Greehey Childrens Cancer Research Institute

United States

Greehey Childrens Cancer Research Institute

United States
SEARCH FILTERS
Time filter
Source Type

Xiao Y.,Greehey Childrens Cancer Research Institute | Hsiao T.-H.,Greehey Childrens Cancer Research Institute | Suresh U.,Greehey Childrens Cancer Research Institute | Chen H.-I.H.,Greehey Childrens Cancer Research Institute | And 6 more authors.
Bioinformatics | Year: 2014

Motivation: When identifying differentially expressed (DE) genes from high-throughput gene expression measurements, we would like to take both statistical significance (such as P-value) and biological relevance (such as fold change) into consideration. In gene set enrichment analysis (GSEA), a score that can combine fold change and P-value together is needed for better gene ranking.Results: We defined a gene significance score π-value by combining expression fold change and statistical significance (P-value), and explored its statistical properties. When compared to various existing methods, π-value based approach is more robust in selecting DE genes, with the largest area under curve in its receiver operating characteristic curve. We applied π-value to GSEA and found it comparable to P-value and t-statistic based methods, with added protection against false discovery in certain situations. Finally, in a gene functional study of breast cancer profiles, we showed that using π-value helps elucidating otherwise overlooked important biological functions. © 2013 The Author 2013. Published by Oxford University Press. All rights reserved.


Antonarakis E.S.,Johns Hopkins University | Lu C.,Johns Hopkins University | Wang H.,Johns Hopkins University | Luber B.,Johns Hopkins University | And 14 more authors.
New England Journal of Medicine | Year: 2014

Background The androgen-receptor isoform encoded by splice variant 7 lacks the ligand-binding domain, which is the target of enzalutamide and abiraterone, but remains constitutively active as a transcription factor. We hypothesized that detection of androgen-receptor splice variant 7 messenger RNA (AR-V7) in circulating tumor cells from men with advanced prostate cancer would be associated with resistance to enzalutamide and abiraterone.Methods: We used a quantitative reverse-transcriptase-polymerase-chain-reaction assay to evaluate AR-V7 in circulating tumor cells from prospectively enrolled patients with metastatic castration-resistant prostate cancer who were initiating treatment with either enzalutamide or abiraterone. We examined associations between AR-V7 status (positive vs. negative) and prostate-specific antigen (PSA) response rates (the primary end point), freedom from PSA progression (PSA progression-free survival), clinical or radiographic progression-free survival, and overall survival.Results: A total of 31 enzalutamide-treated patients and 31 abiraterone-treated patients were enrolled, of whom 39% and 19%, respectively, had detectable AR-V7 in circulating tumor cells. Among men receiving enzalutamide, AR-V7-positive patients had lower PSA response rates than AR-V7-negative patients (0% vs. 53%, P = 0.004) and shorter PSA progression-free survival (median, 1.4 months vs. 6.0 months; P< 0.001), clinical or radiographic progression-free survival (median, 2.1 months vs. 6.1 months; P< 0.001), and overall survival (median, 5.5 months vs. not reached; P = 0.002). Similarly, among men receiving abiraterone, AR-V7-positive patients had lower PSA response rates than AR-V7-negative patients (0% vs. 68%, P = 0.004) and shorter PSA progression-free survival (median, 1.3 months vs. not reached; P< 0.001), clinical or radiographic progression-free survival (median, 2.3 months vs. not reached; P< 0.001), and overall survival (median, 10.6 months vs. not reached, P = 0.006). The association between AR-V7 detection and therapeutic resistance was maintained after adjustment for expression of full-length androgen receptor messenger RNA.Conclusions: Detection of AR-V7 in circulating tumor cells from patients with castration-resistant prostate cancer may be associated with resistance to enzalutamide and abiraterone. These findings require large-scale prospective validation. Copyright © 2014 Massachusetts Medical Society. All rights reserved.


Dayanc B.E.,Roswell Park Cancer Institute | Dayanc B.E.,Inonu University | Bansal S.,Roswell Park Cancer Institute | Bansal S.,Greehey Childrens Cancer Research Institute | And 3 more authors.
International Journal of Hyperthermia | Year: 2013

Purpose: Previously we showed that mild thermal stress increased natural killer (NK) cell-mediated tumour cytotoxicity and that this could be blocked by anti-NKG2D or anti-MICA (major histolocompatability complex (MHC) class I related chain A) antibodies. Here, we investigated the role of the transcription factor heat shock factor 1 (HSF1) in thermal regulation of MICA expression in tumour cells in vitro and in vivo. Materials and methods: Hyperthermia experiments were conducted in vitro and in mice using a target temperature of 39.5 °C. Apoptotic cells and NK cells in situ were visualised by use of the TUNEL assay or expression of NKp46 respectively. Using Colo205 cells, HSF1 message was blocked utilising siRNA while luciferase reporter assays were used to measure the activity of the MICA promoter in vitro. Cell surface MICA was measured by flow cytometry. Results: Following whole body hyperthermia (WBH), tumour tissues showed an increase in NK cells and apoptosis. Mild thermal stress resulted in a transient increase in surface MICA and enhanced NK cytotoxicity of the Colo205 colon cancer cell line. Silencing (mRNA) HSF1 expression in Colo205 cells prevented the thermal enhancement of MICA message and surface protein levels, with partial loss of thermally enhanced NK cytotoxicity. Mutations of the HSF1 binding site on the MICA promoter implicated HSF1 in the thermal enhancement of MICA. Some, but not all, patient-derived colon tumour derived xenografts also exhibited an enhanced MICA message expression after WBH. Conclusions: Up-regulation of MICA expression in Colo205 cells and enhanced sensitivity to NK cell killing following mild thermal stress is dependent upon HSF1. © 2013 Informa UK Ltd.


Lei X.,Greehey Childrens Cancer Research Institute | Lei X.,University of Texas Health Science Center at San Antonio | Bai Z.,Greehey Childrens Cancer Research Institute | Bai Z.,University of Texas Health Science Center at San Antonio | And 14 more authors.
Nature Cell Biology | Year: 2010

Kaposi's sarcoma-associated herpesvirus (KSHV) is causally linked to several acquired immune deficiency syndrome-related malignancies, including Kaposi's sarcoma, primary effusion lymphoma (PEL) and a subset of multicentric Castleman's disease. Control of viral lytic replication is essential for KSHV latency, evasion of the host immune system and induction of tumours. Here, we show that deletion of a 14 microRNA (miRNA) cluster from the KSHV genome significantly enhances viral lytic replication as a result of reduced NF-κB activity. The miRNA cluster regulates the NF-kappa;B pathway by reducing expression of IBα protein, an inhibitor of NF-kappa;B complexes. Computational and miRNA seed mutagenesis analyses were used to identify KSHV miR-K1, which directly regulates the IBα protein level by targeting the 3′UTR of its transcript. Expression of miR-K1 is sufficient to rescue NF-kappa;B activity and inhibit viral lytic replication, whereas inhibition of miR-K1 in KSHV-infected PEL cells has the opposite effect. Thus, KSHV encodes an miRNA to control viral replication by activating the NF-kappa;B pathway. These results demonstrate an important role for KSHV miRNAs in regulating viral latency and lytic replication by manipulating the host survival pathway. © 2010 Macmillan Publishers Limited. All rights reserved.


Song M.,Greehey Childrens Cancer Research Institute | Hakala K.,University of Texas Health Science Center at San Antonio | Weintraub S.T.,University of Texas Health Science Center at San Antonio | Shiio Y.,Greehey Childrens Cancer Research Institute | Shiio Y.,University of Texas Health Science Center at San Antonio
Journal of Proteome Research | Year: 2011

Mutation of the BRCA1 tumor suppressor gene predisposes women to hereditary breast and ovarian cancers. BRCA1 forms a heterodimer with BARD1. The BRCA1/BARD1 heterodimer has ubiquitin ligase activity, considered to play crucial roles in tumor suppression and DNA damage response. Nevertheless, relevant BRCA1 substrates are poorly defined. We have developed a new approach to systematically identify the substrates of ubiquitin ligases by identifying proteins that display an enhanced incorporation of His-tagged ubiquitin upon ligase coexpression; using this method, we identified several candidate substrates for BRCA1. These include scaffold attachment factor B2 (SAFB2) and Tel2 as well as BARD1. BRCA1 was found to enhance SAFB protein expression and induce Tel2 nuclear translocation. Identification of the ubiquitination substrates has been a major obstacle to understanding the functions of ubiquitin ligases. The quantitative proteomics approach we devised for the identification of BRCA1 substrates will facilitate the identification of ubiquitin ligase-substrate pairs. © 2011 American Chemical Society.


Lai Y.,Greehey Childrens Cancer Research Institute | Qiao M.,Greehey Childrens Cancer Research Institute | Song M.,Greehey Childrens Cancer Research Institute | Weintraub S.T.,University of Texas Health Science Center at San Antonio | And 2 more authors.
PLoS ONE | Year: 2011

Background: The von Hippel-Lindau (VHL) tumor suppressor gene encodes a component of a ubiquitin ligase complex, which is best understood as a negative regulator of hypoxia inducible factor (HIF). VHL ubiquitinates and degrades the α subunits of HIF, and this is proposed to suppress tumorigenesis and tumor angiogenesis. However, several lines of evidence suggest that there are unidentified substrates or targets for VHL that play important roles in tumor suppression. Methodology/Principal Findings: Employing quantitative proteomics, we developed an approach to systematically identify the substrates of ubiquitin ligases and using this method, we identified the Myb-binding protein p160 as a novel substrate of VHL. Conclusions/Significance: A major barrier to understanding the functions of ubiquitin ligases has been the difficulty in pinpointing their ubiquitination substrates. The quantitative proteomics approach we devised for the identification of VHL substrates will be widely applicable to other ubiquitin ligases. © 2011 Lai et al.


Shen-Gunther J.,U.S. Army | Rebeles J.,Greehey Childrens Cancer Research Institute | Rebeles J.,University of North Carolina at Chapel Hill
Gynecologic Oncology | Year: 2013

Goals To define the analytical and clinical performance of a human papillomavirus (HPV) custom-designed microarray targeting the HPV L1 gene for viral genotyping. Methods Microarray probes were designed by cataloging the genome sequence of all 120 known HPV types to generate tiling probes using eArray® software against the unique L1 capsid gene segments targeted by MY09/11 and FAP59/64 primers. The microarray (1 slide × 8 arrays × 60 K features) synthesized in situ by inkjet printing was tested using synthetic type-specific HPV DNA and existing HPV DNA from cervical cytology. The synthetic HPV L1 segments (genotypes 6, 11, 16, 18, 31, 33, 35, 45, 53, 58, 66, 73, 83) were manufactured from sequences stored in the NCBI taxonomy database. Using the hybridization patterns of the synthetic HPV DNA as the Support Vector Machine classifier, HPV DNA from patient samples were genotyped and compared to antecedent DNA sequencing/BLAST® results for concordance. Results 16 cytology-derived HPV DNA samples and 13 synthetic type-specific HPV DNA samples were tested singly, in duplicate, or in combination on 40 arrays. The synthetic HPV DNA hybridization patterns were found to be uniquely distinctive to serve well as a classifier of unknown HPV-containing specimens. For the 16 HPV DNA + samples classified, 15 were concordant with DNA sequencing results. In 6/16 (38%) samples, the microarray hybridization pattern revealed ≥ 2 concurrent HPV infections. Conclusion The novel "HPV Array" was sensitive and specific for detecting single and multiple infections. This proof-of-principle project demonstrated the accuracy and advantages of microarray technology for HPV genotyping.


Kurmasheva R.T.,Greehey Childrens Cancer Research Institute | Houghton P.J.,Greehey Childrens Cancer Research Institute
Cancer Chemotherapy and Pharmacology | Year: 2016

In the USA, the overall cure rate for all childhood cancers is seventy percent, and in many patients that ultimately fail curative therapy, initial responses to current multimodality treatments (surgery, radiation therapy and chemotherapy) is good, with overall 5-year event-free survival approaching 80 %. However, current approaches to curative therapy result in significant morbidity and long-term sequelae, including cardiac dysfunction and cognitive impairment. Furthermore, dose-intensive chemotherapy with conventional agents has not significantly improved outcomes for patients that present with advanced or metastatic disease. Classical cytotoxic agents remain the backbone for curative therapy of both hematologic and solid tumors of childhood. While ‘molecularly’ targeted agents have shown some clinical activity, responses are often modest and of short duration; hence, there is a need to identify new classes of cytotoxic agent that are effective in patients at relapse and that have reduced or different toxicity profiles to normal tissues. Here we review the pediatric preclinical testing program experience of testing novel agents, and the value and limitations of preclinical xenograft models and genetically engineered mouse models for developing novel agents for treatment of childhood cancer. © 2016 Springer-Verlag Berlin Heidelberg


Araujo P.R.,Greehey Childrens Cancer Research Institute | Yoon K.,Greehey Childrens Cancer Research Institute | Ko D.,UTSA | Smith A.D.,University of Southern California | And 4 more authors.
Comparative and Functional Genomics | Year: 2012

Translation regulation plays important roles in both normal physiological conditions and diseases states. This regulation requires cis-regulatory elements located mostly in 5′; and 3′; UTRs and trans-regulatory factors (e.g., RNA binding proteins (RBPs)) which recognize specific RNA features and interact with the translation machinery to modulate its activity. In this paper, we discuss important aspects of 5′; UTR-mediated regulation by providing an overview of the characteristics and the function of the main elements present in this region, like uORF (upstream open reading frame), secondary structures, and RBPs binding motifs and different mechanisms of translation regulation and the impact they have on gene expression and human health when deregulated. Copyright © 2012 Patricia R. Araujo et al.


PubMed | Greehey Childrens Cancer Research Institute
Type: Journal Article | Journal: Cancer chemotherapy and pharmacology | Year: 2016

In the USA, the overall cure rate for all childhood cancers is seventy percent, and in many patients that ultimately fail curative therapy, initial responses to current multimodality treatments (surgery, radiation therapy and chemotherapy) is good, with overall 5-year event-free survival approaching 80%. However, current approaches to curative therapy result in significant morbidity and long-term sequelae, including cardiac dysfunction and cognitive impairment. Furthermore, dose-intensive chemotherapy with conventional agents has not significantly improved outcomes for patients that present with advanced or metastatic disease. Classical cytotoxic agents remain the backbone for curative therapy of both hematologic and solid tumors of childhood. While molecularly targeted agents have shown some clinical activity, responses are often modest and of short duration; hence, there is a need to identify new classes of cytotoxic agent that are effective in patients at relapse and that have reduced or different toxicity profiles to normal tissues. Here we review the pediatric preclinical testing program experience of testing novel agents, and the value and limitations of preclinical xenograft models and genetically engineered mouse models for developing novel agents for treatment of childhood cancer.

Loading Greehey Childrens Cancer Research Institute collaborators
Loading Greehey Childrens Cancer Research Institute collaborators