Person:
Kurek, Kyle

Profile Picture

Email Address

AA Acceptance Date

Birth Date

Research Projects

Organizational Units

Job Title

Last Name

Kurek

First Name

Kyle

Name

Kurek, Kyle
Author's Publications: search.filters.isAuthorOfPublication.c1e74ab1-b281-49ec-a60e-6d718993c48a

Search Results

Now showing 1 - 3 of 3
  • Thumbnail Image
    Publication
    MicroRNA paraffin-based studies in osteosarcoma reveal reproducible independent prognostic profiles at 14q32
    (BioMed Central, 2013) Kelly, Andrew D; Haibe-Kains, Benjamin; Janeway, Katherine; Hill, Katherine E; Howe, Eleanor; Goldsmith, Jeffrey; Kurek, Kyle; Perez-Atayde, Antonio; Francoeur, Nancy; Fan, Jian-Bing; April, Craig; Schneider, Hal; Gebhardt, Mark; Culhane, Aedin; Quackenbush, John; Spentzos, Dimitrios
    Background: Although microRNAs (miRNAs) are implicated in osteosarcoma biology and chemoresponse, miRNA prognostic models are still needed, particularly because prognosis is imperfectly correlated with chemoresponse. Formalin-fixed, paraffin-embedded tissue is a necessary resource for biomarker studies in this malignancy with limited frozen tissue availability. Methods: We performed miRNA and mRNA microarray formalin-fixed, paraffin-embedded assays in 65 osteosarcoma biopsy and 26 paired post-chemotherapy resection specimens and used the only publicly available miRNA dataset, generated independently by another group, to externally validate our strongest findings (n = 29). We used supervised principal components analysis and logistic regression for survival and chemoresponse, and miRNA activity and target gene set analysis to study miRNA regulatory activity. Results: Several miRNA-based models with as few as five miRNAs were prognostic independently of pathologically assessed chemoresponse (median recurrence-free survival: 59 months versus not-yet-reached; adjusted hazards ratio = 2.90; P = 0.036). The independent dataset supported the reproducibility of recurrence and survival findings. The prognostic value of the profile was independent of confounding by known prognostic variables, including chemoresponse, tumor location and metastasis at diagnosis. Model performance improved when chemoresponse was added as a covariate (median recurrence-free survival: 59 months versus not-yet-reached; hazard ratio = 3.91; P = 0.002). Most prognostic miRNAs were located at 14q32 - a locus already linked to osteosarcoma - and their gene targets display deregulation patterns associated with outcome. We also identified miRNA profiles predictive of chemoresponse (75% to 80% accuracy), which did not overlap with prognostic profiles. Conclusions: Formalin-fixed, paraffin-embedded tissue-derived miRNA patterns are a powerful prognostic tool for risk-stratified osteosarcoma management strategies. Combined miRNA and mRNA analysis supports a possible role of the 14q32 locus in osteosarcoma progression and outcome. Our study creates a paradigm for formalin-fixed, paraffin-embedded-based miRNA biomarker studies in cancer.
  • Thumbnail Image
    Publication
    Loss-of-Function Mutations in PTPN11 Cause Metachondromatosis, But Not Ollier Disease or Maffucci Syndrome
    (Public Library of Science, 2011) Campos-Xavier, Belinda; Superti-Furga, Andrea; Ikegawa, Shiro; Cormier-Daire, Valerie; Pansuriya, Twinkal C.; Savarirayan, Ravi; Andreucci, Elena; Vikkula, Miikka; Garavelli, Livia; Pottinger, Caroline; Ogino, Toshihiko; Sakai, Akinori; Regazzoni, Bianca M.; Wuyts, Wim; Sangiorgi, Luca; Pedrini, Elena; Bowen, Margot E.; Kurek, Kyle; Boyden, Eric David; Holm, Ingrid; Bonafé, Luisa; Bovée, Judith V.; de Sousa, Sérgio b.; Zhu, Meijun; Kozakewich, Harry; Kasser, James; Seidman, Jonathan; Warman, Matthew
    Metachondromatosis (MC) is a rare, autosomal dominant, incompletely penetrant combined exostosis and enchondromatosis tumor syndrome. MC is clinically distinct from other multiple exostosis or multiple enchondromatosis syndromes and is unlinked to \(EXT1\) and \(EXT2\), the genes responsible for autosomal dominant multiple osteochondromas (MO). To identify a gene for MC, we performed linkage analysis with high-density SNP arrays in a single family, used a targeted array to capture exons and promoter sequences from the linked interval in 16 participants from 11 MC families, and sequenced the captured DNA using high-throughput parallel sequencing technologies. DNA capture and parallel sequencing identified heterozygous putative loss-of-function mutations in \(PTPN11\) in 4 of the 11 families. Sanger sequence analysis of \(PTPN11\) coding regions in a total of 17 MC families identified mutations in 10 of them (5 frameshift, 2 nonsense, and 3 splice-site mutations). Copy number analysis of sequencing reads from a second targeted capture that included the entire \(PTPN11\) gene identified an additional family with a 15 kb deletion spanning exon 7 of \(PTPN11\). Microdissected MC lesions from two patients with \(PTPN11\) mutations demonstrated loss-of-heterozygosity for the wild-type allele. We next sequenced \(PTPN11\) in DNA samples from 54 patients with the multiple enchondromatosis disorders Ollier disease or Maffucci syndrome, but found no coding sequence \(PTPN11\) mutations. We conclude that heterozygous loss-of-function mutations in \(PTPN11\) are a frequent cause of MC, that lesions in patients with MC appear to arise following a ‘‘second hit,’’ that MC may be locus heterogeneous since 1 familial and 5 sporadically occurring cases lacked obvious disease-causing \(PTPN11\) mutations, and that \(PTPN11\) mutations are not a common cause of Ollier disease or Maffucci syndrome.
  • Thumbnail Image
    Publication
    Expansion Thoracoplasty Affects Lung Growth and Morphology in a Rabbit Model: A Pilot Study
    (Springer-Verlag, 2011) Olson, J. Casey; Kurek, Kyle; Mehta, Hemal P.; Warman, Matthew; Snyder, Brian
    Background: Thoracic insufficiency syndrome represents a novel form of postnatal restrictive respiratory disease occurring in children with early-onset scoliosis and chest wall anomalies. Expansion thoracoplasty improves lung volumes in children with thoracic insufficiency syndrome; however, how it affects lung development is unknown. Questions/purposes: Using a rabbit model of thoracic insufficiency syndrome, we evaluated the effect of expansion thoracoplasty on the response of biologic mechanisms in the alveolar microstructure. Methods: Using archived material from a previous experiment, 10 4-week-old New Zealand rabbits were divided into three groups: normal (n = 3), disease (n = 3), and treated (n = 4). Left ribs four to eight were tethered in seven rabbits at age 5 weeks to induce hypoplasia of the left hemithorax (disease). At age 10 weeks, four of these rabbits were treated by expansion thoracoplasty (treated). At age 24 weeks, lungs were excised and processed. Alveolar density and parenchymal airspace were measured on histologic sections. Immunohistochemistry was performed for vascular endothelial growth factor receptor 2 (angiogenesis), KI-67 (cell proliferation), and RAM-11 (macrophages). Results: Alveolar walls were poorly perfused and airspace fraction was larger (emphysematous) in disease rabbits than normal or treated rabbits. Immunohistochemistry provided inconclusive evidence to support the concept that pulmonary hypoplasia is induced by thoracic insufficiency syndrome and controlled by expansion thoracoplasty. Conclusions: Treatment of thoracic insufficiency syndrome by expansion thoracoplasty may prevent emphysematous changes in the alveolar microstructure, thereby enhancing gas exchange.