Citations
Mayo Clinic
551 citation(s) found for "Qian, N X".
Abstract 4069: Trimethylation and acetylation of Histone H3K27 modulates 5-fluorouracil response by regulating DPYD expression
Wu, Rentian , Nie, Qian , Tapper, Erin E. , Jerde, Calvin R. , Offer, Steven M. , Diasio, Robert B. , Offer, Steven M
Cancer Research | July 31, 2017 | Volume: 77 | Issue: 13_Supplement | Pages: 4069-4069
Abstract The antimetabolite 5-fluorouracil (5-FU) is one of the most widely used chemotherapy drugs. Dihydropyrimidine dehydrogenase (DPD) initiates the catabolic degradation of 5-FU to inactive metabolites and is widely accepted as a major determinant of 5-FU response and toxicity. While genetic variants in DPYD have been shown to variants may affect 5-FU metabolism, they are rare events and do not completely explain the reported variability in DPD function or the resultant differences in treatment response. Here, we report that DPYD expression is epigenetically regulated by histone modification at relevant promoter and enhancer regions. Using both chemical inhibitors and genetic approaches, we show that that H3K27 tri-methylation (H3K27me3) at the DPYD promoter is regulated by the epigenetic modifiers Ezh2 and UTX. Promoter H3K27me3 suppresses DPYD expression by inhibiting the binding of the transcription factor PU.1 bindingto the promoter and ,increases sensitivity leading to increased resistance to 5-FU. In a cohort of healthy volunteers, H3K27me3 levels were inversely correlated with An enhancer that regulates DPYD expression was also identified. Modifying the H3K27 status of the DPYD promoter or enhancer modulates DPYD gene expression. Deletions and mutations on the DPYD promoter or enhancer abolish their transcription regulation function. Enrichment of H3K27me3 at the DPYD promoter was negatively correlated with both DPYD expression and DPD enzyme activity in peripheral blood mononuclear cellsspecimens from healthy volunteers. Lastly, tumor expression data suggests that DPYD repression by Ezh2 is a strong predictor ofs poor survival in 5-FU treated cancers. By using a combination of in silico prediction and in vitro reporter assays we also identified a functional enhancer region for DPYD that is also likely to be clinically relevant to 5-FU treatment outcome. Collectively, the presentthese findings suggest that a previously uncharacterized mechanisms regulates DPD expression and may likely contribute to tumor resistance to 5-FU. Citation Format: Rentian Wu, Qian Nie, Erin E. Tapper, Calvin R. Jerde, Steven M. Offer, Robert B. Diasio. Trimethylation and acetylation of Histone H3K27 modulates 5-fluorouracil response by regulating DPYD expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4069. doi:10.1158/1538-7445.AM2017-4069
Mutation in BRAF V600E: A Poor Prognostic Marker in Stage III Colon Cancers With Deficient MMR?—Reply
Shi, Qian , Sinicrope, Frank A. , Alberts, Steven R. , Shi, Qian
JAMA Oncology | June 15, 2017 | Volume: 3 | Issue: 9 | Pages: 1285
Prospective pooled analysis of six phase III trials investigating duration of adjuvant (adjuv) oxaliplatin-based therapy (3 vs 6 months) for patients (pts) with stage III colon cancer (CC): The IDEA (International Duration Evaluation of Adjuvant chemothera
Sobrero, Alberto F. , Shields, Anthony F. , Sougklakos, Ioannis, Bonnetain, Franck, Watanabe, Toshiaki , Boukovinas, Ioannis , Renfro, Lindsay A. , Grothey, Axel, Niedzwiecki, Donna , Shi, Qian , Yoshino, Takayuki , Paul, James , Taı̈eb, Julien , Kerr, Rachel , Labianca, Roberto , Meyerhardt, Jeffrey A. , Torri, Valter , André, Thierry , Sargent, Daniel J. , Iveson, Timothy , Niedzwiecki, Donna
Journal of Clinical Oncology | June 13, 2017 | Volume: 35 | Issue: 18_suppl | Pages: LBA1-LBA1
10.1200/jco.2017.35.18_suppl.lba1
LBA1 Background: Since 2004, 6 months (m) of oxaliplatin (oxali)-based treatment has been the standard of care as adjuvant therapy for stage III CC. Since oxali is associated with cumulative neurotoxicity, shorter duration of adjuv therapy could spare pts toxicity and lead to substantial saving in health expenditures. Methods: A prospective, pre-planned pooled analysis of 6 concurrently conducted randomized phase III trials (SCOT, TOSCA, Alliance/SWOG 80702, IDEA France (GERCOR/PRODIGE), ACHIEVE, HORG) was performed to evaluate the non-inferiority (NI) of 3m compared with 6m (ref) of adjuv FOLFOX/XELOX. The primary endpoint was disease-free survival (DFS), defined as time from enrolment to relapse, 2nd CRC, and death (all causes). NI was to be declared if the 2-sided 95% confidence interval (CI) for DFS hazard ratio (HR 3m v 6m) estimated by a stratified Cox model was below 1.12. NI was examined within regimen and stage subgroups as pre-planned. Results: The analysis included 12,834 pts from 12 countries, accrued from 6/07 to 12/15. Stage distribution: 13% T1-2, 66% T3, 21% T4; 28% N2; 40% received XELOX. G3+ neurotoxicity was higher in the 6m v 3m arm (16 v 3% FOLFOX, 9 v 3% XELOX, p<0.0001). With a median follow-up of 39 mos, 3263 DFS events were observed. Overall, the 3 year DFS rate was 74.6% (3m) and 75.5% (6m), with estimated DFS HR of 1.07 (95%CI, 1.00-1.15). The 3m v 6m DFS HRs were 1.16 (95%CI, 1.06-1.26) and 0.95 (95% CI, 0.85-1.06) for FOLFOX and XELOX treated pts, respectively. The 3m v 6m DFS HRs were 1.01 (95%CI, 0.90-1.12) in T1-3 N1, and 1.12 (95%CI, 1.03-1.23) for T4 or N2 pts. Conclusions: While NI was not established for the overall cohort, NI of 3m v 6m oxali-based adjuv therapy was supported for XELOX. As each IDEA trial treated varying proportions of pts with XELOX (0 to 75%), the regimen interaction likely produced the differential outcomes observed between individual studies. Certain substages (T1-3 N1) also showed NI for 3m v 6m. These data provide a framework for discussions on risks and benefits of individualized adjuv therapy approaches. Support: U10CA180821, U10CA180882, U10CA180888, U10CA180835, INCA, PHRC2009, EME 09/800/34, HTA 14/140/84, CRUK C1348/A15960, JFMC. Clinical trial information: NCT01150045.
Development of diabetes does not alter behavioral and molecular circadian rhythms in a transgenic rat model of type 2 diabetes mellitus
Qian, Jingyi , Thomas, Anthony P., Schroeder, Analyne , Rakshit, Kuntol, Colwell, Christopher S. , Matveyenko, Aleksey V.
American Journal of Physiology-Endocrinology and Metabolism | May 2, 2017 | Volume: 313 | Issue: 2 | Pages: E213-E221
10.1152/ajpendo.00406.2016
| PMID 28465284
Metabolic state and circadian clock function exhibit a complex bidirectional relationship. Circadian disruption increases propensity for metabolic dysfunction, whereas common metabolic disorders such as obesity and type 2 diabetes (T2DM) are associated with impaired circadian rhythms. Specifically, alterations in glucose availability and glucose metabolism have been shown to modulate clock gene expression and function in vitro; however, to date, it is unknown whether development of diabetes imparts deleterious effects on the suprachiasmatic nucleus (SCN) circadian clock and SCN-driven outputs in vivo. To address this question, we undertook studies in aged diabetic rats transgenic for human islet amyloid polypeptide, an established nonobese model of T2DM (HIP rat), which develops metabolic defects closely recapitulating those present in patients with T2DM. HIP rats were also cross-bred with a clock gene reporter rat model (Per1:luciferase transgenic rat) to permit assessment of the SCN and the peripheral molecular clock function ex vivo. Utilizing these animal models, we examined effects of diabetes on 1) behavioral circadian rhythms, 2) photic entrainment of circadian activity, 3) SCN and peripheral tissue molecular clock function, and 4) melatonin secretion. We report that circadian activity, light-induced entrainment, molecular clockwork, as well as melatonin secretion are preserved in the HIP rat model of T2DM. These results suggest that despite the well-characterized ability of glucose to modulate circadian clock gene expression acutely in vitro, SCN clock function and key behavioral and physiological outputs appear to be preserved under chronic diabetic conditions characteristic of nonobese T2DM.
A hierarchical Bayesian design for randomized Phase II clinical trials with multiple groups
Yin, Jun , Qin, Rui , Erlichman, Charles , Shi, Qian , Sargent, Daniel J. , Shi, Qian
Journal of Biopharmaceutical Statistics | April 27, 2017 | Volume: 28 | Issue: 3 | Pages: 451-462
The MicroRNA-199a/214 Cluster Targets E-Cadherin and Claudin-2 and Promotes High Glucose-Induced Peritoneal Fibrosis
Che, Ming-wen, Shi, Tiantian , Feng, Shidong, Li, Huan , Feng, Ning , Lou, Weijuan , Dou, Jianhua, Tang, Guangbo , Huang, Chen , Xu, Guoshuang , Qian, Qi , Sun, Shiren , He, Lijie , Wang, Hanmin , He, Lijie , Zhang, Xiaomin
Journal of the American Society of Nephrology | April 20, 2017 | Volume: 28 | Issue: 8 | Pages: 2459-2471
10.1681/asn.2016060663
| PMID 28428333
Serum response factor (SRF) was found to be involved in the phenotypic transition and fibrosis of the peritoneal membrane during treatment with peritoneal dialysis (PD), but the exact mechanism remains unclear. SRF regulates microRNAs (miRNAs) that contain the SRF-binding consensus (CArG) element in the promoter region. Therefore, we investigated whether the miR-199a/214 gene cluster, which contains a CArG element in its promoter, is directly regulated by SRF. High-glucose (HG) treatment significantly unregulated the expression of the miR-199a-5p/214–3p gene cluster in human peritoneal mesothelial cells (HPMCs). By chromatin immunoprecipitation and reporter assays, we found that SRF binds to the miR-199a-5p/214–3p gene cluster promoter after HG stimulation. In vitro , in HPMCs, silencing of miR-199a-5p or miR-214–3p inhibited the HG-induced phenotypic transition and cell migration but enhanced cell adhesion, whereas ectopic expression of mimic oligonucleotides had the opposite effects. Both miR-199a-5p and miR-214–3p targeted claudin-2 and E-cadherin mRNAs. In a PD rat model, treatment with an SRF inhibitor silenced miR-199a-5p and miR-214–3p and alleviated HG-PD fluid–induced damage and fibrosis. Overall, this study reveals a novel SRF–miR-199a/miR-214–E-cadherin/claudin-2 axis that mediates damage and fibrosis in PD.
Clinical Calculator for Early Mortality in Metastatic Colorectal Cancer: An Analysis of Patients From 28 Clinical Trials in the Aide et Recherche en Cancérologie Digestive Database
Renfro, Lindsay A. , Goldberg, Richard M. , Sobrero, Alberto , Adams, Richard , Seymour, Michel , Heinemann, Volker , Schmoll, Hans‐Joachim , Douillard, Jean‐Yves , Hurwitz, Herbert I. , Fuchs, Charles S. , Díaz‐Rubio, Eduardo , Porschen, Rainer, Tournigand, Christophe , Chibaudel, Benoist , Hoff, Paulo M. , Kabbinavar, Fairooz F. , Falcone, Alfredo , Punt, Cornelis J.A. , Hecht, J. Randolph, Souglakos, John , Bokemeyer, Carsten , Gramont, Aimery de , Seymour, Matthew T, Hurwitz, Herbert, Díaz-Rubio, Eduardo, Tebbutt, Niall C. , van Cutsem, Eric, Saltz, Leonard, de Gramont, Aimery, Grothey, Axel , Cutsem, Eric Van , Saltz, Leonard B. , Sargent, Daniel J. , Falcone, Alfredo , Seymour, Matthew T , Adams, Richard , Schmoll, Hans-Joachim , Chibaudel, Benoist
Journal of Clinical Oncology | April 17, 2017 | Volume: 35 | Issue: 17 | Pages: 1929-1937
10.1200/jco.2016.71.5771
| PMID 28414610
Purpose Factors contributing to early mortality after initiation of treatment of metastatic colorectal cancer are poorly understood. Materials and Methods Data from 22,654 patients enrolled in 28 randomized phase III trials contained in the ARCAD (Aide et Recherche en Cancérologie Digestive) database were pooled. Multivariable logistic regression models for 30-, 60-, and 90-day mortality were constructed, including clinically and statistically significant patient and disease factors and interaction terms. A calculator (nomogram) for 90-day mortality was developed and validated internally using bootstrapping methods and externally using a 10% random holdout sample from each trial. The impact of early progression on the likelihood of survival to 90 days was examined with time-dependent Cox proportional hazards models. Results Mortality rates were 1.4% at 30 days, 3.4% at 60 days, and 5.5% at 90 days. Among baseline factors, advanced age, lower body mass index, poorer performance status, increased number of metastatic sites, BRAF mutant status, and several laboratory parameters were associated with increased likelihood of early mortality. A multivariable model for 90-day mortality showed strong internal discrimination (C-index, 0.77) and good calibration across risk groups as well as accurate predictions in the external validation set, both overall and within patient subgroups. Conclusion A validated clinical nomogram has been developed to quantify the risk of early death for individual patients during initial treatment of metastatic colorectal cancer. This tool may be used for patient eligibility assessment or risk stratification in future clinical trials and to identify patients requiring more or less aggressive therapy and additional supportive measures during and after treatment.
Anorectal Function and Quality of Life in Patients With Early Stage Rectal Cancer Treated With Chemoradiation and Local Excision
Lynn, Patricio B. , Renfro, Lindsay A. , Carrero, Xiomara W., Shi, Qian , Strombom, Paul L., Chow, Oliver S. , Strombom, Paul L., García‐Aguilar, Julio , Shi, Qian
Diseases of the Colon & Rectum | April 6, 2017 | Volume: 60 | Issue: 5 | Pages: 459-468
10.1097/dcr.0000000000000758
| PMID 28383445
BACKGROUND: Little is known about anorectal function and quality of life after chemoradiation followed by local excision, which is an alternative to total mesorectal excision for selected patients with early rectal cancer. OBJECTIVE: The purpose of this study was to prospectively assess anorectal function and health-related quality of life of patients with T2N0 rectal cancer who were treated with an alternative approach. DESIGN: This was a prospective, phase II trial. SETTINGS: The study was multicentric (American College of Surgeons Oncology Group trial Z6041). INTERVENTIONS: Patients with stage cT2N0 rectal adenocarcinomas were treated with an oxaliplatin/capecitabine-based chemoradiation regimen followed by local excision. MAIN OUTCOME MEASURES: Anorectal function and quality of life were assessed at enrollment and 1 year postoperatively with the Fecal Incontinence Severity Index, Fecal Incontinence Quality of Life scale, and Functional Assessment of Cancer Therapy-Colorectal Questionnaire. Results were compared, and multivariable analysis was performed to identify predictors of outcome. RESULTS: Seventy-one patients (98%) were evaluated at enrollment and 66 (92%) at 1 year. Compared with baseline, no significant differences were found on Fecal Incontinence Severity Index scores at 1 year. Fecal Incontinence Quality of Life results were significantly worse in the lifestyle (p < 0.001), coping/behavior (p < 0.001), and embarrassment (p = 0.002) domains. There were no differences in the Functional Assessment of Cancer Therapy overall score, but the physical well-being subscale was significantly worse and emotional well-being was improved after surgery. Treatment with the original chemoradiation regimen predicted worse depression/self-perception and embarrassment scores in the Fecal Incontinence Quality of Life, and male sex was predictive of worse scores in the Functional Assessment of Cancer Therapy overall score and trial outcome index. LIMITATIONS: Small sample size, relatively short follow-up, and absence of information before cancer diagnosis were study limitations. CONCLUSIONS: Chemoradiation followed by local excision had minimal impact on anorectal function 1 year after surgery. Overall quality of life remained stable, with mixed effects on different subscales. This information should be used to counsel patients about expected outcomes.
Bostwick, David G., Lieber, Michael M., Jenkins, Robert B. , Qian, J.
The Japanese Journal of Urology | April 6, 2017 | Volume: 89 | Issue: 2 | Pages: 267
Characterization of fusion genes in common and rare epithelial ovarian cancer histologic subtypes
Earp, Madalene A. , Li, Qian , Cunningham, Julie M. , Natanzon, Yanina , Kalli, Kimberly R., Hou, Xiaonan , Weroha, S. John , Haluska, Paul , Lawrenson, Kate , Gayther, Simon A. , Goode, Ellen L. , Winham, Stacey J. , Raghavan, Rama , Dai, Junqiang , Wang, Chen , Fridley, Brooke L. , Lawrenson, Kate
Oncotarget | April 1, 2017 | Volume: 8 | Issue: 29 | Pages: 46891-46899