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Browsing by Author "Yu, Menggang"
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Item Autotaxin expression and its connection with the TNF-alpha-NF-κB axis in human hepatocellular carcinoma(BMC, 2010-03-31) Wu, Jian-Min; Xu, Yan; Skill, Nicholas J.; Sheng, Hongmiao; Zhao, Zhenwen; Yu, Menggang; Saxena, Romil; Maluccio, Mary A.; Surgery, School of MedicineBackground Autotaxin (ATX) is an extracellular lysophospholipase D that generates lysophosphatidic acid (LPA) from lysophosphatidylcholine (LPC). Both ATX and LPA have been shown to be involved in many cancers. However, the functional role of ATX and the regulation of ATX expression in human hepatocellular carcinoma (HCC) remain elusive. Results In this study, ATX expression was evaluated in tissues from 38 human HCC and 10 normal control subjects. ATX was detected mainly in tumor cells within tissue sections and its over-expression in HCC was specifically correlated with inflammation and liver cirrhosis. In addition, ATX expression was examined in normal human hepatocytes and liver cancer cell lines. Hepatoma Hep3B and Huh7 cells displayed stronger ATX expression than hepatoblastoma HepG2 cells and normal hepatocytes did. Proinflammtory cytokine tumor necrosis factor alpha (TNF-α) promoted ATX expression and secretion selectively in Hep3B and Huh7 cells, which led to a corresponding increase in lysophospholipase-D activity. Moreover, we explored the mechanism governing the expression of ATX in hepatoma cells and established a critical role of nuclear factor-kappa B (NF-κB) in basal and TNF-α induced ATX expression. Further study showed that secreted enzymatically active ATX stimulated Hep3B cell invasion. Conclusions This report highlights for the first time the clinical and biological evidence for the involvement of ATX in human HCC. Our observation that links the TNF-α/NF-κB axis and the ATX-LPA signaling pathway suggests that ATX is likely playing an important role in inflammation related liver tumorigenesis.Item Evaluating the role of serotonin in hot flashes after breast cancer using acute tryptophan depletion.(Wolters Kluwer, 2009) Carpenter, Janet S.; Yu, Menggang; Wu, Jingwei; Von Ah, Diane; Milata, Jennifer; Otte, Julie L.; Johns, Shelley; Schneider, Bryan; Storniolo, Anna Maria; Salomon, Ronald; Desta, Zeuresenay; Cao, Donghua; Jin, Yan; Philips, Santosh; Skaar, Todd C.OBJECTIVE: Among women with breast cancer, hot flashes are frequent, severe, and bothersome symptoms that can negatively impact quality of life and compromise compliance with life-saving medications (eg, tamoxifen and aromatase inhibitors). Clinicians' abilities to treat hot flashes are limited due to inadequate understanding of physiological mechanisms involved in hot flashes. Using an acute tryptophan depletion paradigm, we tested whether alterations in central serotonin levels were involved in the induction of hot flashes in women with breast cancer. METHODS: This was a within-participant, double-blind, controlled, balanced, crossover study. Twenty-seven women completed two 9-hour test days. On one test day, women ingested a concentrated amino acid drink and encapsulated amino acids (no tryptophan) according to published procedures that have been shown to have specific effects on serotonin within 4.5 to 7 hours. On the other test day, women ingested a control drink. Serial venous blood sampling and objective hot flash monitoring were used to evaluate response to each condition. RESULTS: Response to acute tryptophan depletion was variable and unexplained by use of selective serotonin reuptake inhibitors, antiestrogens, breast cancer disease and treatment variables, or genetic polymorphisms in serotonin receptor and transporter genes. Contrary to our hypothesis, hot flashes were not worsened with acute tryptophan depletion. CONCLUSIONS: Physiologically documented and self-reported hot flashes were not exacerbated by tryptophan depletion. Additional mechanistic research is needed to better understand the etiology of hot flashes.Item Group variable selection via convex log-exp-sum penalty with application to a breast cancer survivor study(Wiley Blackwell (Blackwell Publishing), 2015-03) Geng, Zhigeng; Wang, Sijian; Yu, Menggang; Monahan, Patrick O.; Champion, Victoria; Wahba, Grace; Biostatistics, School of Public HealthIn many scientific and engineering applications, covariates are naturally grouped. When the group structures are available among covariates, people are usually interested in identifying both important groups and important variables within the selected groups. Among existing successful group variable selection methods, some methods fail to conduct the within group selection. Some methods are able to conduct both group and within group selection, but the corresponding objective functions are non-convex. Such a non-convexity may require extra numerical effort. In this article, we propose a novel Log-Exp-Sum(LES) penalty for group variable selection. The LES penalty is strictly convex. It can identify important groups as well as select important variables within the group. We develop an efficient group-level coordinate descent algorithm to fit the model. We also derive non-asymptotic error bounds and asymptotic group selection consistency for our method in the high-dimensional setting where the number of covariates can be much larger than the sample size. Numerical results demonstrate the good performance of our method in both variable selection and prediction. We applied the proposed method to an American Cancer Society breast cancer survivor dataset. The findings are clinically meaningful and may help design intervention programs to improve the qualify of life for breast cancer survivors.Item Identification of subgroups with differential treatment effects for longitudinal and multiresponse variables(Wiley, 2016-11-20) Loh, Wei-Yin; Man, Michael; Fu, Haoda; Champion, Victoria L.; Yu, Menggang; School of NursingWe describe and evaluate a regression tree algorithm for finding subgroups with differential treatments effects in randomized trials with multivariate outcomes. The data may contain missing values in the outcomes and covariates, and the treatment variable is not limited to two levels. Simulation results show that the regression tree models have unbiased variable selection and the estimates of subgroup treatment effects are approximately unbiased. A bootstrap calibration technique is proposed for constructing confidence intervals for the treatment effects. The method is illustrated with data from a longitudinal study comparing two diabetes drugs and a mammography screening trial comparing two treatments and a control.Item Imatinib mesylate for plexiform neurofibromas in patients with neurofibromatosis type 1: a phase 2 trial(Elsevier, 2012-12) Robertson, Kent A.; Nalepa, Grzegorz; Yang, Feng-Chun; Bowers, Daniel C.; Ho, Chang Y.; Hutchins, Gary D.; Croop, James M.; Vik, Terry A.; Denne, Scott C.; Parada, Luis F.; Hingtgen, Cynthia M.; Walsh, Laurence E.; Yu, Menggang; Pradhan, Kamnesh R.; Edwards-Brown, Mary K.; Cohen, Mervyn D.; Fletcher, James W.; Travers, Jeffrey B.; Staser, Karl W.; Lee, Melissa W.; Sherman, Marcie R.; Davis, Cynthia J.; Miller, Lucy C.; Ingram, David A.; Clapp, D. Wade; Pediatrics, School of MedicineBACKGROUND: Plexiform neurofibromas are slow-growing chemoradiotherapy-resistant tumours arising in patients with neurofibromatosis type 1 (NF1). Currently, there are no viable therapeutic options for patients with plexiform neurofibromas that cannot be surgically removed because of their proximity to vital body structures. We undertook an open-label phase 2 trial to test whether treatment with imatinib mesylate can decrease the volume burden of clinically significant plexiform neurofibromas in patients with NF1. METHODS: Eligible patients had to be aged 3-65 years, and to have NF1 and a clinically significant plexiform neurofibroma. Patients were treated with daily oral imatinib mesylate at 220 mg/m(2) twice a day for children and 400 mg twice a day for adults for 6 months. The primary endpoint was a 20% or more reduction in plexiform size by sequential volumetric MRI imaging. Clinical data were analysed on an intention-to-treat basis; a secondary analysis was also done for those patients able to take imatinib mesylate for 6 months. This trial is registered with ClinicalTrials.gov, number NCT01673009. FINDINGS: Six of 36 patients (17%, 95% CI 6-33), enrolled on an intention-to-treat basis, had an objective response to imatinib mesylate, with a 20% or more decrease in tumour volume. Of the 23 patients who received imatinib mesylate for at least 6 months, six (26%, 95% CI 10-48) had a 20% or more decrease in volume of one or more plexiform tumours. The most common adverse events were skin rash (five patients) and oedema with weight gain (six). More serious adverse events included reversible grade 3 neutropenia (two), grade 4 hyperglycaemia (one), and grade 4 increases in aminotransferase concentrations (one). INTERPRETATION: Imatinib mesylate could be used to treat plexiform neurofibromas in patients with NF1. A multi-institutional clinical trial is warranted to confirm these results.Item Joint models for longitudinal and survival data(2014-07-11) Yang, Lili; Gao, Sujuan; Yu, Menggang; Tu, Wanzhu; Callahan, Christopher M.; Zollinger, TerrellEpidemiologic and clinical studies routinely collect longitudinal measures of multiple outcomes. These longitudinal outcomes can be used to establish the temporal order of relevant biological processes and their association with the onset of clinical symptoms. In the first part of this thesis, we proposed to use bivariate change point models for two longitudinal outcomes with a focus on estimating the correlation between the two change points. We adopted a Bayesian approach for parameter estimation and inference. In the second part, we considered the situation when time-to-event outcome is also collected along with multiple longitudinal biomarkers measured until the occurrence of the event or censoring. Joint models for longitudinal and time-to-event data can be used to estimate the association between the characteristics of the longitudinal measures over time and survival time. We developed a maximum-likelihood method to joint model multiple longitudinal biomarkers and a time-to-event outcome. In addition, we focused on predicting conditional survival probabilities and evaluating the predictive accuracy of multiple longitudinal biomarkers in the joint modeling framework. We assessed the performance of the proposed methods in simulation studies and applied the new methods to data sets from two cohort studies.Item Joint Models for Multiple Longitudinal Processes and Time-to-event Outcome(Taylor & Francis, 2016) Yang, Lili; Yu, Menggang; Gao, Sujuan; Department of Biostatistics, Richard M. Fairbanks School of Public HealthJoint models are statistical tools for estimating the association between time-to-event and longitudinal outcomes. One challenge to the application of joint models is its computational complexity. Common estimation methods for joint models include a two-stage method, Bayesian and maximum-likelihood methods. In this work, we consider joint models of a time-to-event outcome and multiple longitudinal processes and develop a maximum-likelihood estimation method using the expectation–maximization algorithm. We assess the performance of the proposed method via simulations and apply the methodology to a data set to determine the association between longitudinal systolic and diastolic blood pressure measures and time to coronary artery disease.Item Marginal and Conditional Distribution Estimation from Double-Sampled Semi-Competing Risks Data(Wiley, 2015-03) Yu, Menggang; Yiannoutsos, Constantin T.; Department of Biostatistics, IU School of MedicineInformative dropout is a vexing problem for any biomedical study. Most existing statistical methods attempt to correct estimation bias related to this phenomenon by specifying unverifiable assumptions about the dropout mechanism. We consider a cohort study in Africa that uses an outreach programme to ascertain the vital status for dropout subjects. These data can be used to identify a number of relevant distributions. However, as only a subset of dropout subjects were followed, vital status ascertainment was incomplete. We use semi-competing risk methods as our analysis framework to address this specific case where the terminal event is incompletely ascertained and consider various procedures for estimating the marginal distribution of dropout and the marginal and conditional distributions of survival. We also consider model selection and estimation efficiency in our setting. Performance of the proposed methods is demonstrated via simulations, asymptotic study and analysis of the study data.Item Medication use in breast cancer survivors compared to midlife women.(Springer, 2013-07) Otte, Julie L.; Skaar, Todd C.; Wu, Jingwei; Yu, Menggang; Ryker, Kristin; Burns, Debra S.; Carpenter, Janet S.PURPOSE: Many breast cancer survivors (BCS) take multiple medications for health problems associated with the treated cancer and other noncancer comorbidities. However, there is no published, large-scale descriptive evaluation of medication use in BCS compared to midlife women. The purpose of this study was (1) to compare the number and types of prescription medications and over-the-counter medications between BCS and midlife women without cancer and (2) to assess possible drug-drug interactions by evaluating the cytochrome P450 isoform properties of medications (inductors and inhibitors) in both groups. METHODS: A cross-sectional, descriptive, comparative design was used. Baseline data from 98 BCS and 138 midlife women without cancer was analyzed from a behavioral intervention trial for menopausal symptoms. RESULTS: BCS were taking significantly more prescription medications and a larger variety of different types of medication classifications (p < 0.05) after controlling for group differences (race, noncancer comorbid conditions, marital status, income, and smoking) in demographics. Twenty-four women were taking at least one medication considered to be a cytochrome P450 isoforms (CYP) inhibitor or inducer capable of clinical drug-drug interactions with no differences in CYP inhibitors or inducers found between groups. CONCLUSION: BCS are taking a vast array of medications during survivorship. It is unclear if prescription medications are managed by a single healthcare provider or several providers. Clinical implications are to monitor for possible interactions among the various prescription medications, over-the-counter medications, and supplements. Implications for behavioral and biomedical research are that clinical studies need to carefully assess and account for multiple medication uses. RELEVANCE OF THE STUDY: The findings of this study are relevant to research and practice for both oncology and general practitioners. The importance of assessing medication information provides information about symptom management in individuals surviving cancer. In addition, the potential interaction of drugs impacts efficacy of various treatments and impacts compliance by patients.Item Paced Respiration for Vasomotor and Other Menopausal Symptoms: A Randomized, Controlled Trial(Office of the Vice Chancellor for Research, 2013-04-05) Carpenter, Janet S.; Burns, Debra S.; Wu, Jingwei; Otte, Julie L.; Yu, MenggangBackground: Paced respiration has been internationally recommended for vasomotor symptoms (e.g., hot flashes, night sweats) despite limited empirical evidence. Objective: To evaluate efficacy of a paced respiration intervention against breathing control and usual care control for vasomotor and other menopausal symptoms. Design: A 16-week, 3-group, partially blinded, controlled trial with 2:2:1 randomization and stratification by group (breast cancer, no cancer) was conducted in a Midwestern city and surrounding area. Participants: 218 randomized women (96 breast cancer survivors, 122 menopausal women without cancer) were recruited through community mailings and registries (29% minority). Interventions: Training, home practice support, and instructions to use the breathing at the time of each hot flash were delivered via compact disc with printed booklet (paced respiration intervention) or digital videodisc with printed booklet (fast shallow breathing control). Usual care control received a letter regarding group assignment. Main Measures: Outcomes included hot flash frequency, severity, and bother (primary), hot flash interference in daily life, perceived control over hot flashes, and mood and sleep disturbances (secondary). Intervention performance, adherence, and adverse events were assessed. Key Results: There were no significant group differences for primary outcomes at 8- or 16-weeks post-randomization. Most intervention participants did not achieve 50% reduction in vasomotor symptoms despite demonstrated ability to correctly do paced respiration and daily practice. Statistically significant differences in secondary outcomes at 8- and 16-weeks were small, not likely to be clinically relevant, and as likely to favor intervention as breathing control. Conclusions: Paced respiration is unlikely to provide clinical benefit for vasomotor or other menopausal symptoms in breast cancer survivors or menopausal women without cancer.