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Supplementary Methods 2 from Systematic CpG Islands Methylation Profiling of Genes in the Wnt Pathway in Epithelial Ovarian Cancer Identifies Biomarkers of Progression-Free Survival

Supplementary Methods 6 from Systematic CpG Islands Methylation Profiling of Genes in the Wnt Pathway in Epithelial Ovarian Cancer Identifies Biomarkers of Progression-Free Survival

Supplementary Methods 3 from Systematic CpG Islands Methylation Profiling of Genes in the Wnt Pathway in Epithelial Ovarian Cancer Identifies Biomarkers of Progression-Free Survival

Supplementary Tables 1-4, Figures 1-3 from Systematic CpG Islands Methylation Profiling of Genes in the Wnt Pathway in Epithelial Ovarian Cancer Identifies Biomarkers of Progression-Free Survival

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Purpose: The combination of a platinum and taxane are standard of care for many cancers, but the utility is often limited due to debilitating neurotoxicity. We examined whether single-nucleotide polymorphisms (SNP) from annotated candidate genes will identify genetic risk for chemotherapy-induced neurotoxicity.Patients and Methods: A candidate–gene association study was conducted to validate the relevance of 1,261 SNPs within 60 candidate genes in 404 ovarian cancer patients receiving platinum/taxane chemotherapy on the SCOTROC1 trial. Statistically significant variants were then assessed for replication in a separate 404 patient replication cohort from SCOTROC1.Results: Significant associations with chemotherapy-induced neurotoxicity were identified and replicated for four SNPs in SOX10, BCL2, OPRM1, and TRPV1. The population attributable risk for each of the four SNPs ranged from 5% to 35%, with a cumulative risk of 62%. According to the multiplicative model, the odds of developing neurotoxicity increase by a factor of 1.64 for every risk genotype. Patients possessing three risk variants have an estimated OR of 4.49 (2.36–8.54) compared to individuals with 0 risk variants. Neither the four SNPs nor the risk score were associated with progression-free survival or overall survival.Conclusions: This study shows that SNPs in four genes have a significant cumulative association with increased risk for the development of chemotherapy-induced neurotoxicity, independent of patient survival. Clin Cancer Res; 19(20); 5769–76. ©2013 AACR.

Purpose: Cell-based approaches were used to identify genetic markers predictive of patients' risk for poor response prior to chemotherapy.Experimental Design: We conducted genome-wide association studies (GWAS) to identify single-nucleotide polymorphisms (SNP) associated with cellular sensitivity to carboplatin through their effects on mRNA expression using International HapMap lymphoblastoid cell lines (LCL) and replicated them in additional LCLs. SNPs passing both stages of the cell-based study were tested for association with progression-free survival (PFS) in patients. Phase 1 validation was based on 377 ovarian cancer patients receiving at least four cycles of carboplatin and paclitaxel from the Australian Ovarian Cancer Study (AOCS). Positive associations were then assessed in phase 2 validation analysis of 1,326 patients from the Ovarian Cancer Association Consortium and The Cancer Genome Atlas.Results: In the initial GWAS, 342 SNPs were associated with carboplatin-induced cytotoxicity, of which 18 unique SNPs were retained after assessing their association with gene expression. One SNP (rs1649942) was replicated in an independent LCL set (Bonferroni adjusted P < 0.05). It was found to be significantly associated with decreased PFS in phase 1 AOCS patients (Pper-allele = 2 × 10−2), with a stronger effect in the subset of women with optimally debulked tumors (Pper-allele = 4 × 10−3). rs1649942 was also associated with poorer overall survival in women with optimally debulked tumors (Pper-allele = 9 × 10−3). However, this SNP was not significant in phase 2 validation analysis with patients from numerous cohorts.Conclusion: This study shows the potential of cell-based, genome-wide approaches to identify germline predictors of treatment outcome and highlights the need for extensive validation in patients to assess their clinical effect. Clin Cancer Res; 17(16); 5490–500. ©2011 AACR.

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PDF file, 75K, Full clinical characteristics of patients from the discovery and replication cohorts.

PDF file, 54K, 60 candidate genes (nerve-related genes, inherited peripheral neuropathy genes, and drug-related genes).

Supplementary Methods 5 from Systematic CpG Islands Methylation Profiling of Genes in the Wnt Pathway in Epithelial Ovarian Cancer Identifies Biomarkers of Progression-Free Survival

PDF file, 69K, 1536 candidate SNPs, chosen based on LD, putative function, and prior literature evidence.

PDF file, 190K, Results of the 69 significant SNPs in the discovery cohort, for both the discovery and replication set. Covariates ECOG performance status, treatment status, time to first toxicity, and grade of GI toxicity.

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Purpose: Wnt pathways control key biological processes that potentially impact on tumor progression and patient survival. We aimed to evaluate DNA methylation at promoter CpG islands (CGI) of Wnt pathway genes in ovarian tumors at presentation and identify biomarkers of patient progression-free survival (PFS).Experimental Design: Epithelial ovarian tumors (screening study n = 120, validation study n = 61), prospectively collected through a cohort study, were analyzed by differential methylation hybridization at 302 loci spanning 189 promoter CGIs at 137 genes in Wnt pathways. The association of methylation and PFS was examined by Cox proportional hazards model.Results: DNA methylation is associated with PFS at 20 of 302 loci (P < 0.05, n = 111), with 5 loci significant at false discovery rate (FDR) less than 10%. A total of 11 of 20 loci retain significance in an independent validation cohort (n = 48, P ≤ 0.05, FDR ≤ 10%), and 7 of these loci, at FZD4, DVL1, NFATC3, ROCK1, LRP5, AXIN1, and NKD1 genes, are independent from clinical parameters (adjusted P < 0.05). Increased methylation at these loci associates with increased hazard of disease progression. A multivariate Cox model incorporates only NKD1 and DVL1, identifying two groups differing in PFS [HR = 2.09; 95% CI (1.39–3.15); permutation test P < 0.005]. Methylation at DVL1 and NFATC3 show significant association with response. Consistent with their epigenetic regulation, reduced expression of FZD4, DVL1, and ROCK1 is an indicator of early-disease relapse in an independent ovarian tumor cohort (n = 311, adjusted P < 0.05).Conclusion: The data highlight the importance of epigenetic regulation of multiple promoter CGIs of Wnt pathway genes in ovarian cancer and identify methylation at NKD1 and DVL1 as independent predictors of PFS. Clin Cancer Res; 17(12); 4052–62. ©2011 AACR.

Supplementary Methods 1 from Systematic CpG Islands Methylation Profiling of Genes in the Wnt Pathway in Epithelial Ovarian Cancer Identifies Biomarkers of Progression-Free Survival

To determine the cost-effectiveness of salvage cryotherapy (SC) in men with radiation recurrent prostate cancer (RRPC).Cost-utility analysis using decision analytic modelling by a Markov model.Compared SC and androgen deprivation therapy (ADT) in a cohort of patients with RRPC (biopsy proven local recurrence, no evidence of metastatic disease). A literature review captured published data to inform the decision model, and resource use data were from the Scottish Prostate Cryotherapy Service. The model was run in monthly cycles for RRPC men, mean age of 70 years. The model was run over the patient lifetime, to assess changes in patient health states and the associated quality of life, survival and cost impacts. Results are reported in terms of the discounted incremental costs and discounted incremental quality-adjusted life years (QALYs) gained between the 2 alternative interventions. Probabilistic sensitivity analysis used a 10,000 iteration Monte Carlo simulation.SC has a high upfront treatment cost, but delays the ongoing monthly cost of ADT. SC is the dominant strategy over the patient lifetime; it is more effective with an incremental 0.56 QALY gain (95% CI 0.28 to 0.87), and less costly with a reduced lifetime cost of £29,719 (€37,619) (95% CI -51,985 to -9243). For a ceiling ratio of £30,000, SC has a 100% probability to be cost-effective. The cost neutral point was at 3.5 years, when the upfront cost of SC (plus any subsequent cumulative cost of side effects and ADT) equates the cumulative cost in the ADT arm. Limitations of our model may arise from its insensitivity to parameter or structural uncertainty.The platform for SC versus ADT cost-effective analysis can be employed to evaluate other treatment modalities or strategies in RRPC. SC is the dominant strategy, costing less over a patient's lifetime with improvements in QALYs.This economic analysis was undertaken as part of the CROP RCT study72677390; it was a pre-trial economic model developed and analysed during the pre-results stage of the RCT.

This article reports a cross-cultural study of Mexican and U.S. leaders in Mexican maquiladoras. The research builds on relational demography to determine if leader ethnicity, regional Mexican culture, and organizational affiliation moderate the impact of leadership behavior on important organizational outcomes. We examined the impacts of specific leader behaviors on follower attitudes and performance. Contrary to expectations from the current cross-cultural leadership literature, managerial leaders from the United States had approximately the same effects on the Mexican workforce as managerial leaders from Mexico. However, regional differences within Mexico and organizational affiliation were significant moderators. We postulate that there are at least two leader prototypes in Mexico: the “transitional” leader and the more “traditional” leader. Additional implications of these findings for leadership in Mexico are discussed.

This article presents a psychoanalytically informed diagnosis of top management team (TMT) dysfunction during TMT training in a public sector organization. Outdoor management development exercises and the psychodynamics of family groups increased the psychological depth of a training intervention, eliciting dysfunctional behavior and facilitating diagnosis based on Bion’s theory of groups. Dysfunctional basic assumption behavior prohibited the group from effectively accomplishing the task of the work group. Implications for trainers and consultants are discussed.

This article reveals the mutability of charisma by tracing changes in the conceptualization of charisma throughout the history of leadership research. Religious, societal, and organizational phases in the conceptualization of charisma are identified. The mutability of charisma has extended charismatic leadership theory from the domain of theology to multiple facets of the organizational sciences. Shifting conceptualizations of charisma that emphasize different elements have facilitated the study of leader traits, leader behaviors, situational contingencies, leader and organizational communications, and organizational cultures. These pluralistic conceptualizations of leadership and charisma have broadened our understanding of charismatic leadership. Yet, we must acknowledge that the breadth of knowledge we have gained has been at the expense of a more profound understanding of any one particular conceptualization of charisma.

Shamir, House, and Arthur (1993) suggested that the effects of charismatic leadership on followers’ motivation are mediated by the increased salience of collective identities in followers’ self-concepts. This study empirically examines the effects of leadership messages on followers’ self-concept accessibilities. Charismatic and integrative (combined charismatic and individualized consideration) leadership increased the accessibility of followers’ collective self-concepts. Individualized consideration increased the accessibility of followers’ private self-concepts. These results support the propositions of the self-concept-based theory of charismatic leadership. Charismatic and integrative leadership messages from a leader resulted in higher follower collective self-concept accessibilities than did routinized messages. This finding underscores the importance of a charismatic leader, even when charismatic messages have become routinized.

Strategic ambiguity is a prevalent and valuable tactic in organizational commu nication. However, the deniability of strategically ambiguous messages, and the resulting utility of strategic ambigui...

This article applies the marketing concept to the no-show problem in health care. The no-show problem at a hospital-based outpatient internal medicine clinic was analyzed to determine the determinants of no-show behavior. Two surveys were conducted: a patient questionnaire, and a telephone interview of patients that had recently missed an appointment. The surveys identified the lack of transportation as an important determinant of no-show behavior among the clinic's low-income and elderly patient population. The authors suggest that effective implementation of the marketing concept requires that health care organizations offer individualized transportation services to and from their facilities.

This article describes leader-follower interactions in a symbolic interactionism framework (Blumer, 1969). The meaning placed on leader behaviors by followers is of importance in understanding the process by which leaders influence followers. It is posited that the meaning-making process of followers mediates the influence of leader behaviors on subsequent follower behaviors. Symbolic leadership can influence followers' meaning-making processes in three ways: through the creation of shared meaning, through the creation of equifinal meaning, or through the creation of idiosyncratic meaning. Methodologies for future research on symbolic leadership and the meaning-making process of followers are suggested.

Organizational consultants employ scientific methodologies to collect data and generate an organizational diagnosis. Between‐method triangulation is a means of leveraging the strengths of several methods while mitigating weaknesses. This article briefly reviews common scientific data collection methodologies and provides an illustration of between‐method triangulation in organizational diagnosis. Interpretations of organizational social reality were based on the triangulation of data from interviews, systematic observation, observer‐as‐participant observation, and archival data. Between‐method triangulation resulted in a more complete assessment of organizational problems than any lone method.

Genomic profiling produces large amounts of data and a challenge remains in identifying relevant biological processes associated with clinical outcome. Many candidate biomarkers have been identified but few have been successfully validated and make an impact clinically. This review focuses on some of the study design issues encountered in data mining for biomarker identification with illustrations of how study design may influence the final results. This includes issues of clinical endpoint use and selection, power, statistical, biological and clinical significance. We give particular attention to study design for the application of supervised clustering methods for identification of gene networks associated with clinical outcome and provide recommendations for future work to increase the success of identification of clinically relevant biomarkers.

The article reviews several books about management science, including “Making Groups Effective,” 2nd edition, by Alvin Zander, “Beyond Machiavelli: Tools for Coping with Conflict,” by Roger Fisher, Elizabeth Kopelman, and Andrea Kupfer Schneider, and “Conducting Meaningful Experiments: 40 Steps to Becoming a Scientist,” by R. Barker Bausell.