Yongzhao Shao, Ph.D.

Expression of cancer testis antigens in human BRCA-associated breast cancers: potential targets for immunoprevention?
Adams, Sylvia; Greeder, Luba; Reich, Elsa; Shao, Yongzhao; Fosina, Denise; Hanson, Nicole; Tassello, Jodie; Singh, Baljit; Spagnoli, Giulio C; Demaria, Sandra; Jungbluth, Achim A
2011 Jul;60(7):999-1007, Cancer immunology immunotherapy
INTRODUCTION: Novel breast cancer risk-reducing strategies for individuals with germline mutations of the BRCA1 and/or BRCA2 genes are urgently needed. Identification of antigenic targets that are expressed in early cancers, but absent in normal breast epithelium of these high-risk individuals, could provide the basis for the development of effective immunoprophylactic strategies. Cancer testis (CT) antigens are potential candidates because their expression is restricted to tumors, and accumulating data suggest that they play important roles in cellular proliferation, stem cell function, and carcinogenesis. The objective of this study was to examine the expression of CT antigens and their frequency in BRCA-associated breast cancers. METHODS: Archived breast cancer tissues (n = 26) as well as morphologically normal breast tissues (n = 7) from women carrying deleterious BRCA 1 and/or 2 mutations were obtained for antigen expression analysis by immunohistochemistry. Expression of the following CT antigens was examined: MAGE-A1, MAGE-A3, MAGE-A4, MAGE-C1.CT7, NY-ESO-1, MAGE-C2/CT10, and GAGE. RESULTS: CT antigens were expressed in 16/26 (61.5%, 95% CI 43-80%) of BRCA-associated cancers, including in situ tumors. Thirteen of twenty-six (50%) breast cancers expressed two or more CT antigens; three cancers expressed all seven CT antigens. MAGE-A was expressed in 13/26 (50%) of cancers, NY-ESO-1 was expressed in 10/26 (38%) of tumors. In contrast, none of the CT antigens were expressed in adjacent or contralateral normal breast epithelium (P = 0.003). CONCLUSIONS: We report a high CT antigen expression rate in BRCA-associated breast cancer as well as the lack of expression of these antigens in benign breast tissue of carriers, identifying CT antigens as potential vaccine targets for breast cancer prevention in these high-risk individuals
— id: 134441, year: 2011, vol: 60, page: 999, stat: Journal Article,

miR-30b/30d Regulation of GalNAc Transferases Enhances Invasion and Immunosuppression during Metastasis
Gaziel-Sovran, Avital; Segura, Miguel F; Di Micco, Raffaella; Collins, Mary K; Hanniford, Douglas; Vega-Saenz de Miera, Eleazar; Rakus, John F; Dankert, John F; Shang, Shulian; Kerbel, Robert S; Bhardwaj, Nina; Shao, Yongzhao; Darvishian, Farbod; Zavadil, Jiri; Erlebacher, Adrian; Mahal, Lara K; Osman, Iman; Hernando, Eva
2011 Jul 12;20(1):104-118, Cancer cell
To metastasize, a tumor cell must acquire abilities such as the capacity to colonize new tissue and evade immune surveillance. Recent evidence suggests that microRNAs can promote the evolution of malignant behaviors by regulating multiple targets. We performed a microRNA analysis of human melanoma, a highly invasive cancer, and found that miR-30b/30d upregulation correlates with stage, metastatic potential, shorter time to recurrence, and reduced overall survival. Ectopic expression of miR-30b/30d promoted the metastatic behavior of melanoma cells by directly targeting the GalNAc transferase GALNT7, resulted in increased synthesis of the immunosuppressive cytokine IL-10, and reduced immune cell activation and recruitment. These data support a key role of miR-30b/30d and GalNAc transferases in metastasis, by simultaneously promoting cellular invasion and immunosuppression
— id: 135264, year: 2011, vol: 20, page: 104, stat: Journal Article,

Correction: The Novel Gamma Secretase Inhibitor RO4929097 Reduces the Tumor Initiating Potential of Melanoma
Huynh, Chanh; Poliseno, Laura; Segura, Miguel F; Medicherla, Ratna; Haimovic, Adele; Menendez, Silvia; Shang, Shulian; Pavlick, Anna; Shao, Yongzhao; Darvishian, Farbod; Boylan, John F; Osman, Iman; Hernando, Eva
2011 ;6(11):?-?, PLoS ONE
[This corrects the article on p. e25264 in vol. 6.]
— id: 141637, year: 2011, vol: 6, page: ?, stat: Journal Article,

The Novel Gamma Secretase Inhibitor RO4929097 Reduces the Tumor Initiating Potential of Melanoma
Huynh, Chanh; Poliseno, Laura; Segura, Miguel F; Medicherla, Ratna; Haimovic, Adele; Menendez, Silvia; Shang, Shulian; Pavlick, Anna; Shao, Yongzhao; Darvishian, Farbod; Boylan, John F; Osman, Iman; Hernando, Eva
2011 ;6(9):e25264-e25264, PLoS ONE
Several reports have demonstrated a role for aberrant NOTCH signaling in melanoma genesis and progression, prompting us to explore if targeting this pathway is a valid therapeutic approach against melanoma. We targeted NOTCH signaling using RO4929097, a novel inhibitor of gamma secretase, which is a key component of the enzymatic complex that cleaves and activates NOTCH. The effects of RO4929097 on the oncogenic and stem cell properties of a panel of melanoma cell lines were tested both in vitro and in vivo, using xenograft models. In human primary melanoma cell lines, RO4929097 decreased the levels of NOTCH transcriptional target HES1. This was accompanied by reduced proliferation and impaired ability to form colonies in soft agar and to organize in tridimensional spheres. Moreover, RO4929097 affected the growth of human primary melanoma xenograft in NOD/SCID/IL2gammaR-/- mice and inhibited subsequent tumor formation in a serial xenotransplantation model, suggesting that inhibition of NOTCH signaling suppresses the tumor initiating potential of melanoma cells. In addition, RO4929097 decreased tumor volume and blocked the invasive growth pattern of metastatic melanoma cell lines in vivo. Finally, increased gene expression of NOTCH signaling components correlated with shorter post recurrence survival in metastatic melanoma cases. Our data support NOTCH inhibition as a promising therapeutic strategy against melanoma
— id: 138712, year: 2011, vol: 6, page: e25264, stat: Journal Article,

Genetic Variants of TSLP and Asthma in an Admixed Urban Population
Liu, Mengling; Rogers, Linda; Cheng, Qinyi; Shao, Yongzhao; Fernandez-Beros, Maria Elena; Hirschhorn, Joel N; Lyon, Helen N; Gajdos, Zofia K Z; Vedantam, Sailaja; Gregersen, Peter; Seldin, Michael F; Bleck, Bertram; Ramasamy, Adaikalavan; Hartikainen, Anna-Liisa; Jarvelin, Marjo-Riitta; Kuokkanen, Mikko; Laitinen, Tarja; Eriksson, Johan; Lehtimaki, Terho; Raitakari, Olli T; Reibman, Joan
2011 ;6(9):e25099-e25099, PLoS ONE
BACKGROUND: Thymic stromal lymphopoietin (TSLP), an IL7-like cytokine produced by bronchial epithelial cells is upregulated in asthma and induces dendritic cell maturation supporting a Th2 response. Environmental pollutants, including tobacco smoke and diesel exhaust particles upregulate TSLP suggesting that TSLP may be an interface between environmental pollution and immune responses in asthma. Since asthma is prevalent in urban communities, variants in the TSLP gene may be important in asthma susceptibility in these populations. OBJECTIVES: To determine whether genetic variants in TSLP are associated with asthma in an urban admixed population. METHODOLOGY AND MAIN RESULTS: Ten tag-SNPs in the TSLP gene were analyzed for association with asthma using 387 clinically diagnosed asthmatic cases and 212 healthy controls from an urban admixed population. One SNP (rs1898671) showed nominally significant association with asthma (odds ratio (OR) = 1.50; 95% confidence interval (95% CI): 1.09-2.05, p = 0.01) after adjusting for age, BMI, income, education and population stratification. Association results were consistent using two different approaches to adjust for population stratification. When stratified by smoking status, the same SNP showed a significantly increased risk associated with asthma in ex-smokers (OR = 2.00, 95% CI: 1.04-3.83, p = 0.04) but not significant in never-smokers (OR = 1.34; 95% CI: 0.93-1.94, p = 0.11). Haplotype-specific score test indicated that an elevated risk for asthma was associated with a specific haplotype of TSLP involving SNP rs1898671 (OR = 1.58, 95% CI: 1.10-2.27, p = 0.01). Association of this SNP with asthma was confirmed in an independent large population-based cohort consortium study (OR = 1.15, 95% CI: 1.07-1.23, p = 0.0003) and the results stratified by smoking status were also validated (ex-smokers: OR = 1.21, 95% CI: 1.08-1.34, p = 0.003; never-smokers: OR = 1.06, 95% CI: 0.94-1.17, p = 0.33). CONCLUSIONS: Genetic variants in TSLP may contribute to asthma susceptibility in admixed urban populations with a gene and environment interaction
— id: 138030, year: 2011, vol: 6, page: e25099, stat: Journal Article,

Headache and Mental Health Symptoms in Residents and Workers Exposed to World Trade Center (WTC) Dust, Gas and Fumes Presenting for Medical Care
Crystal, S. C.; Julian, M. -C.; Reibman, J.; Liu, M.; Shao, Y.; Oh, C.; Henry, K. A.
2010 AUG ;50(8):S2-S2, Headache
— id: 112182, year: 2010, vol: 50, page: S2, stat: Journal Article,

Tests for normality based on entropy divergences
Guo J; Alemayehu D; Shao Y
2010 ;2:408-418, Statistics in biopharmaceutical research
— id: 114804, year: 2010, vol: 2, page: 408, stat: Journal Article,

Genome-Wide Association Study to Identify Single Nucleotide Polymorphisms (SNPs) Associated With the Development of Erectile Dysfunction in African-American Men After Radiotherapy for Prostate Cancer
Kerns, Sarah L; Ostrer, Harry; Stock, Richard; Li, William; Moore, Julian; Pearlman, Alexander; Campbell, Christopher; Shao, Yongzhao; Stone, Nelson; Kusnetz, Lynda; Rosenstein, Barry S
2010 Dec 1;78(5):1292-1300, International journal of radiation oncology biology physics
PURPOSE: To identify single nucleotide polymorphisms (SNPs) associated with erectile dysfunction (ED) among African-American prostate cancer patients treated with external beam radiation therapy. METHODS AND MATERIALS: A cohort of African-American prostate cancer patients treated with external beam radiation therapy was observed for the development of ED by use of the five-item Sexual Health Inventory for Men (SHIM) questionnaire. Final analysis included 27 cases (post-treatment SHIM score </=7) and 52 control subjects (post-treatment SHIM score >/=16). A genome-wide association study was performed using approximately 909,000 SNPs genotyped on Affymetrix 6.0 arrays (Affymetrix, Santa Clara, CA). RESULTS: We identified SNP rs2268363, located in the follicle-stimulating hormone receptor (FSHR) gene, as significantly associated with ED after correcting for multiple comparisons (unadjusted p = 5.46 x 10(-8), Bonferroni p = 0.028). We identified four additional SNPs that tended toward a significant association with an unadjusted p value < 10(-6). Inference of population substructure showed that cases had a higher proportion of African ancestry than control subjects (77% vs. 60%, p = 0.005). A multivariate logistic regression model that incorporated estimated ancestry and four of the top-ranked SNPs was a more accurate classifier of ED than a model that included only clinical variables. CONCLUSIONS: To our knowledge, this is the first genome-wide association study to identify SNPs associated with adverse effects resulting from radiotherapy. It is important to note that the SNP that proved to be significantly associated with ED is located within a gene whose encoded product plays a role in male gonad development and function. Another key finding of this project is that the four SNPs most strongly associated with ED were specific to persons of African ancestry and would therefore not have been identified had a cohort of European ancestry been screened. This study demonstrates the feasibility of a genome-wide approach to investigate genetic predisposition to radiation injury
— id: 114802, year: 2010, vol: 78, page: 1292, stat: Journal Article,

Replication Of An Association Of The Interleukin-1 Receptor Antagonist Gene With Asthma In An Adult Urban Admixed Population
Shao Y; Liu M; Rogers Q; Cheng M; Fernandez-Beros P; Gregersen M; Seldin J; Hirschhorn J; Reibman J
2010 ;181:?-? #A1321, American journal of respiratory & critical care medicine
— id: 114874, year: 2010, vol: 181, page: ?, stat: Journal Article,

COSMATOS, D. and CHOW, S.-C. (eds). Translational Medicine: Strategies and Statistical Methods. Chapman & Hall/CRC, New York, 2009. xiv + 224 pp. [...].ISBN 9781584888727
Shao, Yongzhao
2010 ;66(2):660-661, Biometrics
— id: 114875, year: 2010, vol: 66, page: 660, stat: Journal Article,

A characterization of multivariate normality through univariate projections
Shao, YZ; Zhou, M
2010 ;101(10):2637-2640, Journal of multivariate analysis
This paper introduces a new characterization of multivariate normality of a random vector based on univariate normality of linear combinations of its components. (C) 2010 Elsevier Inc. All rights reserved. $$:
— id: 114803, year: 2010, vol: 101, page: 2637, stat: Journal Article,

Sample Size Analysis for Pharmacogenetic Studies
Tseng, Chi-hong; Shao, Yongzhao
2010 AUG ;2(3):319-328, Statistics in biopharmaceutical research
Pharmacogenetic studies identify the genetic factors that influence the intersubject variation in drug response. This article proposes a general framework to determine sample size in pharmacogenetic studies. Simple closed form solutions for the sample size are derived for continuous and binary outcomes. To extend the application to pharmacogenomic studies, where a large number of gene-treatment interactions are evaluated simultaneously, we advocate the use of false discovery rate (FDR) in controlling false positive proportion. We adapt the method proposed by Shao and Tseng (2007) to facilitate adjustment for correlation among multiple tests for better control of false positives and power. A real example is given and simulation studies are carried out to demonstrate the performance of the proposed method
— id: 135637, year: 2010, vol: 2, page: 319, stat: Journal Article,

Limit Theorems for -Divergences Based on k-Spacings
Jimenez, R; Shao, YZ
2009 ;38(5):695-710, Communications in statistics: theory & methods
We study the asymptotic behavior of the divergence-based statistic [image omitted] where X1X2Xn are the order statistics of a random sample of size n, G is a known continuous distribution, is a convex function on (0,+), k1 is a fixed integer, and N the smallest integer greater than or equal to (n+1)/k. Laws of large numbers and central limit theorems for W,n(G,k) are established under sharp conditions on and an information-type inequality is obtained to characterize the unknown fixed distribution which generated the data. Application to goodness-of-fit tests are discussed with respect to general consistency and asymptotic power for several widely used and various k. $$:
— id: 114873, year: 2009, vol: 38, page: 695, stat: Journal Article,

Optimal Two-Stage Designs to Evaluate a Series of New Agents or Treatments
Mukhi, Vandana; Shao, Yongzhao
2009 ;1(4):377-387, Statistics in biopharmaceutical research
— id: 114581, year: 2009, vol: 1, page: 377, stat: Journal Article,

Immunization of Malignant Melanoma Patients with Full-Length NY-ESO-1 Protein Using TLR7 Agonist Imiquimod as Vaccine Adjuvant
Adams, Sylvia; O'Neill, David W; Nonaka, Daisuke; Hardin, Elizabeth; Chiriboga, Luis; Siu, Kimberly; Cruz, Crystal M; Angiulli, Angelica; Angiulli, Francesca; Ritter, Erika; Holman, Rose Marie; Shapiro, Richard L; Berman, Russell S; Berner, Natalie; Shao, Yongzhao; Manches, Olivier; Pan, Linda; Venhaus, Ralph R; Hoffman, Eric W; Jungbluth, Achim; Gnjatic, Sacha; Old, Lloyd; Pavlick, Anna C; Bhardwaj, Nina
2008 Jul 1;181(1):776-784, Journal of immunology
T cell-mediated immunity to microbes and to cancer can be enhanced by the activation of dendritic cells (DCs) via TLRs. In this study, we evaluated the safety and feasibility of topical imiquimod, a TLR7 agonist, in a series of vaccinations against the cancer/testis Ag NY-ESO-1 in patients with malignant melanoma. Recombinant, full-length NY-ESO-1 protein was administered intradermally into imiquimod preconditioned sites followed by additional topical applications of imiquimod. The regimen was very well tolerated with only mild and transient local reactions and constitutional symptoms. Secondarily, we examined the systemic immune response induced by the imiquimod/NY-ESO-1 combination, and show that it elicited both humoral and cellular responses in a significant fraction of patients. Skin biopsies were assessed for imiquimod's in situ immunomodulatory effects. Compared with untreated skin, topical imiquimod induced dermal mononuclear cell infiltrates in all patients composed primarily of T cells, monocytes, macrophages, myeloid DCs, NK cells, and, to a lesser extent, plasmacytoid DCs. DC activation was evident. This study demonstrates the feasibility and excellent safety profile of a topically applied TLR7 agonist used as a vaccine adjuvant in cancer patients. Imiquimod's adjuvant effects require further evaluation and likely need optimization of parameters such as formulation, dose, and timing relative to Ag exposure for maximal immunogenicity
— id: 79260, year: 2008, vol: 181, page: 776, stat: Journal Article,

Systematic missing-at-random (SMAR) design and analysis for translational research studies
Belitskaya-Levy, Ilana; Shao, Yongzhao; Goldberg, Judith D
2008 ;4(1):1- 26, International Journal of Biostatistics
Translational research studies often involve a central study (e.g. clinical trial, cohort of patients, etc.) and multiple investigators who are each interested in addressing different research questions using the same patient population. However, it is often impossible for the investigators to include all patients in all of the ancillary translational research substudies that are part of the main study. This arises due to time and budgetary constraints and other logistical considerations. In this paper, we propose a prospective Systematic Missing-At-Random study design (SMAR) with planned partially missing covariates collected using a nested random sampling scheme that allows an integrated statistical analysis across all domains of data. We propose an algorithm for data analysis that incorporates the features of the design. We show that the SMAR design is computationally and statistically efficient as well as cost effective using simulation studies and a published data example. An extension to a two-stage prospective-retrospective design is discussed.
— id: 136935, year: 2008, vol: 4, page: 1, stat: Journal Article,

A Monte Carlo approach for change-point detection in the Cox proportional hazards model
Liu, Mengling; Lu, Wenbin; Shao, Yongzhao
2008 Aug 30;27(19):3894-3909, Statistics in medicine
Detecting a time lag of treatment effect or identifying change points in a hazard function is of great interest and importance in survival analysis. The testing procedures hereto are primarily based on analytical approximations for the asymptotic null distribution of either the likelihood ratio test or the score test. In the presence of random censoring and/or covariates, however, the justification for the limiting distribution often requires some technical assumptions and conditions that are difficult to verify in practice. Moreover, a satisfactory asymptotic theory for testing the existence of multiple change points in hazard function has not emerged. In this paper, we consider maximal score tests for detecting change point(s) in the Cox proportional hazards model with censored data. We propose to use a simple Monte Carlo approach for assessing the statistical significance of tests. The proposed approach is applicable for testing a single change point in the Cox model with covariates and sample stratifications over various types of candidate regions, including discrete time-point sets or disjoint intervals. We also show that the proposed test statistics and the Monte Carlo procedure are well applicable under situations with multiple change points. Simulation studies and an analysis of a real data from a randomized cancer trial are conducted to demonstrate the finite-sample performance of the proposed approach
— id: 108164, year: 2008, vol: 27, page: 3894, stat: Journal Article,

Antiangiogenic effects of noscapine enhance radioresponse for GL261 tumors
Newcomb, Elizabeth W; Lukyanov, Yevgeniy; Alonso-Basanta, Michelle; Esencay, Mine; Smirnova, Iva; Schnee, Tona; Shao, Yongzhao; Devitt, Mary Louise; Zagzag, David; McBride, William; Formenti, Silvia C
2008 Aug 1;71(5):1477-1484, International journal of radiation oncology biology physics
PURPOSE: To assess the effects of noscapine, a tubulin-binding drug, in combination with radiation in a murine glioma model. METHODS AND MATERIALS: The human T98G and murine GL261 glioma cell lines treated with noscapine, radiation, or both were assayed for clonogenic survival. Mice with established GL261 hind limb tumors were treated with noscapine, radiation, or both to evaluate the effect of noscapine on radioresponse. In a separate experiment with the same treatment groups, 7 days after radiation, tumors were resected and immunostained to measure proliferation rate, apoptosis, and angiogenic activity. RESULTS: Noscapine reduced clonogenic survival without enhancement of radiosensitivity in vitro. Noscapine combined with radiation significantly increased tumor growth delay: 5, 8, 13, and 18 days for control, noscapine alone, radiation alone, and the combination treatment, respectively (p < 0.001). To assess the effect of the combination of noscapine plus radiation on the tumor vasculature, tubule formation by the murine endothelial 2H11 cells was tested. Noscapine with radiation significantly inhibited tubule formation compared with radiation alone. By immunohistochemistry, tumors treated with the combination of noscapine plus radiation showed a decrease in BrdU incorporation, an increase in apoptosis by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling, and a decrease in tumor vessel density compared with tumors treated with radiation alone. CONCLUSION: Noscapine enhanced the sensitivity of GL261 glioma tumors to radiation, resulting in a significant tumor growth delay. An antiangiogenic mechanism contributed to the effect. These findings are clinically relevant, particularly in view of the mild toxicity profile of this drug
— id: 82921, year: 2008, vol: 71, page: 1477, stat: Journal Article,

Linkage analysis
Shao, Yongzhao
Encyclopedia of quantitative risk analysis and assessment Hoboken, N.J. : John Wiley, 2008,
Linkage analysis is an important initial step in localizing and identifying genes in the chromosomes that underlie many human diseases and other traits of interest. Frequently, linkage analysis proceeds by comparing the inheritance pattern of the trait and that of the genetic markers to establish linkage between the trait and marker loci. This article provides a brief overview of commonly used methods for linkage analysis, which include model-free and model-based methods for mapping qualitative- and quantitative-trait loci. Issues on the design of linkage studies are also briefly discussed
— id: 5452, year: 2008, vol: , page: ?, stat: Chapter,

A hybrid Bayesian-frequentist approach to evaluate clinical trial designs for tests of superiority and non-inferiority
Shao, Yongzhao; Mukhi, Vandana; Goldberg, Judith D
2008 Feb 20;27(4):504-519, Statistics in medicine
Specification of the study objective of superiority or non-inferiority at the design stage of a phase III clinical trial can sometimes be very difficult due to the uncertainty that surrounds the efficacy level of the experimental treatment. This uncertainty makes it tempting for investigators to design a trial that would allow testing of both superiority and non-inferiority hypotheses. However, when a conventional single-stage design is used to test both hypotheses, the sample size is based on the chosen primary objective of either superiority or non-inferiority. In this situation, the power of the test for the secondary objective can be low, which may lead to a large loss of resources. Potentially low reproducibility is another major concern for the single-stage design in phase III trials, because significant findings of confirmatory trials are required to be reproducible. In this paper, we propose a hybrid Bayesian-frequentist approach to evaluate reproducibility and power in single-stage designs for phase III trials to test both superiority and non-inferiority. The essence of the proposed approach is to express the uncertainty that surrounds the efficacy of the experimental treatment as a probability distribution. Then one can use Bayes formula with simple graphical techniques to evaluate reproducibility and power adequacy
— id: 79289, year: 2008, vol: 27, page: 504, stat: Journal Article,

Imiquimod -- a TLR 7 agonist as vaccine adjuvant
Adams S; O'Neill D; Pavlick A; Hardin E; Nonaka D; Chiriboga L; Siu K; Shapiro R; Berman R; Strober B; Cruz C; Angiulli A; Manchez O; Berner N; Mukhi V; Shao Y; Bhardwaj N
2007 ;:- #8545, Proceedings (American Society of Clinical Oncology)
— id: 73377, year: 2007, vol: , page: , stat: Journal Article,

Asymptotic distribution for symmetric spacing statistics
Jimenez, Raul; Shao, Yongzhao
2007 ;36:37-46, Communications in statistics: theory & methods
— id: 71649, year: 2007, vol: 36, page: 37, stat: Journal Article,

Noscapine enhances tumor radioresponse in the GL261 glioma model: Implications for glioma therapy
Lukyanov, Y; Newcomb, EW; Aionso-Basanta, M; Schnee, T; Shao, Y; McBride, WH; Formenti, SC
2007 JAN ;69(3):S591-S592, International journal of radiation oncology biology physics
— id: 87196, year: 2007, vol: 69, page: S591, stat: Journal Article,

The geldanamycin analogue 17-allylamino-17-demethoxygeldanamycin inhibits the growth of GL261 glioma cells in vitro and in vivo
Newcomb, Elizabeth W; Lukyanov, Yevgeniy; Schnee, Tona; Esencay, Mine; Fischer, Ingeborg; Hong, David; Shao, Yongzhao; Zagzag, David
2007 Sep;18(8):875-882, Anti-cancer drugs
Geldanamycin is a naturally occurring benzoquinone ansamycin product of Streptomyces geldanus that binds the protein chaperone heat shock protein 90. As geldanamycin binds to heat shock protein 90 interfering with its function and heat shock protein 90 is overexpressed in many cancers, heat shock protein 90 has become a target for cancer therapy. As the geldanamycin analogue 17-allylamino-17-demethoxygeldanamycin has a favorable toxicity profile, it is being tested extensively in clinical trials in patients with advanced cancer. In this study, GL261 glioma cells from C57BL/6 mice were used to investigate the anti-tumor effect of 17-allylamino-17-demethoxygeldanamycin both in vitro and in vivo. Heat shock protein 90 inhibitors possess potent anti-proliferative activity, usually at low nanomolar ranges, owing to their pharmacological characteristics of binding tightly to heat shock protein 90, coupled with a slow dissociation rate. We found that 17-allylamino-17-demethoxygeldanamycin at doses as low as 200 nmol/l showed anti-tumor activity within 24 h of treatment. Treatment with 17-allylamino-17-demethoxygeldanamycin arrested GL261 cells in the G2 phase of the cell cycle associated with the downregulation of cyclin B1. Low doses of 17-allylamino-17-demethoxygeldanamycin significantly inhibited migration of GL261 cells within 16 h of treatment, concomitant with the downregulation of phosphorylated focal adhesion kinase and matrix metalloproteinase 2 secretion. Using an orthotopic glioma model with well-established intracranial tumors, 3 weekly cycles of 17-allylamino-17-demethoxygeldanamycin significantly reduced tumor volumes of treated animals compared with untreated controls (P=0.002). Given these promising results, clinical testing of 17-allylamino-17-demethoxygeldanamycin or other novel heat shock protein 90 inhibitors being developed should be considered for glioma patients whose tumors remain refractory to most current treatment regimens
— id: 73901, year: 2007, vol: 18, page: 875, stat: Journal Article,

Sample size calculation with dependence adjustment for FDR-control in microarray studies
Shao, Yongzhao; Tseng, Chi-Hong
2007 Oct 15;26(23):4219-4237, Statistics in medicine
DNA microarrays have been widely used for the purpose of simultaneously monitoring a large number of gene expression levels to identify differentially expressed genes. Statistical methods for the adjustment of multiple testing have been discussed extensively in the literature. An important further challenge is the existence of dependence among test statistics due to reasons such as gene co-regulation. To plan large-scale genomic studies, sample size determination with appropriate adjustment for both multiple testing and potential dependency among test statistics is crucial to avoid an abundance of false-positive results and/or serious lack of power. We introduce a general approach for calculating sample sizes for two-way multiple comparisons in the presence of dependence among test statistics to ensure adequate overall power when the false discovery rates are controlled. The usefulness of the proposed method is demonstrated via numerical studies using both simulated data and real data from a well-known study of leukaemia.
— id: 71633, year: 2007, vol: 26, page: 4219, stat: Journal Article,

Interval mapping of quantitative trait loci for time-to-event data with the proportional hazards mixture cure model
Liu, Mengling; Lu, Wenbin; Shao, Yongzhao
2006 Dec;62(4):1053-1061, Biometrics
Interval mapping using normal mixture models has been an important tool for analyzing quantitative traits in experimental organisms. When the primary phenotype is time-to-event, it is natural to use survival models such as Cox's proportional hazards model instead of normal mixtures to model the phenotype distribution. An extra challenge for modeling time-to-event data is that the underlying population may consist of susceptible and nonsusceptible subjects. In this article, we propose a semiparametric proportional hazards mixture cure model which allows missing covariates. We discuss applications to quantitative trait loci (QTL) mapping when the primary trait is time-to-event from a population of mixed susceptibility. This model can be used to characterize QTL effects on both susceptibility and time-to-event distribution, and to estimate QTL location. The model can naturally incorporate covariate effects of other risk factors. Maximum likelihood estimates for the parameters in the model as well as their corresponding variance estimates can be obtained numerically using an EM-type algorithm. The proposed methods are assessed by simulations under practical settings and illustrated using a real data set containing survival times of mice after infection with Listeria monocytogenes. An extension to multiple intervals is also discussed
— id: 72131, year: 2006, vol: 62, page: 1053, stat: Journal Article,

Mixture cure model with an application to interval mapping of quantitative trait loci
Liu, Mengling; Lu, Wenbin; Shao, Yongzhao
2006 Dec;12(4):421-440, Lifetime data analysis
When censored time-to-event data are used to map quantitative trait loci (QTL), the existence of nonsusceptible subjects entails extra challenges. If the heterogeneous susceptibility is ignored or inappropriately handled, we may either fail to detect the responsible genetic factors or find spuriously significant locations. In this article, an interval mapping method based on parametric mixture cure models is proposed, which takes into consideration of nonsusceptible subjects. The proposed model can be used to detect the QTL that are responsible for differential susceptibility and/or time-to-event trait distribution. In particular, we propose a likelihood-based testing procedure with genome-wide significance levels calculated using a resampling method. The performance of the proposed method and the importance of considering the heterogeneous susceptibility are demonstrated by simulation studies and an application to survival data from an experiment on mice infected with Listeria monocytogenes
— id: 69432, year: 2006, vol: 12, page: 421, stat: Journal Article,

False discovery rate for statistical designs to test both superiority and non-inferiority in controlled
Mukhi, Vandana; Goldberg, Judith; Shao, Yongzhao
2006 ;:4289-4296, Proceedings (American Statistical Association)
— id: 71028, year: 2006, vol: , page: 4289, stat: Journal Article,

The combination of ionizing radiation and peripheral vaccination produces long-term survival of mice bearing established invasive GL261 gliomas
Newcomb, Elizabeth W; Demaria, Sandra; Lukyanov, Yevgeniy; Shao, Yongzhao; Schnee, Tona; Kawashima, Noriko; Lan, Li; Dewyngaert, J Keith; Zagzag, David; McBride, William H; Formenti, Silvia C
2006 Aug 1;12(15):4730-4737, Clinical cancer research
PURPOSE: High-grade glioma treatment includes ionizing radiation therapy. The high invasiveness of glioma cells precludes their eradication and is responsible for the dismal prognosis. Recently, we reported the down-regulation of MHC class I (MHC-I) products in invading tumor cells in human and mouse GL261 gliomas. Here, we tested the hypothesis that whole-brain radiotherapy (WBRT) up-regulates MHC-I expression on GL261 tumors and enhances the effectiveness of immunotherapy. EXPERIMENTAL DESIGN: MHC-I molecule expression on GL261 cells was analyzed in vitro and in vivo by flow cytometry and immunohistochemistry, respectively. To test the response of established GL261 gliomas to treatment, mice with measurable (at CT imaging) brain tumors were randomly assigned to four groups receiving (a) no treatment, (b) WBRT in two fractions of 4 Gy, (c) vaccination with irradiated GL261 cells secreting granulocyte-macrophage colony-stimulating factor, or (d) WBRT and vaccination. Endpoints were tumor response and survival. RESULTS: An ionizing radiation dose of 4 Gy maximally up-regulated MHC-I molecules on GL261 cells in vitro. In vivo, WBRT induced the expression of the beta2-microglobulin light chain subunit of the MHC class I complex on glioma cells invading normal brain and increased CD4+ and CD8+ T cell infiltration. However, the survival advantage obtained with WBRT or vaccination alone was minimal. In contrast, WBRT in combination with vaccination increased long-term survival to 40% to 80%, compared with 0% to 10% in the other groups (P < 0.002). Surviving animals showed antitumor immunity by rejecting challenge tumors. CONCLUSION: Ionizing radiation can be successfully combined with peripheral vaccination for the treatment of established high-grade gliomas
— id: 67436, year: 2006, vol: 12, page: 4730, stat: Journal Article,

Radiation Sensitivity of GL261 Murine Glioma Model and Enhanced Radiation Response by Flavopiridol
Newcomb, Elizabeth W; Lymberis, Stella C; Lukyanov, Yevgeniy; Shao, Yongzhao; Schnee, Tona; Devitt, Marylou; Rosenstein, Barry S; Zagzag, David; Formenti, Silvia C
2006 Jan;5(1):93-99, Cell cycle
Response of a solid tumor to radiation treatment depends, in part, on the intrinsic radiosensitivity of tumor cells, the proliferation rate of tumor cells between radiation treatments and the hypoxic state of the tumor cells. A successful radiosensitizing agent would target S-phase cells and hypoxia. Recently, we demonstrated the anti-tumor effects of flavopiridol in the GL261 murine glioma model might involve 1) recruitment of tumor cells to S-phase (Newcomb et al Cell Cycle 2004; 3:230-234) and 2) an anti-angiogenic effect on the tumor vasculature by downregulation of hypoxia-inducible factor -1alpha (HIF-1alpha) (Newcomb et al Neuro-Oncology 2005; 7:225-235). Given that flavopiridol has demonstrated radiosensitizing activity in several murine tumor models, we tested whether it would enhance the response of GL261 tumors to radiation. In the present study, we evaluated the intrinsic radiation sensitivity of the GL261 glioma model using the tumor control/cure dose of radiation assay (TCD(50)). We found that a single dose of 65 Gy (CI 57.1-73.1) was required to cure 50% of the tumors locally. Using the tumor growth delay assay, fractionated radiation (5 fractions of 5 Gy over 10 days) combined with flavopiridol (5 mg/kg) given three times weekly for 3 cycles produced a significant growth delay. Our results indicate that the GL261 murine glioma model mimics the radioresistance encountered in human gliomas, and thus should prove useful in identifying promising new investigational radiosensitizers for use in the treatment of glioma patients
— id: 62423, year: 2006, vol: 5, page: 93, stat: Journal Article,

Growth rate of sample size for an increasing number of multiple comparisons
Shao, Yongzhao; Tseng, Chi-Hong
2006 ;:359-364, Proceedings (American Statistical Association)
— id: 71027, year: 2006, vol: , page: 359, stat: Journal Article,

Simultaneous DNA content/cytoplasmic immunoglobulin analysis is a sensitive flow cytometric method for the diagnosis of plasma cell myeloma
Islam, H; Lee, M; Shao, Y; Lin, K; Alexa, L; Jagannath, S; Mazumder, A; Inghirami, G; Sen, F
2005 ;85(Suppl 1):235A-235A, Laboratory investigation
— id: 50469, year: 2005, vol: 85, page: 235A, stat: Journal Article,

Simultaneous DNA content/cytoplasmic immunoglobulin analysis is a sensitive flow cytometric method for the diagnosis of plasma cell myeloma
Islam, H; Lee, M; Shao, Y; Lin, K; Alexa, L; Jagannath, S; Mazumder, A; Inghirami, G; Sen, F
2005 ;18(Suppl 1):235A-235A, Modern pathology
— id: 50439, year: 2005, vol: 18, page: 235A, stat: Journal Article,

Possible association of p53 codon 72 polymorphism with susceptibility to adult and pediatric high-grade astrocytomas
Parhar, Preeti; Ezer, Rona; Shao, Yongzhao; Allen, Jeffrey C; Miller, Douglas C; Newcomb, Elizabeth W
2005 Jun 13;137(1-2):98-103, Brain research. Molecular brain research
Polymorphisms in codon 72 of the p53 tumor suppressor gene have been associated with susceptibility to human cancer. We wished to evaluate whether variant allelic forms of the p53 protein were associated with brain tumors. In this study, we scored 135 brain tumor samples (92 adult and 43 pediatric cases consisting of 64 high-grade astrocytomas and 71 non-astrocytomas) for the P53 Arg72Pro polymorphisms. Our data show that the genotype frequencies of P53 Arg72Pro vary not only between patients with brain tumors and controls, but also between different histological subtypes of brain tumors. Specifically, we found (i) that the genotype distributions of the P53 Arg72Pro between all brain tumors and controls were statistically significant (P < 0.001) as well as their variant allele frequencies between cases and controls (P < 0.001); (ii) that there was a significant increase in the Arg/Pro heterozygous genotype among high-grade astrocytomas compared with non-astrocytomas (P = 0.002); and (iii) that there was a significant increase in the Arg/Pro heterozygous genotype among high-grade astrocytomas containing transdominant as well as recessive p53 mutations compared with controls (P = 0.002). Our results suggest a possible association between P53 Arg72Pro polymorphisms and susceptibility to brain tumors, particularly high-grade astrocytomas
— id: 55956, year: 2005, vol: 137, page: 98, stat: Journal Article,

Adjustment for transmission heterogeneity in mapping complex genetic diseases using mixture models and score tests
Shao, Yongzhao
2005 ;:383-393, Proceedings (American Statistical Association)
— id: 69434, year: 2005, vol: , page: 383, stat: Journal Article,

Asymptotics for the likelihood ratio test in a two-component normal mixture model
Liu, X; Shao, YZ
2004 JUN 1 ;123(1):61-81, Journal of statistical planning & inference
This paper characterizes the asymptotic properties of the likelihood ratio test (LRT) statistic for testing homogeneity in a two-component normal mean mixture model. We justify that the LRT statistic 2lambda(n) is asymptotically equivalent to the square of the supremum of the stochastic process Studied in Bickel and Chernoff (Statistics and Probability: A Raghu Raj Bahadur Festschrift (1993) 83). In particular, we prove that 2lambda(n) diverges to +infinity at a rate of log log n which confirms a conjecture of Hartigan (Proceedings of Berkeley Conference in Honor of Jerzy Neyman and Jack Kiefer (1985)). More specifically, under the null hypothesis we prove the following fact: lim(n-->infinity) P{2lambda(n) - log logn + log(2pi(2)) less than or equal to x} = exp(-c(-x/2)), x is an element of R (C) 2003 Elsevier B.V. All rights reserved
— id: 46657, year: 2004, vol: 123, page: 61, stat: Journal Article,

Testing homogeneity in gamma mixture models
Liu X; Parsarica C; Shao Y
2003 ;30:227-239, Scandinavian journal of statistics, theory & applications
— id: 43257, year: 2003, vol: 30, page: 227, stat: Journal Article,

Asymptotics for likelihood ratio tests under loss of indentifiability
Liu X; Shao Y
2003 ;31:807-832, Annals of statistics
— id: 43258, year: 2003, vol: 31, page: 807, stat: Journal Article,

A marginal likelihood model for family-based data
Lo, Shaw-Hwa; Liu, Xin; Shao, Yongzhao
2003 Jul;67(Pt 4):357-366, Annals of human genetics
This paper presents a marginal likelihood model for family-based data based upon the transmission of marker alleles from each heterozygous parent to his/her affected children. The proposed model, extending the maximum-likelihood-binomial (MLB) method and the disequilibrium maximum-likelihood-binomial (DMLB) method (Abel et al. 1998; Abel & Muller-Myhsok, 1998; Huang & Jiang, 1999), is adaptive to linkage disequilibrium (LD) and linkage heterogeneity. Compared with other procedures, the likelihood ratio test (LRT) derived from the proposed model enjoys superior qualities. First, simulations indicate that the power of the LRT is greater than that of the TDT or DMLB in all of our studied scenarios. Second, when we applied the LRT and other tests to a Tourette Syndrome data, the result was data favorable to the use of the LRT. Therefore, we recommend the use of the LRT as an additional linkage test wherever applicable, especially when the amount of LD is uncertain
— id: 43218, year: 2003, vol: 67, page: 357, stat: Journal Article,

On robustness and efficiency of power divergence statistics
Jimenez R; Shao Y
2001 ;10(2):241-248, Test (Sociedad Espanola de Estadistica y de Investigacion Operativa)
— id: 62470, year: 2001, vol: 10, page: 241, stat: Journal Article,

Consistency of the maximum product of spacings methods and estimation of a unimodal distribution
Shao Y
2001 ;11:1125-1140, Statistica Sinica
— id: 62426, year: 2001, vol: 11, page: 1125, stat: Journal Article,

Rate of convergence for bootstrapped empirical measures
Shao Y
2001 ;53:293-298, Statistics & probability letters
— id: 62466, year: 2001, vol: 53, page: 293, stat: Journal Article,

On kernel estimation of a multiveriate distribution function
Jin Z; Shao Y
1999 ;41:163-168, Statistics & probability letters
— id: 62467, year: 1999, vol: 41, page: 163, stat: Journal Article,

Maximum product of spacings method: a unified definition with illustration for strong consistency
Shao Y; Hahn MG
1999 ;43:489-499, Illinois journal of mathematics
— id: 62469, year: 1999, vol: 43, page: 489, stat: Journal Article,

Strong consistency of the maximum product of spacings estimates with applications to nonparametrics
Shao Y; Hahn MG
1999 ;51:31-49, Annals of the Institute of Statistical Mathematics
— id: 62468, year: 1999, vol: 51, page: 31, stat: Journal Article,

Entropy of random partitions and its applications
Shao Y; Jimenez R
1998 ;11:417-433, Journal of theoretical probability
— id: 62427, year: 1998, vol: 11, page: 417, stat: Journal Article,

Some extensions of the kernel estimator of a distribution function
Shao Y; Xiang X
1997 ;34:301-308, Statistics & probability letters
— id: 62425, year: 1997, vol: 34, page: 301, stat: Journal Article,

On a distribution-free test of fit for continuous distribution functions
Shao Y; Hahn MG
1996 ;23:63-73, Scandinavian journal of statistics, theory & applications
— id: 62428, year: 1996, vol: 23, page: 63, stat: Journal Article,

Limit theorems for the logrithms of sample spacings
Shao Y; Hahn MG
1995 ;24:121-132, Statistics & probability letters
— id: 62424, year: 1995, vol: 24, page: 121, stat: Journal Article,

Maximum spacing estimates: a generalization and improvement on maximum likelihood estimates
Shao Y; Hahn MG
1994 ;35:417-431, Progress in Probabilty
— id: 63595, year: 1994, vol: 35, page: 417, stat: Journal Article,

Preclinical evaluation of intravenously administered 111In- and 90Y-labeled B72.3 immunoconjugate (GYK-DTPA) in beagle dogs
Quadri SM; Shao Y; Blum JE; Leichner PK; Williams JR; Vriesendorp HM
1993 Jul;20(5):559-570, Nuclear medicine & biology
B72.3, a monoclonal antibody with reactivity against human adenocarcinomas was obtained from the Cytogen Corporation in the form of an immunoconjugate coupled with linker-chelator GYK-DTPA by using proprietary carbohydrate directed site specific chemistry. The immunoconjugate was radiolabeled with indium-111 or yttrium-90. A preclinical analysis was performed in 10 normal beagle dogs. The pharmacokinetics of intravenously administered indium- and yttrium-labeled immunoconjugates were compared serially in blood, bone marrow and urine samples. Compared to 90Y less of the 111In label ended up in urine and more was found in blood and bone marrow. Indium-labeled B72.3 GYK-DTPA had relatively higher uptake in most glandular tissues than 111In-labeled antiferritin immunoconjugate. Bone marrow toxicity was the dose limiting side effect after intravenous infusion of 90Y-labeled B72.3 GYK-DTPA. Toxicity was also observed in the liver but not in other organ systems. Recently other investigators obtained similar results with these immunoconjugates in human patients. A preclinical pharmacokinetic analysis of radioimmunoconjugates in beagle dogs provided useful information regarding bone marrow toxicity, liver toxicity and in vivo instability of the immunoconjugate. Data suggest that for future trials in human patients, a more stable chelated immunoconjugate for yttrium is needed to achieve less liver uptake and a better correlation with the 111In-labeled product than the 90Y-labeled B72.3 GYK-DTPA used in this investigation
— id: 43065, year: 1993, vol: 20, page: 559, stat: Journal Article,

Fractionated intravenous administration of 90Y-labeled B72.3 GYK-DTPA immunoconjugate in beagle dogs
Vriesendorp HM; Shao Y; Blum JE; Quadri SM; Williams JR
1993 Jul;20(5):571-578, Nuclear medicine & biology
B72.3, a monoclonal antibody with reactivity against human adenocarcinomas, was coupled with linker-chelator GYK-DTPA using carbohydrate mediated conjugation chemistry and radiolabeled with yttrium-90. Single and double intravenous injections of radioimmunoconjugate were compared for acute and late normal tissue toxicity in 15 beagle dogs. The second injection was given 4 or 8 days after the first. Pharmacokinetics of the radioimmunoconjugate in blood, bone marrow and urine were similar for first and second injections. Only bone marrow (acute) and liver (late) toxicity were observed. Both liver and bone marrow toxicity were decreased by fractionation of the injections. After double injections, the total equitoxic dose was 15 and 60% higher for bone marrow and liver toxicity, respectively. The mechanisms of normal tissue protection offered by fractionated radioimmunoglobulin therapy (RIT) remain to be defined. Fractionated RIT will have a better therapeutic ratio than single injection RIT, if antitumor effects appear to be less susceptible to fractionation than normal tissues
— id: 43064, year: 1993, vol: 20, page: 571, stat: Journal Article,

An exposition of Talagrand's matching thorems
Hahn MG; Shao Y
1992 ;30:3-38, Progress in Probabilty
— id: 63594, year: 1992, vol: 30, page: 3, stat: Journal Article,