Ann Arbor Veterans Administration Medical Center

Ann Arbor, MI, United States

Ann Arbor Veterans Administration Medical Center

Ann Arbor, MI, United States
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Shiratsuchi H.,University of Michigan | Wang Z.,University of Michigan | Chen G.,University of Michigan | Ray P.,University of Michigan | And 7 more authors.
Journal of Thoracic Oncology | Year: 2017

Introduction We have previously demonstrated that a subset of lung cancer cells express higher CYP24A1 mRNA, a metabolizing enzyme for 1,25-D3, compared to benign tumors or surrounding normal lung and that high CYP24A1 mRNA expression is associated with poor prognosis in resected lung adenocarcinoma (AC). We hypothesized that CYP24A1 has oncogenic potential and increased CYP24A1 expression may contribute to tumor growth, whereas, CYP24A1 targeting may reduce tumor burden. Methods Two low CYP24A1 expressing human lung cancer cell lines (SK-LU-1 and Calu-6) were stably transfected either with an empty lentiviral vector or with the CYP24A1 expressing vector. Over-expression of mRNA and protein levels of CYP24A1 in SK-LU-1 and Calu-6 were confirmed using qRT-PCR and immunoblotting respectively. Next, effects of targeting CYP24A1 were examined in lung cancer cells (A549 and H441), which express higher basal levels of CYP24A1. Finally, we studied the effects of stable knockdown of CYP24A1 in xenograft models. Results Over-expression of CYP24A1 correlated with accelerated cell growth and invasion compared to control vector-transfected cells. CYP24A1 over-expression also increased RAS protein expression. Knockdown of CYP24A1 using either si- or shRNA reduced CYP24A1 mRNA and protein expression and significantly decreased cell proliferation (30-60%) and reduced mitochondrial DNA content compared to non-targeting (NT) si-/shRNA transfected/transduced cells. Transfection with CYP24A1 siRNA also decreased total RAS protein, thus reducing phosphorylated AKT. Importantly, stable knockdown of CYP24A1 in A549 and H441 lung tumor xenograft models resulted in tumor growth delay and smaller tumor size as evident from tumor bioluminescence and tumor volume measurement studies. Such observations were correlated with decreased tumor cell proliferation as evidenced by reduced Ki67 and Cyclin D staining. Conclusions Our data suggest that CYP24A1 has oncogenic properties mediated by increasing RAS signaling, targeting of which may provide an alternate strategy to treat a subset of lung AC. © 2016 International Association for the Study of Lung Cancer

Liberzon I.,Ann Arbor Veterans Administration Medical Center | Liberzon I.,University of Michigan | McCabe K.,George Mason University | Phan K.L.,University of Illinois at Chicago | Phan K.L.,Jesse Brown Medical Center
Depression and Anxiety | Year: 2013

Objective Generalized social anxiety disorder (GSAD) is characterized by excessive fear of public scrutiny and reticence in social engagement. Previous studies have probed the neural basis of GSAD often using static, noninteractive stimuli (e.g., face photographs) and have identified dysfunction in fear circuitry. We sought to investigate brain-based dysfunction in GSAD during more real-world, dynamic social interactions, focusing on the role of reward-related regions that are implicated in social decision-making. Methods Thirty-six healthy individuals (healthy control [HC]) and 36 individuals with GSAD underwent functional magnetic resonance imaging (fMRI) scanning while participating in a behavioral economic game ("Trust Game") involving iterative exchanges with fictive partners who acquire differential reputations for reciprocity. We investigated brain responses to reciprocation of trust in one's social partner, and how these brain responses are modulated by partner reputation for repayment. Results In both HC and GSAD, receipt of reciprocity robustly engaged ventral striatum, a region implicated in reward. In HC, striatal responses to reciprocity were specific to partners who have consistently returned the investment ("cooperative partners"), and were absent for partners who lack a cooperative reputation. In GSAD, modulation of striatal responses by partner reputation was absent. Social anxiety severity predicted diminished responses to cooperative partners. Conclusion These results suggest abnormalities in GSAD in reward-related striatal mechanisms that may be important for the initiation, valuation, and maintenance of cooperative social relationships. Moreover, this study demonstrates that dynamic, interactive task paradigms derived from economics can help illuminate novel mechanisms of pathology in psychiatric illnesses in which social dysfunction is a cardinal feature. © 2013 Wiley Periodicals, Inc.

Kim S.Y.H.,University of Michigan | Uhlmann R.A.,University of Michigan | Appelbaum P.S.,New York State Psychiatric Institute | Knopman D.S.,Mayo Medical School | And 5 more authors.
Alzheimer's and Dementia | Year: 2010

Background: Research involving incapacitated persons with dementia entails complex scientific, legal, and ethical issues, making traditional surveys of layperson views on the ethics of such research challenging. We therefore assessed the impact of democratic deliberation (DD), involving balanced, detailed education and peer deliberation, on the views of those responsible for persons with dementia. Methods: One hundred and seventy-eight community-recruited caregivers or primary decision-makers for persons with dementia were randomly assigned to either an all-day DD session group or a control group. Educational materials used for the DD session were vetted for balance and accuracy by an interdisciplinary advisory panel. We assessed the acceptability of family-surrogate consent for dementia research ("surrogate-based research") from a societal policy perspective as well as from the more personal perspectives of deciding for a loved one or for oneself (surrogate and self-perspectives), assessed at baseline, immediately post-DD session, and 1 month after DD date, for four research scenarios of varying risk-benefit profiles. Results: At baseline, a majority in both the DD and control groups supported a policy of family consent for dementia research in all research scenarios. The support for a policy of family consent for surrogate-based research increased in the DD group, but not in the control group. The change in the DD group was maintained 1 month later. In the DD group, there were transient changes in attitudes from surrogate or self-perspectives. In the control group, there were no changes from baseline in attitude toward surrogate consent from any perspective. Conclusions: Intensive, balanced, and accurate education, along with peer deliberation provided by democratic deliberation, led to a sustained increase in support for a societal policy of family consent in dementia research among those responsible for dementia patients. © 2010 The Alzheimer's Association. All rights reserved.

O'Malley M.,University of Michigan | Healy P.,University of Michigan | Daignault S.,University of Michigan | Ramnath N.,University of Michigan | Ramnath N.,Ann Arbor Veterans Administration Medical Center
Oncology (Switzerland) | Year: 2013

Background: Chemotherapy-associated neutropenia has been reported to be a pharmacodynamic marker of response in some advanced solid tumors. Factors that accelerate drug clearance lead to lower plasma concentrations and toxicity, including neutropenia. Smoking accelerates the metabolism of several drugs, including chemotherapy. We sought to study the effects of smoking on gemcitabine-induced neutropenia in this retrospective study. Methods: Smoking status and neutropenia along with other clinical parameters were recorded in 151 patients receiving first-line gemcitabine-based chemotherapy for advanced solid tumors. Results: Tumor types included breast (9.3%), lung (4.6%), pancreatobiliary (70.9%), or other/unknown primary cancer (15.2%). Logistic regression showed that never smokers had increased neutropenia versus current smokers (odds ratio: 3.5; 95% confidence interval, CI: 1.1-11.4). A 5-unit increase in pack-years reduced the odds of having higher neutropenia toxicity by 6.3% (95% CI 12 to 1%; p = 0.036). Conclusion: Smokers had less neutropenia than nonsmokers, a finding that was more pronounced with increasing pack-years. This pharmacodynamic marker of gemcitabine-induced neutropenia may result in less efficacy of gemcitabine. Future prospective trials should correlate smoking, metabolizing phenotype, neutropenia, and response to gemcitabine therapy. © 2013 S. Karger AG, Basel.

Gillespie E.F.,University of Michigan | Raychaudhuri N.,University of Michigan | Papageorgiou K.I.,University of Michigan | Atkins S.J.,University of Michigan | And 6 more authors.
Investigative Ophthalmology and Visual Science | Year: 2012

Purpose. CD40-CD40 ligand (CD40L) interactions appear to play pathogenic roles in autoimmune disease. Here we quantify CD40 expression on fibrocytes, circulating, and bone marrow-derived progenitor cells. The functional consequences of CD40 ligation are determined since these may promote tissue remodeling linked with thyroid-associated ophthalmopathy (TAO). Methods. CD40 levels on cultivated fibrocytes and orbital fibroblasts (GOFB) from patients with Graves' disease (GD), as well as fibrocyte abundance, were determined by flow cytometry. CD40 mRNA expression was evaluated by real-time PCR, whereas response to CD40 ligation was measured by Luminex and RT-PCR. Protein kinase B (Akt) and nuclear factor (NF)-κ B (NF-κB) signaling were determined by Western blot and immunofluorescence. Results. Basal CD40 expression on fibrocytes is greater than that on GOFB. IFN-γ up regulates CD40 in both cell types and its actions are mediated at the pretranslational level. Fibrocytes produce high levels of cytokines, including interleukin-6 (IL-6), TNF-α, IL-8, MCP-1, and RANTES (Regulated on Activation, Normal T Cell Expressed and Secreted) in response to CD40L. IL-6 induction results from an increase in steady state IL-6 mRNA, and is mediated through Akt and NF-κB activation. Circulating CD40+CD45+Col1+ fibrocytes are far more frequent in vivo in donors with TAO compared with healthy subjects. Conclusions. Particularly high levels of functional CD40 are displayed by fibrocytes. CD40L-provoked signaling results in the production of several cytokines. Among these, IL-6 expression is mediated through Akt and NF-κB pathways. The frequency of circulating CD40+ fibrocytes is markedly increased in patients with TAO, suggesting that this receptor might represent a therapeutic target for TAO. © 2012 The Association for Research in Vision and Ophthalmology, Inc.

Burke D.T.,University of Michigan | Kozloff K.M.,University of Michigan | Chen S.,University of Michigan | West J.L.,University of Michigan | And 5 more authors.
Genome Research | Year: 2012

Finding the causative genetic variations that underlie complex adult traits is a significant experimental challenge. The unbiased search strategy of genome-wide association (GWAS) has been used extensively in recent human population studies. These efforts, however, typically find only a minor fraction of the genetic loci that are predicted to affect variation. As an experimental model for the analysis of adult polygenic traits, we measured a mouse population for multiple phenotypes and conducted a genome-wide search for effector loci. Complex adult phenotypes, related to body size and bone structure, were measured as component phenotypes, and each subphenotype was associated with a genomic spectrum of candidate effector loci. The strategy successfully detected several loci for the phenotypes, at genome-wide significance, using a single, modestsized population (N = 505). The effector loci each explain 2%-10% of the measured trait variation and, taken together, the loci can account for over 25% of a trait's total population variation. A replicate population (N = 378) was used to confirm initially observed loci for one trait (femur length), and, when the two groups were merged, the combined population demonstrated increased power to detect loci. In contrast to human population studies, our mouse genome-wide searches find loci that individually explain a larger fraction of the observed variation. Also, the additive effects of our detected mouse loci more closely match the predicted genetic component of variation. The genetic loci discovered are logical candidates for components of the genetic networks having evolutionary conservation with human biology.

Sripada C.S.,University of Michigan | Gonzalez R.,University of Michigan | Luan Phan K.,University of Michigan | Luan Phan K.,Ann Arbor Veterans Administration Medical Center | And 2 more authors.
Human Brain Mapping | Year: 2011

Making choices between payoffs available at different points in time reliably engages a decision-making brain circuit that includes medial prefrontal cortex (mPFC), posterior cingulate cortex (PCC), and ventral striatum (VS). Previous neuroimaging studies produced differing accounts of the functions of these regions, including that these regions: (1) are sensitive to the value of rewards discounted by a function of delay ('subjective value'); (2) are differentially sensitive to the availability of an immediate reward; and (3) are implicated in impulsive decision-making. In this event-related fMRI study of 20 volunteers, these hypotheses were investigated simultaneously using a delay discounting task in which magnitude of rewards and stimulus type, i.e., the presence or absence of an immediate option, were independently varied, and in which participants' trait impulsivity was assessed with the Barratt Impulsiveness Scale. Results showed that mPFC, PCC, and VS are sensitive to the subjective value of rewards, whereas mPFC and PCC, but not VS, are sensitive to the presence of an immediate reward in the choice option. Moderation by individual differences in trait impulsivity was specific to the mPFC. Conjunction analysis showed significant overlap in mPFC and PCC for the main effects of subjective value and stimulus type, indicating these regions may serve multiple distinct roles during intertemporal decision-making. These findings significantly advance our understanding of the specificity and overlap of functions subserved by different regions involved in intertemporal decision-making, and help to reconcile conflicting accounts in the literature. © 2010 Wiley-Liss, Inc.

Chen H.,University of Michigan | Chen H.,Huazhong University of Science and Technology | Mester T.,University of Michigan | Raychaudhuri N.,University of Michigan | And 5 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2014

Context: Thyroid-associated ophthalmopathy (TAO) is the component of Graves' disease characterized by orbital inflammation and connective tissue remodeling. The IGF-1 receptor (IGF-1R) and TSH receptor (TSHR) form a physical and functional complex in orbital fibroblasts.Asubset of these fibroblasts is derivedfrominfiltratingCD34 fibrocytes.Teprotumumab(RV 001, R1507) is ahuman monoclonal anti-IGF-1R blocking antibody currently undergoing a phase 2 clinical trial in patients with active TAO. CopyrightObjective: To determine whether teprotumumab inhibits the induction by TSH of IL-6 and IL-8 in fibrocytes.Design: Fibrocytes were treated without or with teprotumumab in combination with IGF-1 or TSH.Main Outcome Measures: IL-6 and IL-8 mRNA expression and protein production were analyzed by real-time PCR and Luminex, respectively. Phosphorylated Akt (S473) levels were analyzed by Western blot. TSHR and IGF-1R display was assessed by flow cytometry.Results: Fibrocyte display of IGF-1R and TSHR was reduced with teprotumumab, as were IGF-1- and TSH-dependent phosphorylated Akt levels. TSH induction of IL-6 and IL-8 mRNA and protein was also reduced by the monoclonal antibody.Conclusions: Teprotumumab attenuates the actions of both IGF-1 and TSH in fibrocytes. Specifically, it blocks the induction of proinflammatory cytokines by TSH. These results provide, at least in part, the molecular rationale for interrogating the therapeutic efficacy of this antibody in TAO. © 2014 by the Endocrine Society.

O'Malley M.,University of Michigan | King A.N.,University of Michigan | Conte M.,University of Michigan | Ellingrod V.L.,University of Michigan | And 2 more authors.
Journal of Thoracic Oncology | Year: 2014

Introduction: Cigarette smoke associated polycyclic aromatic hydrocarbons can induce key drug-metabolizing enzymes of cytochrome P450 and isoforms of the glucuronyl transferases families. These enzymes metabolize several systemic therapies for lung cancer. Induction of these enzymes may lead to accelerated clearance with resultant impact on systemic therapy efficacy and toxicity in smokers compared with nonsmokers. This article reviews published literature regarding the influence of smoking as it relates to alteration of metabolism of systemic therapy in lung cancer. Methods: A structured search of the National Library of Medicine's PubMed/MEDLINE identified relevant articles. Data were abstracted and analyzed to summarize the findings. Results: Studies that analyzed pharmacokinetic data were prospective. Smokers receiving erlotinib exhibited rapid clearance, requiring a higher dose to reach equivalent systemic exposure compared with nonsmokers. Smokers receiving irinotecan also demonstrated increased clearance and lower systemic exposure. There was no difference in clearance of paclitaxel or docetaxel in smokers. Chemotherapy-associated neutropenia was worse in nonsmokers compared with smokers in patients treated with paclitaxel, docetaxel, irinotecan, and gemcitabine. Conclusions: Systemic therapy for lung cancer has a narrow therapeutic index such that small changes in plasma concentrations or exposure in smokers may result in suboptimal therapy and poor outcomes. Smoking cessation must be emphasized at each clinical visit. However, prospective trials should take into consideration the effects of smoking history on drug pharmacokinetics and efficacy. The metabolizing enzyme phenotype in smokers may require individualized dose algorithms for specific agents. © 2014 by the International Association for the Study of Lung Cancer.

Halverson S.,University of Michigan | Schipper M.,University of Michigan | Blas K.,University of Michigan | Lee V.,University of Michigan | And 6 more authors.
Radiotherapy and Oncology | Year: 2011

Background: The Cancer of the Prostate Risk Assessment (CAPRA) was developed to predict freedom from biochemical failure (FFBF) following radical prostatectomy (RP). Its utility following external beam radiation therapy (EBRT) has not been externally evaluated. Methods: A retrospective study of 612 patients treated with dose-escalated EBRT at the University of Michigan Medical Center. Results: Compared to the derivation cohort, EBRT treated patients had higher-risk disease (28% with CAPRA of 6-10 vs. 5%, respectively). A total of 114 patients (19%) had BF with 5-year BF ranging from 7% with CAPRA 0-3 to 35% with CAPRA 7-10. For RT patients the risk of BF at 5-year was similar to 4 surgical cohorts for CAPRA scores 0-2 but lower for all CAPRA scores ≥ 3. The difference favoring RT increased with increasing CAPRA score reaching a 27-50% absolute improved at 5-years for CAPRA scores of 6-10. On multivariate analysis each CAPRA point increased the risk of BF (p < 0.0001) while Gleason pattern 5 in the biopsy also increased BF (p = 0.01) and long-term androgen deprivation therapy (ADT) significantly reduced the risk of BF (p = 0.015). Conclusions: Compared to surgical series the risk of BF was lower with dose-escalated EBRT with the greatest difference at the highest CAPRA scores. © 2011 Elsevier Ireland Ltd. All rights reserved.

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