft-tissue sarcoma with molecular and cellular features of developing skeletal muscle. Rhabdomyosarcoma has two major histologic subtypes, embryonal and alveolar, each with distinct clinical, molecular, and genetic features. Genomic ... Full text Link to item Cite

A novel algorithm for simplification of complex gene classifiers in cancer.

Journal Article Cancer Res · September 15, 2013 The clinical application of complex molecular classifiers as diagnostic or prognostic tools has been limited by the time and cost needed to apply them to patients. Using an existing 50-gene expression signature known to separate two molecular subtypes of t ... Full text Link to item Cite

PAX-FOXO1 fusion status drives unfavorable outcome for children with rhabdomyosarcoma: a children's oncology group report.

Journal Article Pediatr Blood Cancer · September 2013 BACKGROUND: Rhabdomyosarcoma (RMS) is divided into two major histological subtypes: alveolar (ARMS) and embryonal (ERMS), with most ARMS expressing one of two oncogenic genes fusing PAX3 or PAX7 with FOXO1 (P3F and P7F, respectively). The Children's Oncolo ... Full text Link to item Cite

A distant, cis-acting enhancer drives induction of Arf by Tgfβ in the developing eye.

Journal Article Dev Biol · August 1, 2013 The Arf tumor suppressor represents one of several genes encoded at the Cdkn2a and Cdkn2b loci in the mouse. Beyond its role blunting the growth of incipient cancer cells, the Arf gene also plays an essential role in development: its gene product, p19(Arf) ... Full text Link to item Cite

Novel orally active epoxyeicosatrienoic acid (EET) analogs attenuate cisplatin nephrotoxicity.

Journal Article FASEB J · August 2013 Nephrotoxicity severely limits the use of the anticancer drug cisplatin. Oxidative stress, inflammation, and endoplasmic reticulum (ER) stress contribute to cisplatin-induced nephrotoxicity. We developed novel orally active epoxyeicosatrienoic acid (EET) a ... Full text Link to item Cite

Dense pattern of embryonal rhabdomyosarcoma, a lesion easily confused with alveolar rhabdomyosarcoma: a report from the Soft Tissue Sarcoma Committee of the Children's Oncology Group.

Journal Article Am J Clin Pathol · July 2013 OBJECTIVES: To examine whether the frequency of fusion-negative alveolar rhabdomyosarcoma (ARMSn) increased coincident with changes in the definition of alveolar histology. METHODS: We re-reviewed alveolar rhabdomyosarcoma (ARMS) in the Children's Oncology ... Full text Link to item Cite

Safety and efficacy of high-dose tamoxifen and sulindac for desmoid tumor in children: results of a Children's Oncology Group (COG) phase II study.

Journal Article Pediatr Blood Cancer · July 2013 BACKGROUND: Desmoid fibromatosis (desmoid tumor, DT) is a soft tissue neoplasm prone to recurrence despite complete surgical resection. Numerous small retrospective reports suggest that non-cytotoxic chemotherapy using tamoxifen and sulindac may be effecti ... Full text Link to item Cite

Children's Oncology Group's 2013 blueprint for research: Soft tissue sarcomas.

Journal Article Pediatr Blood Cancer · June 2013 In the US, approximately 850-900 children are diagnosed each year with soft tissue sarcomas (STS). Key findings from recent Children's Oncology Group (COG) clinical trials include safe reduction in therapy for low risk rhabdomyosarcoma (RMS), validation of ... Full text Link to item Cite

Arf induction by Tgfβ is influenced by Sp1 and C/ebpβ in opposing directions.

Journal Article PLoS One · 2013 Recent studies show that Arf, a bona fide tumor suppressor, also plays an essential role during mouse eye development. Tgfβ is required for Arf promoter activation in developing mouse eyes, and its capacity to induce Arf depends on Smads 2/3 as well as p38 ... Full text Link to item Cite

p19Arf represses platelet-derived growth factor receptor β by transcriptional and posttranscriptional mechanisms.

Journal Article Mol Cell Biol · November 2012 In addition to cancer surveillance, p19(Arf) plays an essential role in blocking signals stemming from platelet-derived growth factor receptor β (Pdgfrβ) during eye development, but the underlying mechanisms have not been clear. We now show that without Ar ... Full text Link to item Cite

The inconvenience of convenience cohorts: rhabdomyosarcoma and the PAX-FOXO1 biomarker.

Journal Article Cancer Epidemiol Biomarkers Prev · July 2012 "Convenience cohorts" comprise individuals thought to represent the general population, but chosen because they are readily available for evaluation, rather than at random. As such, these methods are subject to bias and may be misleading. Convenience cohor ... Full text Link to item Cite

Retinoic acid fails to induce cell cycle arrest with myogenic differentiation in rhabdomyosarcoma.

Journal Article Pediatr Blood Cancer · June 2012 BACKGROUND: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Current treatment strategies do not cure most children with recurrent or high-risk disease, underlying the need for novel therapeutic approaches. Retinoic acid has been ... Full text Link to item Cite

Temporally distinct roles for tumor suppressor pathways in cell cycle arrest and cellular senescence in Cyclin D1-driven tumor.

Journal Article Mol Cancer · May 1, 2012 BACKGROUND: Cellular senescence represents a tumor suppressive response to a variety of aberrant and oncogenic insults. We have previously described a transgenic mouse model of Cyclin D1-driven senescence in pineal cells that opposes tumor progression. We ... Full text Link to item Cite

Desmoid tumor in children and adolescents: The influence of age

Chapter · January 1, 2012 Desmoid tumor is a soft tissue neoplasm that can occur in children as well as adults. Formally classified as an intermediate-grade neoplasm, it is known to have a locally invasive growth that can lead to severe and sometimes life-threatening problems. The ... Full text Cite

Prognostic significance and tumor biology of regional lymph node disease in patients with rhabdomyosarcoma: a report from the Children's Oncology Group.

Journal Article J Clin Oncol · April 1, 2011 PURPOSE: Regional lymph node disease (RLND) is a component of the risk-based treatment stratification in rhabdomyosarcoma (RMS). The purpose of this study was to determine the contribution of RLND to prognosis for patients with RMS. PATIENTS AND METHODS: P ... Full text Link to item Cite

Myogenesis and rhabdomyosarcoma the Jekyll and Hyde of skeletal muscle.

Book · 2011 Rhabdomyosarcoma, a neoplasm composed of skeletal myoblast-like cells, represents the most common soft tissue sarcoma in children. The application of intensive chemotherapeutics and refined surgical and radiation therapy approaches have improved survival f ... Full text Link to item Cite

Nonrhabdomyosarcoma soft tissue sarcoma in children: Developing new treatments based on a better understanding of disease biology

Chapter · December 1, 2010 Nonrhabdomyosarcoma soft tissue sarcomas (NRSTS) are a large and very -heterogeneous group of cancers in children. Although approximately 550 NRSTS diagnoses in the US each year represent only approximately 4% of cases of childhood cancer, NRSTS comprise n ... Full text Cite

Tgfbeta signaling directly induces Arf promoter remodeling by a mechanism involving Smads 2/3 and p38 MAPK.

Journal Article J Biol Chem · November 12, 2010 We have investigated how the Arf gene product, p19(Arf), is activated by Tgfβ during mouse embryo development to better understand how this important tumor suppressor is controlled. Taking advantage of new mouse models, we provide genetic evidence that Arf ... Full text Link to item Cite

Childhood rhabdomyosarcoma: new insight on biology and treatment.

Journal Article Curr Oncol Rep · November 2010 Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of childhood. The two most common histologic variants are the embryonal and alveolar subtypes. Although successive collaborative group clinical trials have improved survival rates for many RMS p ... Full text Link to item Cite

Expression of the Arf tumor suppressor gene is controlled by Tgfbeta2 during development.

Journal Article Development · June 2009 The Arf tumor suppressor (also known as Cdkn2a) acts as an oncogene sensor induced by ;abnormal' mitogenic signals in incipient cancer cells. It also plays a crucial role in embryonic development: newborn mice lacking Arf are blind due to a pathological pr ... Full text Link to item Cite

p18Ink4c and p53 Act as tumor suppressors in cyclin D1-driven primitive neuroectodermal tumor.

Journal Article Cancer Res · January 15, 2009 The retinoblastoma (RB) tumor suppressor pathway is likely important in primitive neuroectodermal tumors (PNET) of the brain. In fact, 10% to 15% of children born with RB mutations develop brain PNETs, commonly in the pineal gland. Cyclin D1, which in asso ... Full text Link to item Cite

Pediatric nonrhabdomyosarcoma soft tissue sarcomas.

Journal Article Oncologist · June 2008 The nonrhabdomyosarcoma soft tissue sarcomas (NRSTSs) are a heterogeneous group of mesenchymal cell neoplasms that account for about 4% of childhood cancers. Because each histologic subtype of NRSTS is rare, they have been poorly studied and little is know ... Full text Link to item Cite

Prolactinoma as the first manifestation of Gardner's syndrome.

Journal Article Pediatr Blood Cancer · February 2008 Familial adenomatous polyposis (FAP) is an inherited condition causing numerous adenomatous colorectal polyps and a markedly elevated risk of colon cancer. FAP may be associated with various extracolonic manifestations such as desmoid fibromatosis and oste ... Full text Link to item Cite

Hematometrocolpos in an adolescent female treated for pelvic Ewing sarcoma.

Journal Article Pediatr Blood Cancer · January 2008 Radiation therapy is often used to achieve local control of pelvic Ewing sarcoma in children. The effects of radiation on the female reproductive tract have been well documented in adults with gynecological malignancies, but the long-term consequences of p ... Full text Link to item Cite

MRI and biologic behavior of desmoid tumors in children.

Journal Article AJR Am J Roentgenol · September 2007 OBJECTIVE: The outcome of desmoid tumor in children cannot be reliably predicted on the basis of histologic findings. We sought to determine whether the postoperative presence of residual or recurrent tumor can be predicted on the basis of demographic vari ... Full text Link to item Cite

Continuous delivery of IFN-beta promotes sustained maturation of intratumoral vasculature.

Journal Article Mol Cancer Res · June 2007 IFNs have pleiotropic antitumor mechanisms of action. The purpose of this study was to further investigate the effects of IFN-beta on the vasculature of human xenografts in immunodeficient mice. We found that continuous, systemic IFN-beta delivery, establi ... Full text Link to item Cite

Vinblastine and methotrexate for desmoid fibromatosis in children: results of a Pediatric Oncology Group Phase II Trial.

Journal Article J Clin Oncol · February 10, 2007 PURPOSE: To determine the efficacy and safety of using vinblastine (Vbl) and methotrexate (Mtx) in children with desmoid-type fibromatosis that is recurrent or not amenable to treatment with radiation or surgery. PATIENTS AND METHODS: A phase II study was ... Full text Link to item Cite

Persistent hyperplastic primary vitreous due to somatic mosaic deletion of the arf tumor suppressor.

Journal Article Invest Ophthalmol Vis Sci · February 2007 PURPOSE: Mice lacking the Arf tumor-suppressor gene develop eye disease reminiscent of persistent hyperplastic primary vitreous (PHPV). The current work explores mechanisms by which Arf promotes eye development, and its absence causes a PHPV-like disease. ... Full text Link to item Cite

Distinguishing undifferentiated embryonal sarcoma of the liver from biliary tract rhabdomyosarcoma: a Children's Oncology Group study.

Journal Article Pediatr Dev Pathol · 2007 Morphologically, the distinction between undifferentiated embryonal sarcoma of the liver (UESL) and biliary tract rhabdomyosarcoma (RMS) can be uncertain because of some shared pathologic similarities. Patients with UESL have been consistently but erroneou ... Full text Link to item Cite

Expression and genomic status of EGFR and ErbB-2 in alveolar and embryonal rhabdomyosarcoma.

Conference Mod Pathol · September 2006 Both epidermal growth factor receptor (EGFR) and ErbB-2 play an important role in cancer biology and constitute promising molecular targets of therapy. EGFR and ErbB-2 expression has been observed in rhabdomyosarcoma cell lines but not analyzed systematica ... Full text Link to item Cite

Regulation of cell lineage specification by the retinoblastoma tumor suppressor.

Journal Article Oncogene · August 28, 2006 Early studies of the retinoblastoma gene (RB) have uncovered its critical role as a regulator of the G(1)/S cell cycle phase progression. Surprisingly, genetic approaches in mammals and nematodes have also shown RB controls cell lineage specification and a ... Full text Link to item Cite

Pharmacologic inhibition of cyclin-dependent kinase 4/6 activity arrests proliferation in myoblasts and rhabdomyosarcoma-derived cells.

Journal Article Mol Cancer Ther · May 2006 Myoblast cell cycle exit and differentiation are mediated in part by down-regulation of cyclin D1 and associated cyclin-dependent kinase (Cdk) activity. Because rhabdomyosarcoma may represent a malignant tumor composed of myoblast-like cells failing to exi ... Full text Link to item Cite

The Arf tumor suppressor regulates platelet-derived growth factor receptor beta signaling: a new view through the eyes of Arf(-/-) mice.

Journal Article Cell Cycle · October 2005 Arf is a key mammalian tumor suppressor gene known to be activated in response to aberrant mitogenic signals leading to both p53-dependent and -independent effects. We recently uncovered a new and somewhat unexpected function for mouse Arf as a regulator o ... Full text Link to item Cite

Arf-dependent regulation of Pdgf signaling in perivascular cells in the developing mouse eye.

Journal Article EMBO J · August 3, 2005 We have established that the Arf tumor suppressor gene regulates mural cell biology in the hyaloid vascular system (HVS) of the developing eye. In the absence of Arf, perivascular cells accumulate within the HVS and prevent its involution. We now demonstra ... Full text Link to item Cite

Pathogenesis of persistent hyperplastic primary vitreous in mice lacking the arf tumor suppressor gene.

Journal Article Invest Ophthalmol Vis Sci · October 2004 PURPOSE: Persistent hyperplastic primary vitreous (PHPV) is an idiopathic developmental eye disease associated with failed involution of the hyaloid vasculature. The present work addressed the pathogenesis of PHPV in a mouse model that replicates many aspe ... Full text Link to item Cite

Arf tumor suppressor promoter monitors latent oncogenic signals in vivo.

Journal Article Proc Natl Acad Sci U S A · December 23, 2003 Induction of the Arf tumor suppressor gene by elevated thresholds of mitogenic signals activates a p53-dependent transcriptional response that triggers either growth arrest or apoptosis, thereby countering abnormal cell proliferation. Conversely, Arf inact ... Full text Link to item Cite

Synovial sarcoma in pediatric patients.

Journal Article AJR Am J Roentgenol · September 2002 Full text Link to item Cite

The Arf tumor suppressor gene promotes hyaloid vascular regression during mouse eye development.

Journal Article Proc Natl Acad Sci U S A · March 19, 2002 A key tumor suppressor mechanism that is disrupted frequently in human cancer involves the ARF and p53 genes. In mouse fibroblasts, the Arf gene product responds to abnormal mitogenic signals to activate p53 and trigger either cell cycle arrest or apoptosi ... Full text Link to item Cite

The proliferative and apoptotic activities of E2F1 in the mouse retina.

Journal Article Oncogene · October 25, 2001 The E2F1 transcription factor controls cell proliferation and apoptosis. E2F1 activity is negatively regulated by the retinoblastoma (RB) protein. To study how inactivation of Rb and dysregulated E2F1 affects the developing retina, we analysed wild-type an ... Full text Link to item Cite

Persistent expression of cyclin D1 disrupts normal photoreceptor differentiation and retina development.

Journal Article Oncogene · October 11, 2001 The differentiation of neuronal cells in the developing mammalian retina is closely coupled to cell cycle arrest and proceeds in a highly organized manner. Cyclin D1, which regulates cell proliferation in many cells, also drives the proliferation of photor ... Full text Link to item Cite

Cytogenetics and the biologic basis of sarcomas.

Journal Article Curr Opin Oncol · July 2000 In this past year, a large number of reports have described cytogenetic and biologic studies of sarcomas. The cytogenetic studies provide further evidence that a growing number of sarcomas seem to be defined by consistent chromosomal abnormalities that can ... Full text Link to item Cite

Cloning and characterization of a novel Kruppel-associated box family transcriptional repressor that interacts with the retinoblastoma gene product, RB.

Journal Article J Biol Chem · March 10, 2000 The retinoblastoma gene product, RB, seems to function as a key tumor suppressor by repressing the expression of genes activated by members of the E2F family of transcription factors. In order to accomplish this, RB has been proposed to interact with a tra ... Full text Link to item Cite

Evidence for apoptosis in dystrophin deficient muscular dystrophy

Conference Journal of Investigative Medicine · January 1, 1999 Duchenne's muscular dystrophy (DMD), the most common form of muscular dystrophy in children, is caused by a mutation in the gene encoding the protein dystrophin, which is normally found in muscle cells. Muscle fibers lacking dystrophin go through cycles of ... Cite

Combination chemotherapy using vinblastine and methotrexate for the treatment of progressive desmoid tumor in children.

Journal Article J Clin Oncol · September 1998 PURPOSE: We report the treatment of 10 children for progressive desmoid tumor not amenable to standard surgical or radiation therapy with the use of vinblastine (VBL) and methotrexate (MTX). PATIENTS AND METHODS: Ten patients aged 6.4 to 18 years with prim ... Full text Link to item Cite

Cytogenetics and the biological basis of sarcomas.

Journal Article Curr Opin Oncol · July 1998 Recently, much research has been directed toward gaining a better understanding of sarcoma biology. To accomplish this goal, researchers have focused on characterizing the cytogenetic abnormalities that are detectable by routine karyotyping. With the use o ... Full text Link to item Cite

Asparaginase-associated lipid abnormalities in children with acute lymphoblastic leukemia.

Journal Article Blood · March 15, 1997 To further elucidate the incidence and potential mechanism of asparaginase-associated lipid abnormalities in children with acute lymphoblastic leukemia (ALL), we serially obtained fasting lipid and lipoprotein studies on 38 of the 43 consecutively diagnose ... Link to item Cite

The retinoblastoma protein: More than meets the eyes

Journal Article Progress in Retinal and Eye Research · January 1, 1997 Over the past 10 years, tumor suppressor genes involved in many human malignancies have been isolated. The retinoblastoma gene was the first such tumor suppressor gene to be cloned. Analysis of the retinoblastoma gene and the retinoblastoma gene product (p ... Full text Cite

Cyclin-mediated inhibition of muscle gene expression via a mechanism that is independent of pRB hyperphosphorylation.

Journal Article Mol Cell Biol · December 1996 It was recently demonstrated that ectopic expression of cyclin D1 inhibits skeletal muscle differentiation and, conversely, that expression of cyclin-dependent kinase (cdk) inhibitors facilitates activation of this differentiation program (S. S. Rao, C. Ch ... Full text Link to item Cite

Genes in the RB pathway and their knockout in mice.

Journal Article Semin Cancer Biol · October 1996 The retinoblastoma susceptibility gene (RB), the first identified human tumor suppressor gene, has been shown to be directly involved in the genesis of a variety of human cancers. RB is actually one of a family of three closely related genes including p107 ... Full text Link to item Cite

Inhibition of myogenic differentiation in proliferating myoblasts by cyclin D1-dependent kinase.

Journal Article Science · February 17, 1995 Although the myogenic regulator MyoD is expressed in proliferating myoblasts, differentiation of these cells is limited to the G0 phase of the cell cycle. Forced expression of cyclin D1, but not cyclins A, B, or E, inhibited the ability of MyoD to transact ... Full text Link to item Cite

Correlation of terminal cell cycle arrest of skeletal muscle with induction of p21 by MyoD.

Journal Article Science · February 17, 1995 Skeletal muscle differentiation entails the coordination of muscle-specific gene expression and terminal withdrawal from the cell cycle. This cell cycle arrest in the G0 phase requires the retinoblastoma tumor suppressor protein (Rb). The function of Rb is ... Full text Link to item Cite

Regulatory mechanisms that coordinate skeletal muscle differentiation and cell cycle withdrawal.

Journal Article Curr Opin Cell Biol · December 1994 Skeletal muscle differentiation entails the coupling of muscle-specific gene expression to terminal withdrawal from the cell cycle. Several models have recently been proposed which attempt to explain how regulated expression and function of myogenic transc ... Full text Link to item Cite

Melphalan-induced toxicity in nude mice following pretreatment with buthionine sulfoximine.

Journal Article Cancer Chemother Pharmacol · 1991 Melphalan-induced toxicity in nude mice following pretreatment with a regimen of L-buthionine sulfoximine (BSO), previously shown to enhance the activity of this alkylating agent against rhabdomyosarcoma and glioma xenografts, was examined. Mice were pretr ... Full text Link to item Cite

Dexamethasone therapy for bacterial meningitis.

Journal Article N Engl J Med · February 16, 1989 Link to item Cite

Buthionine sulfoximine-mediated depletion of glutathione in intracranial human glioma-derived xenografts.

Journal Article Biochem Pharmacol · November 15, 1988 D-54 MG, a human glioma-derived continuous cell line growing as subcutaneous or intracranial xenografts in athymic mice, was found to be sensitive to the effects of D,L-buthionine-(SR)-sulfoximine, a selective inhibitor of gamma-glutamylcysteine synthetase ... Full text Link to item Cite

Melphalan transport, glutathione levels, and glutathione-S-transferase activity in human medulloblastoma.

Journal Article Cancer Res · October 1, 1988 Melphalan transport, glutathione levels, and glutathione-S-transferase activity were measured in two continuous human medulloblastoma cell lines and transplantable xenografts in athymic nude mice, TE-671 and Daoy. In vitro mean glutathione levels were 10.0 ... Link to item Cite

Experimental chemotherapy of human medulloblastoma cell lines and transplantable xenografts with bifunctional alkylating agents.

Journal Article Cancer Res · August 1, 1988 A series of bifunctional alkylators were tested against the genotypically and phenotypically heterogeneous continuous human medulloblastoma cell lines, TE-671, Daoy, and D283 Med in vitro and against TE-671 and Daoy growing as s.c. and intracranial xenogra ... Link to item Cite

Enhanced melphalan cytotoxicity following buthionine sulfoximine-mediated glutathione depletion in a human medulloblastoma xenograft in athymic mice.

Journal Article Cancer Res · May 15, 1988 The effect and therapeutic consequences of buthionine-(SR)-sulfoximine (BSO)-mediated depletion of glutathione in the human medulloblastoma-derived cell line, TE-671, growing as s.c. xenografts in athymic nude mice were examined. The glutathione content of ... Link to item Cite