Publications by authors named "Nitai D Mukhopadhyay"

37 Publications

Target volume definition for staple line recurrences of non-small cell lung cancer.

Rep Pract Oncol Radiother 2021 30;26(6):861-868. Epub 2021 Dec 30.

Department of Radiation Oncology, Virginia Commonwealth University Health System, Richmond, VA, United States.

Background: Staple line (SL) recurrences of non-small cell lung cancer (NSCLC) are commonly treated with radiotherapy (RT), but the target volume definition - whole SL versus focused on recurrence - is unclear. The aim of the study was to determine the appropriate target volume for RT of SL recurrences.

Materials And Methods: Twenty-two consecutive patients (20 stage I, 2 stage II) treated with salvage RT for SL recurrences were retrospectively analyzed. Imaging features at the time of SL recurrence were evaluated to guide target volume definition.

Results: All patients had complete tumor resection (wedge resection in 10 (45%) and lobectomy in 12 (55%) patients). 14 (64%) patients had risk factors for recurrence, including surgical margins ≤ 2 cm, angiolymphatic and visceral pleural invasion. After a median 26 months (9-67), all 22 patients developed SL recurrence which was metabolically active on PET in all and biopsy-confirmed in 18/22 (82%) patients. All patients underwent RT targeting the location of the SL recurrence only. 13/22 (59%) patients had additional PE T-negative nodular or linear SL changes that were not included in the irradiated volume. After a median 17 months (9-34) 10/22 (45%) patients recurred either regionally 6/10 (60%), in the lungs 4/10 (40%) or distally 3/10 (30%). No patient recurred at the SL. Two-year overall and disease-free survival rates after RT were 71% and 65%, respectively.

Conclusion: RT to SL recurrences alone results in excellent local control. Additional treatment to reduce regional and distant recurrences should be considered.
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http://dx.doi.org/10.5603/RPOR.a2021.0090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8726443PMC
December 2021

Anticholinergic Medication Burden in Parkinson's Disease Outpatients.

J Parkinsons Dis 2022 ;12(2):599-606

Department of Neurology, Virginia Commonwealth University, Richmond, VA, USA.

Background: Individuals with Parkinson's disease (PD) may be especially vulnerable to future cognitive decline from anticholinergic medications.

Objective: To characterize anticholinergic medication burden, determine the co-occurrence of anticholinergic and cholinesterase inhibitors, and to assess the correlations among anticholinergic burden scales in PD outpatients.

Methods: We studied 670 PD outpatients enrolled in a clinic registry between 2012 and 2020. Anticholinergic burden was measured with the Anticholinergic Cognitive Burden Scale (ACB), Anticholinergic Drug Scale (ADS), Anticholinergic Risk Scale (ARS), and Drug Burden Index-Anticholinergic component (DBI-Ach). Correlations between scales were assessed with weighted kappa coefficients.

Results: Between 31.5 to 46.3% of PD patients were taking medications with anticholinergic properties. Among the scales applied, the ACB produced the highest prevalence of medications with anticholinergic properties (46.3%). Considering only medications with definite anticholinergic activity (scores of 2 or 3 on ACB, ADS, or ARS), the most common anticholinergic drug classes were antiparkinsonian (8.2%), antipsychotic (6.4%), and urological (3.3%) medications. Cholinesterase inhibitors and medications with anticholinergic properties were co-prescribed to 5.4% of the total cohort. The most highly correlated scales were ACB and ADS (κ= 0.71), ACB and ARS (κ= 0.67), and ADS and ARS (κ= 0.55).

Conclusion: A high proportion of PD patients (20%) were either taking antiparkinsonian, urological, or antipsychotic anticholinergic medications or were co-prescribed anticholinergic medications and cholinesterase inhibitors. By virtue of its detection of a high prevalence of anticholinergic medication usage and its high correlation with other scales, our data support use of the ACB scale to assess anticholinergic burden in PD patients.
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http://dx.doi.org/10.3233/JPD-212769DOI Listing
April 2022

Interprofessional Image Verification Workshop for Physician and Physics Residents: A Multi-Institutional Experience.

Int J Radiat Oncol Biol Phys 2021 11 8;111(4):1058-1065. Epub 2021 Aug 8.

Department of Radiation Oncology, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.

Purpose: Verification of patient position through pretreatment setup imaging is crucial in modern radiation therapy. As treatment complexity increases and technology evolves, physicist-physician collaboration becomes imperative for safe and successful radiation delivery. Despite the importance of both, residency programs lack formal interprofessional education (IPE) activities or structured training for image verification. Here we show the impact of an interprofessional image verification workshop for residents in a multi-institutional setting.

Methods: The workshop included a lecture by the attending physicist and physician, and hands-on image registration practice by learners (medical physics residents, MP; and radiation oncology residents, RO). All participants filled out pre- and postactivity surveys and rated their comfort from 1 to 10 in (A) selecting what type of imaging to order for a given case and (B) independently assessing the setup quality based on imaging. A paired 1-tailed t test (α = 0.05) was used to evaluate significance; Spearman rank correlation coefficient was used to assess correlation of ratings and RO postgraduate year (PGY). Surveys had free-response questions about IPE and image verification activities in residency.

Results: A total of 71 residents from 7 institutions participated between 2018 and 2020. Pre- and postsurveys were completed by 50 residents (38RO, 12MP) and showed an increase in (A) from 5.5 ± 2.2 to 7.1 ± 1.6 (P < .001) and in (B) from 5.1 ± 2.3 to 6.8 ± 1.5 (P < .001), with significant increases per subgroup (A = 1.8 ± 1.7, P < .001; B = 1.9 ± 1.8, P <. 001; A = 1.1 ± 1.4, P = .012; B = 1.2 ± 1.6, P = .016). RO confidence scores moderately correlated with PGY. Survey responses indicated that image verification training is mostly unstructured, with extent of exposure varying by program and attending; most with little-to-no training. Time constraints were identified as the main barrier. IPE was noted as a useful way to incorporate different perspectives into the process.

Conclusions: Formal image verification training increases resident comfort with setup imaging review and provides opportunities for interprofessional collaboration in radiation oncology residency programs.
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http://dx.doi.org/10.1016/j.ijrobp.2021.07.1706DOI Listing
November 2021

Statistical Modeling of Longitudinal Data with Non-ignorable Non-monotone Missingness with Semiparametric Bayesian and Machine Learning Components.

Sankhya B (2008) 2021 May 9;83(1):152-169. Epub 2020 Mar 9.

Department of Biostatistics, Virginia Commonwealth University, 830 East Main Street, Richmond, VA.

In longitudinal studies, outcomes are measured repeatedly over time and it is common that not all the patients will be measured throughout the study. For example patients can be lost to follow-up (monotone missingness) or miss one or more visits (non-monotone missingness); hence there are missing outcomes. In the longitudinal setting, we often assume the missingness is related to the unobserved data, which is non-ignorable. Pattern-mixture models (PMM) analyze the joint distribution of outcome and patterns of missingness in longitudinal data with non-ignorable nonmonotone missingness. Existing methods employ PMM and impute the unobserved outcomes using the distribution of observed outcomes, conditioned on missing patterns. We extend the existing methods using latent class analysis (LCA) and a shared-parameter PMM. The LCA groups patterns of missingness with similar features and the shared-parameter PMM allows a subset of parameters to be different between latent classes when fitting a model. We also propose a method for imputation using distribution of observed data conditioning on latent class. Our model improves existing methods by accommodating data with small sample size. In a simulation study our estimator had smaller mean squared error than existing methods. Our methodology is applied to data from a phase II clinical trial that studies quality of life of patients with prostate cancer receiving radiation therapy.
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http://dx.doi.org/10.1007/s13571-019-00222-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209781PMC
May 2021

PLK1 Induces Chromosomal Instability and Overrides Cell-Cycle Checkpoints to Drive Tumorigenesis.

Cancer Res 2021 03 29;81(5):1293-1307. Epub 2020 Dec 29.

Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, Virginia.

Polo-like kinase 1 (PLK1) is an essential cell-cycle regulator that is frequently overexpressed in various human cancers. To determine whether Plk1 overexpression drives tumorigenesis, we established transgenic mouse lines that ubiquitously express increased levels of Plk1. High Plk1 levels were a driving force for different types of spontaneous tumors. Increased Plk1 levels resulted in multiple defects in mitosis and cytokinesis, supernumerary centrosomes, and compromised cell-cycle checkpoints, allowing accumulation of chromosomal instability (CIN), which resulted in aneuploidy and tumor formation. Clinically, higher expression of PLK1 positively associated with an increase in genome-wide copy-number alterations in multiple human cancers. This study provides evidence that aberrant expression of PLK1 triggers CIN and tumorigenesis and highlights potential therapeutic opportunities for CIN-positive cancers. SIGNIFICANCE: These findings establish roles for PLK1 as a potent proto-oncogene and a CIN gene and provide insights for the development of effective treatment regimens across PLK1-overexpressing and CIN-positive cancers.
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http://dx.doi.org/10.1158/0008-5472.CAN-20-1377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026515PMC
March 2021

Utilization of Multiparametric MRI of Prostate in Patients under Consideration for or Already in Active Surveillance: Correlation with Imaging Guided Target Biopsy.

Diagnostics (Basel) 2020 Jun 29;10(7). Epub 2020 Jun 29.

Department of Urology, Virginia Commonwealth University Health System, 401 North 12th Street, Richmond, VA 23298, USA.

This study sought to assess the value of multiparametric magnetic resonance image (mp-MRI) in patients with a prostate cancer (PCa) Gleason score of 6 or less under consideration for or already in active surveillance and to determine the rate of upgrading by target biopsy. Three hundred and fifty-four consecutive men with an initial transrectal ultrasound-guided (TRUS) biopsy-confirmed PCa Gleason score of 6 or less under clinical consideration for or already in active surveillance underwent mp-MRI and were retrospectively reviewed. One hundred and nineteen of 354 patients had cancer-suspicious regions (CSRs) at mp-MRI. Each CSR was assigned a Prostate Imaging Reporting and Data System (PI-RADS) score based on PI-RADS v2. One hundred and eight of 119 patients underwent confirmatory imaging-guided biopsy for CSRs. Pathology results including Gleason score (GS) and percentage of specimens positive for PCa were recorded. Associations between PI-RADS scores and findings at target biopsy were evaluated using logistic regression. At target biopsy, 81 of 108 patients had PCa (75%). Among them, 77 patients had upgrading (22%, 77 of 354 patients). One hundred and forty-six CSRs in 108 patients had PI-RADS 3 = 28, 4 = 66, and 5 = 52. The upgraded rate for each category of CSR was for PI-RADS 3 (5 of 28, 18%), 4 (47 of 66, 71%) and 5 (49 of 52, 94%). Using logistic regression analysis, differences in PI-RADS scores from 3 to 5 are significantly associated with the probability of disease upgrade (20%, 73%, and 96% for PI-RADS score of 3, 4, and 5, respectively). Adding mp-MRI to patients under consideration for or already in active surveillance helps to identify undiagnosed PCa of a higher GS or higher volume resulting in upgrading in 22%.
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http://dx.doi.org/10.3390/diagnostics10070441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400343PMC
June 2020

Posttranscriptional Inhibition of Protein Tyrosine Phosphatase Nonreceptor Type 23 by Staphylococcal Nuclease and Tudor Domain Containing 1: Implications for Hepatocellular Carcinoma.

Hepatol Commun 2019 Sep 15;3(9):1258-1270. Epub 2019 Jul 15.

Department of Human and Molecular Genetics Virginia Commonwealth University Richmond VA.

Oncoprotein staphylococcal nuclease and tudor domain containing 1 (SND1) regulates gene expression at a posttranscriptional level in multiple cancers, including hepatocellular carcinoma (HCC). Staphylococcal nuclease (SN) domains of SND1 function as a ribonuclease (RNase), and the tudor domain facilitates protein-oligonucleotide interaction. In the present study, we aimed to identify RNA interactome of SND1 to obtain enhanced insights into gene regulation by SND1. RNA interactome was identified by immunoprecipitation (IP) of RNA using anti-SND1 antibody from human HCC cells followed by RNA immunoprecipitation sequencing (RIP-Seq). Among RNA species that showed more than 10-fold enrichment over the control, we focused on the tumor suppressor protein tyrosine phosphatase nonreceptor type 23 (PTPN23) because its regulation by SND1 and its role in HCC are not known. PTPN23 levels were down-regulated in human HCC cells versus normal hepatocytes and in human HCC tissues versus normal adjacent liver, as revealed by immunohistochemistry. In human HCC cells, knocking down SND1 increased and overexpression of SND1 decreased PTPN23 protein. RNA binding and degradation assays revealed that SND1 binds to and degrades the 3'-untranslated region (UTR) of PTPN23 messenger RNA (mRNA). Tetracycline-inducible PTPN23 overexpression in human HCC cells resulted in significant inhibition in proliferation, migration, and invasion and tumorigenesis. PTPN23 induction caused inhibition in activation of tyrosine-protein kinase Met (c-Met), epidermal growth factor receptor (EGFR), Src, and focal adhesion kinase (FAK), suggesting that, as a putative phosphatase, PTPN23 inhibits activation of these oncogenic kinases. PTPN23 is a novel target of SND1, and our findings identify PTPN23 as a unique tumor suppressor for HCC. PTPN23 might function as a homeostatic regulator of multiple kinases, restraining their activation.
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http://dx.doi.org/10.1002/hep4.1400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719750PMC
September 2019

Classical and Bayesian random-effects meta-analysis models with sample quality weights in gene expression studies.

BMC Bioinformatics 2019 Jan 9;20(1):18. Epub 2019 Jan 9.

Department of Biostatistics, Virginia Commonwealth University, Richmond, Virginia, USA.

Background: Random-effects (RE) models are commonly applied to account for heterogeneity in effect sizes in gene expression meta-analysis. The degree of heterogeneity may differ due to inconsistencies in sample quality. High heterogeneity can arise in meta-analyses containing poor quality samples. We applied sample-quality weights to adjust the study heterogeneity in the DerSimonian and Laird (DSL) and two-step DSL (DSLR2) RE models and the Bayesian random-effects (BRE) models with unweighted and weighted data, Gibbs and Metropolis-Hasting (MH) sampling algorithms, weighted common effect, and weighted between-study variance. We evaluated the performance of the models through simulations and illustrated application of the methods using Alzheimer's gene expression datasets.

Results: Sample quality adjusting within study variance (w) models provided an appropriate reduction of differentially expressed (DE) genes compared to other weighted functions in classical RE models. The BRE model with a uniform(0,1) prior was appropriate for detecting DE genes as compared to the models with other prior distributions. The precision of DE gene detection in the heterogeneous data was increased with the DSLR2w weighted model compared to the DSLw weighted model. Among the BRE weighted models, the wweighted- and unweighted-data models and both Gibbs- and MH-based models performed similarly. The w weighted common-effect model performed similarly to the unweighted model in the homogeneous data, but performed worse in the heterogeneous data. The wweighted data were appropriate for detecting DE genes with high precision, while the wweighted between-study variance models were appropriate for detecting DE genes with high overall accuracy. Without the weight, when the number of genes in microarray increased, the DSLR2 performed stably, while the overall accuracy of the BRE model was reduced. When applying the weighted models in the Alzheimer's gene expression data, the number of DE genes decreased in all metadata sets with the DSLR2wweighted and the wweighted between study variance models. Four hundred and forty-six DE genes identified by the wweighted between study variance model could be potentially down-regulated genes that may contribute to good classification of Alzheimer's samples.

Conclusions: The application of sample quality weights can increase precision and accuracy of the classical RE and BRE models; however, the performance of the models varied depending on data features, levels of sample quality, and adjustment of parameter estimates.
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http://dx.doi.org/10.1186/s12859-018-2491-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6327440PMC
January 2019

Diabetes mellitus and radiation induced lung injury after thoracic stereotactic body radiotherapy.

Radiother Oncol 2018 11 22;129(2):270-276. Epub 2018 Sep 22.

Department of Radiation Oncology, Virginia Commonwealth University, Richmond, USA.

Background: Radiographic radiation induced lung injury (RILI) is frequently observed after stereotactic body radiotherapy (SBRT). Models of radiographic change can identify patient risk factors that predict clinical toxicity. We examined the association between radiographic lung changes and lung tissue dose-density response over time with clinical risk factors for RILI, such as diabetes.

Methods: 424 baseline and follow up CT scans at 3, 6, and 12 months post-treatment were analyzed in 116 patients (27 with diabetes) undergoing thoracic SBRT. Volumes of dense/hazy regions and lung parenchyma dose-density response curves were evaluated with respect to follow up time, diabetes, and other factors.

Results: Dense and hazy tissue regions were larger in the diabetic population, with the effect most pronounced at 3 months. Similarly, dose-density response curves showed greater density change versus dose in the diabetic group (all p < 0.05). Diabetes, time, the interaction of diabetes and time, smoking status, African American race, baseline lung density, and tumor location were significantly associated with radiographic changes on mixed effect analyses. PTV size, pulmonary function, and medication exposure did not significantly impact RILI. Clinical grade 1-2 pneumonitis was more prevalent in diabetic patients (p = 0.02). However, radiographic change did not correlate with clinical pneumonitis.

Conclusions: The presence of diabetes and other clinical factors is associated with increased volume and density of radiographic RILI after lung SBRT, most prominently early after treatment. This is the first report demonstrating the increased severity of RILI after SBRT in diabetic patients. Increased caution treating diabetic patients may be warranted.
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http://dx.doi.org/10.1016/j.radonc.2018.08.024DOI Listing
November 2018

Astrocyte Elevated Gene-1 Regulates Macrophage Activation in Hepatocellular Carcinogenesis.

Cancer Res 2018 11 4;78(22):6436-6446. Epub 2018 Sep 4.

Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia.

Chronic inflammation is a known hallmark of cancer and is central to the onset and progression of hepatocellular carcinoma (HCC). Hepatic macrophages play a critical role in the inflammatory process leading to HCC. The oncogene Astrocyte elevated gene-1 () regulates NFκB activation, and germline knockout of in mice (AEG-1) results in resistance to inflammation and experimental HCC. In this study, we developed conditional hepatocyte- and myeloid cell-specific AEG-1 mice (AEG-1 and AEG-1, respectively) and induced HCC by treatment with N-nitrosodiethylamine (DEN) and phenobarbital (PB). AEG-1 mice exhibited a significant reduction in disease severity compared with control littermates, while AEG-1 mice were profoundly resistant. , AEG-1 hepatocytes exhibited increased sensitivity to stress and senescence. Notably, AEG-1 macrophages were resistant to either M1 or M2 differentiation with significant inhibition in migration, endothelial adhesion, and efferocytosis activity, indicating that AEG-1 ablation renders macrophages functionally anergic. These results unravel a central role of AEG-1 in regulating macrophage activation and indicate that AEG-1 is required in both tumor cells and tumor microenvironment to stimulate hepatocarcinogenesis. These findings distinguish a novel role of macrophage-derived oncogene AEG-1 from hepatocellular AEG-1 in promoting inflammation and driving tumorigenesis. .
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http://dx.doi.org/10.1158/0008-5472.CAN-18-0659DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6239947PMC
November 2018

Low-dose splenic irradiation prior to hematopoietic cell transplantation in hypersplenic patients with myelofibrosis.

Leuk Lymphoma 2017 12 31;58(12):2983-2984. Epub 2017 May 31.

a Department of Radiation Oncology , Virginia Commonwealth University , Richmond , VA , USA.

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http://dx.doi.org/10.1080/10428194.2017.1321747DOI Listing
December 2017

A novel role of astrocyte elevated gene-1 (AEG-1) in regulating nonalcoholic steatohepatitis (NASH).

Hepatology 2017 08 30;66(2):466-480. Epub 2017 Jun 30.

Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA.

Nonalcoholic steatohepatitis (NASH) is the most prevalent cause of chronic liver disease in the Western world. However, an optimum therapy for NASH is yet to be established, mandating more in-depth investigation into the molecular pathogenesis of NASH to identify novel regulatory molecules and develop targeted therapies. Here, we unravel a unique function of astrocyte elevated gene-1(AEG-1)/metadherin in NASH using a transgenic mouse with hepatocyte-specific overexpression of AEG-1 (Alb/AEG-1) and a conditional hepatocyte-specific AEG-1 knockout mouse (AEG-1 ). Alb/AEG-1 mice developed spontaneous NASH whereas AEG-1 mice were protected from high-fat diet (HFD)-induced NASH. Intriguingly, AEG-1 overexpression was observed in livers of NASH patients and wild-type (WT) mice that developed steatosis upon feeding HFD. In-depth molecular analysis unraveled that inhibition of peroxisome proliferator-activated receptor alpha activity resulting in decreased fatty acid β-oxidation, augmentation of translation of fatty acid synthase resulting in de novo lipogenesis, and increased nuclear factor kappa B-mediated inflammation act in concert to mediate AEG-1-induced NASH. Therapeutically, hepatocyte-specific nanoparticle-delivered AEG-1 small interfering RNA provided marked protection from HFD-induced NASH in WT mice.

Conclusion: AEG-1 might be a key molecule regulating initiation and progression of NASH. AEG-1 inhibitory strategies might be developed as a potential therapeutic intervention in NASH patients. (Hepatology 2017;66:466-480).
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http://dx.doi.org/10.1002/hep.29230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5519412PMC
August 2017

A Phase II Study to Prevent Radiation-induced Rectal Injury With Lovastatin.

Am J Clin Oncol 2018 06;41(6):544-548

Biostatistics.

Purpose: Physician reported symptomatic late rectal injury occurs in about 5% to 25% of patients treated with radiation therapy for prostate cancer, depending on the treatment technique. Patients, however, report clinically meaningful declines in bowel/rectal function regardless of the technique used. Lovastatin has been shown to protect mice from late radiation injury. This study was designed to determine if lovastatin might reduce the incidence of late rectal injury in patients receiving radiation therapy for prostate cancer.

Materials And Methods: Patients with adenocarcinoma of the prostate receiving radiotherapy with curative intent were eligible. A portion of the rectum had to receive at least 60 Gy. Gastrointestinal functioning was assessed using both physician-reported and patient-reported instruments at baseline and at prescribed intervals during and after treatment. Lovastatin (20 to 80 mg/d) was started on day 1 of radiation and continued for 12 months. Patients were followed for an additional 12 months. The primary endpoint was physician-reported rectal toxicity ≥grade 2 during the first 2 years after treatment.

Results: A total of 20/53 (38%) patients developed grade 2 or higher toxicity during the 2-year follow-up period. Seventeen patients had 1 or more unresolved gastrointestinal symptom at the end of 2 years, 3 (6%) of which were grade 2 and none were of higher grade.

Conclusions: The primary endpoint of the study was not met. Lovastatin, as administered in this trial, did not reduce the incidence of grade 2 or higher rectal toxicity compared with historical controls.
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http://dx.doi.org/10.1097/COC.0000000000000320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5247423PMC
June 2018

Constitutive Activation of DNA Damage Checkpoint Signaling Contributes to Mutant p53 Accumulation via Modulation of p53 Ubiquitination.

Mol Cancer Res 2016 05 10;14(5):423-36. Epub 2016 Mar 10.

Division of Hematology, Oncology, and Palliative Care, Virginia Commonwealth University, Richmond, Virginia. VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia.

Unlabelled: Many mutant p53 proteins exhibit an abnormally long half-life and overall increased abundance compared with wild-type p53 in tumors, contributing to mutant p53's gain-of-function oncogenic properties. Here, a novel mechanism is revealed for the maintenance of mutant p53 abundance in cancer that is dependent on DNA damage checkpoint activation. High-level mutant p53 expression in lung cancer cells was associated with preferential p53 monoubiquitination versus polyubiquitination, suggesting a role for the ubiquitin/proteasome system in regulation of mutant p53 abundance in cancer cells. Interestingly, mutant p53 ubiquitination status was regulated by ataxia-telangectasia mutated (ATM) activation and downstream phosphorylation of mutant p53 (serine 15), both in resting and in genotoxin-treated lung cancer cells. Specifically, either inhibition of ATM with caffeine or mutation of p53 (serine 15 to alanine) restored MDM2-dependent polyubiquitination of otherwise monoubiquitinated mutant p53. Caffeine treatment rescued MDM2-dependent proteasome degradation of mutant p53 in cells exhibiting active DNA damage signaling, and ATM knockdown phenocopied the caffeine effect. Importantly, in cells analyzed individually by flow cytometry, p53 levels were highest in cells exhibiting the greatest levels of DNA damage response, and interference with DNA damage signaling preferentially decreased the relative percentage of cells in a population with the highest levels of mutant p53. These data demonstrate that active DNA damage signaling contributes to high levels of mutant p53 via modulation of ubiquitin/proteasome activity toward p53.

Implication: The ability of DNA damage checkpoint signaling to mediate accumulation of mutant p53 suggests that targeting this signaling pathway may provide therapeutic gain. Mol Cancer Res; 14(5); 423-36. ©2016 AACR.
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http://dx.doi.org/10.1158/1541-7786.MCR-15-0363DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5110038PMC
May 2016

Multivariate Granger Causality Analysis of Obesity Related Variables.

Austin Biom Biostat 2015;2(2). Epub 2015 Jun 19.

Department of Biostatistics, Virginia Commonwealth University, USA.

Obesity is a complex health outcome that is a combination of multiple health indicators. Here we attempt to explore the dependence network among multiple aspects of obesity. Two longitudinal cohort studies across multiple decades have been used. The concept of causality is defined similar to Granger causality among multiple time series, however, modified to accommodate multivariate time series as the nodes of the network. Our analysis reveals relatively central position of physical measurements and blood chemistry measures in the overall network across both genders. Also there are some patterns specific to only male or female population. The geometry of the causality network is expected to help in our strategy to control the increasing trend of obesity rate.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4743668PMC
June 2015

A Preliminary Study on Racial Differences in HMOX1, NFE2L2, and TGFβ1 Gene Polymorphisms and Radiation-Induced Late Normal Tissue Toxicity.

Int J Radiat Oncol Biol Phys 2015 Oct 6;93(2):436-43. Epub 2015 Jun 6.

Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia. Electronic address:

Purpose: This study tested whether racial differences in genetic polymorphisms of 4 genes involved in wound repair and response to radiation can be used to predict the occurrence of normal tissue late effects of radiation therapy and indicate potential therapeutic targets.

Methods And Materials: This prospective study examined genetic polymorphisms that modulate the expression of 4 genes involved in inflammation and fibrosis and response to radiation (HMOX1, NFE2L2, NOS3, and TGFβ1). DNA from blood samples of 179 patients (∼ 80% breast and head and neck) collected at the time of diagnosis by their radiation oncologist as exhibiting late normal tissue toxicity was used for the analysis. Patient demographics were as follows: 56% white, 43% African American, 1% other. Allelic frequencies of the different polymorphisms of the participants were compared with those of the general American population stratified by race. Twenty-six additional patients treated with radiation, but without toxicity at 3 months or later after therapy, were also analyzed.

Results: Increased frequency of a long GT repeat in the HMOX1 promoter was associated with late effects in both African American and white populations. The single nucleotide polymorphisms (SNP) rs1800469 in the TGFβ1 promoter and the rs6721961 SNP in the NFE2L2 promoter were also found to significantly associate with late effects in African Americans but not whites. A combined analysis of these polymorphisms revealed that >90% of African American patients with late effects had at least 1 of these minor alleles, and 58% had 2 or more. No statistical significance was found relating the studied NOS3 polymorphisms and normal tissue toxicity.

Conclusions: These results support a strong association between wound repair and late toxicities of radiation. The presence of these genetic risk factors can vary significantly among different ethnic groups, as demonstrated for some of the SNPs. Future studies should account for the possibility of such ethnic heterogeneity in the late toxicities of radiation.
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http://dx.doi.org/10.1016/j.ijrobp.2015.05.049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4575610PMC
October 2015

Astrocyte Elevated Gene-1 (AEG-1) Contributes to Non-thyroidal Illness Syndrome (NTIS) Associated with Hepatocellular Carcinoma (HCC).

J Biol Chem 2015 Jun 5;290(25):15549-15558. Epub 2015 May 5.

Departments of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia 23298; Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23298; VCU Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, Virginia 23298. Electronic address:

Non-thyroidal illness syndrome (NTIS), characterized by low serum 3,5,3'-triiodothyronine (T3) with normal l-thyroxine (T4) levels, is associated with malignancy. Decreased activity of type I 5'-deiodinase (DIO1), which converts T4 to T3, contributes to NTIS. T3 binds to thyroid hormone receptor, which heterodimerizes with retinoid X receptor (RXR) and regulates transcription of target genes, such as DIO1. NF-κB activation by inflammatory cytokines inhibits DIO1 expression. The oncogene astrocyte elevated gene-1 (AEG-1) inhibits RXR-dependent transcription and activates NF-κB. Here, we interrogated the role of AEG-1 in NTIS in the context of hepatocellular carcinoma (HCC). T3-mediated gene regulation was analyzed in human HCC cells, with overexpression or knockdown of AEG-1, and primary hepatocytes from AEG-1 transgenic (Alb/AEG-1) and AEG-1 knock-out (AEG-1KO) mice. Serum T3 and T4 levels were checked in Alb/AEG-1 mice and human HCC patients. AEG-1 and DIO1 levels in human HCC samples were analyzed by immunohistochemistry. AEG-1 inhibited T3-mediated gene regulation in human HCC cells and mouse hepatocytes. AEG-1 overexpression repressed and AEG-1 knockdown induced DIO1 expression. An inverse correlation was observed between AEG-1 and DIO1 levels in human HCC patients. Low T3 with normal T4 was observed in the sera of HCC patients and Alb/AEG-1 mice. Inhibition of co-activator recruitment to RXR and activation of NF-κB were identified to play a role in AEG-1-mediated down-regulation of DIO1. AEG-1 thus might play a role in NTIS associated with HCC and other cancers.
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http://dx.doi.org/10.1074/jbc.M115.649707DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505468PMC
June 2015

The Role of Nitric Oxide Synthase Uncoupling in Tumor Progression.

Mol Cancer Res 2015 Jun 27;13(6):1034-43. Epub 2015 Feb 27.

Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia.

Unlabelled: Here, evidence suggests that nitric oxide synthases (NOS) of tumor cells, in contrast with normal tissues, synthesize predominantly superoxide and peroxynitrite. Based on high-performance liquid chromatography analysis, the underlying mechanism for this uncoupling is a reduced tetrahydrobiopterin:dihydrobiopterin ratio (BH4:BH2) found in breast, colorectal, epidermoid, and head and neck tumors compared with normal tissues. Increasing BH4:BH2 and reconstitution of coupled NOS activity in breast cancer cells with the BH4 salvage pathway precursor, sepiapterin, causes significant shifts in downstream signaling, including increased cGMP-dependent protein kinase (PKG) activity, decreased β-catenin expression, and TCF4 promoter activity, and reduced NF-κB promoter activity. Sepiapterin inhibited breast tumor cell growth in vitro and in vivo as measured by a clonogenic assay, Ki67 staining, and 2[18F]fluoro-2-deoxy-D-glucose-deoxyglucose positron emission tomography (FDG-PET). In summary, using diverse tumor types, it is demonstrated that the BH4:BH2 ratio is lower in tumor tissues and, as a consequence, NOS activity generates more peroxynitrite and superoxide anion than nitric oxide, resulting in important tumor growth-promoting and antiapoptotic signaling properties.

Implications: The synthetic BH4, Kuvan, is used to elevate BH4:BH2 in some phenylketonuria patients and to treat diseases associated with endothelial dysfunction, suggesting a novel, testable approach for correcting an abnormality of tumor metabolism to control tumor growth.
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http://dx.doi.org/10.1158/1541-7786.MCR-15-0057-TDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4470720PMC
June 2015

AEG-1 regulates retinoid X receptor and inhibits retinoid signaling.

Cancer Res 2014 Aug;74(16):4364-77

Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, Virginia. Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia. VCU Institute of Molecular Medicine (VIMM), Virginia Commonwealth University, Richmond, Virginia.

Retinoid X receptor (RXR) regulates key cellular responses such as cell growth and development, and this regulation is frequently perturbed in various malignancies, including hepatocellular carcinoma (HCC). However, the molecule(s) that physically govern this deregulation are mostly unknown. Here, we identified RXR as an interacting partner of astrocyte-elevated gene-1 (AEG-1)/metadherin (MTDH), an oncogene upregulated in all cancers. Upon interaction, AEG-1 profoundly inhibited RXR/retinoic acid receptor (RAR)-mediated transcriptional activation. Consequently, AEG-1 markedly protected HCC and acute myelogenous leukemia (AML) cells from retinoid- and rexinoid-induced cell death. In nontumorigenic cells and primary hepatocytes, AEG-1/RXR colocalizes in the nucleus in which AEG-1 interferes with recruitment of transcriptional coactivators to RXR, preventing transcription of target genes. In tumor cells and AEG-1 transgenic hepatocytes, overexpressed AEG-1 entraps RXR in cytoplasm, precluding its nuclear translocation. In addition, ERK, activated by AEG-1, phosphorylates RXR that leads to its functional inactivation and attenuation of ligand-dependent transactivation. In nude mice models, combination of all-trans retinoic acid (ATRA) and AEG-1 knockdown synergistically inhibited growth of human HCC xenografts. The present study establishes AEG-1 as a novel homeostatic regulator of RXR and RXR/RAR that might contribute to hepatocarcinogenesis. Targeting AEG-1 could sensitize patients with HCC and AML to retinoid- and rexinoid-based therapeutics.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-0421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4135401PMC
August 2014

Astrocyte elevated gene-1 and c-Myc cooperate to promote hepatocarcinogenesis in mice.

Hepatology 2015 Mar 23;61(3):915-29. Epub 2015 Jan 23.

Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA.

Unlabelled: Astrocyte elevated gene-1 (AEG-1) and c-Myc are overexpressed in human hepatocellular carcinoma (HCC) functioning as oncogenes. AEG-1 is transcriptionally regulated by c-Myc, and AEG-1 itself induces c-Myc by activating the Wnt/β-catenin-signaling pathway. We now document the cooperation of AEG-1 and c-Myc in promoting hepatocarcinogenesis by analyzing hepatocyte-specific transgenic mice expressing either AEG-1 (albumin [Alb]/AEG-1), c-Myc (Alb/c-Myc), or both (Alb/AEG-1/c-Myc). Wild-type and Alb/AEG-1 mice did not develop spontaneous HCC. Alb/c-Myc mice developed spontaneous HCC without distant metastasis, whereas Alb/AEG-1/c-Myc mice developed highly aggressive HCC with frank metastasis to the lungs. Induction of carcinogenesis by N-nitrosodiethylamine significantly accelerated the kinetics of tumor formation in all groups. However, in Alb/AEG-1/c-Myc, the effect was markedly pronounced with lung metastasis. In vitro analysis showed that Alb/AEG-1/c-Myc hepatocytes acquired increased proliferation and transformative potential with sustained activation of prosurvival and epithelial-mesenchymal transition-signaling pathways. RNA-sequencing analysis identified a unique gene signature in livers of Alb/AEG-1/c-Myc mice that was not observed when either AEG-1 or c-Myc was overexpressed. Specifically, Alb/AEG-1/c-Myc mice overexpressed maternally imprinted noncoding RNAs (ncRNAs), such as Rian, Meg-3, and Mirg, which are implicated in hepatocarcinogenesis. Knocking down these ncRNAs significantly inhibited proliferation and invasion by Alb/AEG-1/c-Myc hepatocytes.

Conclusion: Our studies reveal a novel cooperative oncogenic effect of AEG-1 and c-Myc that might explain the mechanism of aggressive HCC. Alb/AEG-1/c-Myc mice provide a useful model to understand the molecular mechanism of cooperation between these two oncogenes and other molecules involved in hepatocarcinogenesis. This model might also be of use for evaluating novel therapeutic strategies targeting HCC.
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http://dx.doi.org/10.1002/hep.27339DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4309751PMC
March 2015

Staphylococcal nuclease domain containing-1 (SND1) promotes migration and invasion via angiotensin II type 1 receptor (AT1R) and TGFβ signaling.

FEBS Open Bio 2014 1;4:353-61. Epub 2014 Apr 1.

Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA 23298, United States ; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, United States ; VCU Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, VA 23298, United States.

Staphylococcal nuclease domain containing-1 (SND1) is overexpressed in human hepatocellular carcinoma (HCC) patients and promotes tumorigenesis by human HCC cells. We now document that SND1 increases angiotensin II type 1 receptor (AT1R) levels by increasing AT1R mRNA stability. This results in activation of ERK, Smad2 and subsequently the TGFβ signaling pathway, promoting epithelial-mesenchymal transition (EMT) and migration and invasion by human HCC cells. A positive correlation was observed between SND1 and AT1R expression levels in human HCC patients. Small molecule inhibitors of SND1, alone or in combination with AT1R blockers, might be an effective therapeutic strategy for late-stage aggressive HCC.
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http://dx.doi.org/10.1016/j.fob.2014.03.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050181PMC
June 2014

Induction of microRNA-21 with exogenous hydrogen sulfide attenuates myocardial ischemic and inflammatory injury in mice.

Circ Cardiovasc Genet 2014 Jun 13;7(3):311-20. Epub 2014 May 13.

From the Pauley Heart Center, Division of Cardiology, Department of Internal Medicine (S.T., A.D., E.M., V.Q.C., C.M., D.D., A.S., B.W.V.T., C.Y., R.A.O., N.V., R.C.K., A.A., F.N.S.) and Department of Biostatistics (N.D.M.), Virginia Commonwealth University, Richmond.

Background: Maintaining physiological levels of hydrogen sulfide during ischemia is necessary to limit injury to the heart. Because of the anti-inflammatory effects of hydrogen sulfide, we proposed that the hydrogen sulfide donor, sodium sulfide (Na2S), would attenuate myocardial injury through upregulation of protective microRNA-21 (miR-21) and suppression of the inflammasome, a macromolecular structure that amplifies inflammation and mediates further injury.

Methods And Results: Na2S-induced miR-21 expression was measured by quantitative polymerase chain reaction in adult primary rat cardiomyocytes and in the mouse heart. We measured inflammasome formation and activity in cardiomyocytes challenged with lipopolysaccharide and ATP or simulated ischemia/reoxygenation and in the heart after regional myocardial ischemia/reperfusion, in the presence or absence of Na2S. To assess the direct anti-inflammatory effects of hydrogen sulfide in vivo, we used a peritonitis model by way of intraperitoneal injection of zymosan A. Na2S attenuated inflammasome formation and activity, measured by counting cytoplasmic aggregates of the scaffold protein apoptosis speck-like protein containing a caspase-recruitment domain (-57%) and caspase-1 activity (-50%) in isolated cardiomyocytes and in the mouse heart (all P<0.05). Na2S also inhibited apoptosis (-38%) and necrosis (-43%) in cardiomyocytes in vitro and reduced myocardial infarct size (-63%) after ischemia/reperfusion injury in vivo (all P<0.05). These protective effects were absent in cells treated with the miR-21 eraser, antagomiR-21, and in miR-21 knockout mice. Na2S also limited the severity of inflammasome-dependent inflammation in the model of peritonitis (P<0.05) in wild-type but not in miR-21 knockout mice.

Conclusions: Na2S induces cardioprotective effects through miR-21-dependent attenuation of ischemic and inflammatory injury in cardiomyocytes.
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http://dx.doi.org/10.1161/CIRCGENETICS.113.000381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4090021PMC
June 2014

Long-term cosmesis and toxicity following 3-dimensional conformal radiation therapy in the delivery of accelerated partial breast irradiation.

Pract Radiat Oncol 2014 May-Jun;4(3):147-152. Epub 2013 Aug 15.

Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia.

Purpose: To evaluate cosmesis and toxicity in early-stage breast cancer patients treated with adjuvant 3D-CRT who received accelerated partial breast irradiation (APBI).

Methods And Materials: From November 2003 to June 2006, 60 breasts on 59 patients were treated with 3-dimensional conformal radiation therapy (3D-CRT) APBI. Patients with stage 0, I, or II breast cancer were eligible if a <3-cm tumor was resected with negative surgical margins, and axillary evaluation documented 0-3 positive nodes. The mean age was 58.7 years (range, 31-88 years). Target volume and critical structure definitions, as well as dose delivery guidelines, were consistent across both institutions. Treatment was twice daily for 5 consecutive days with 3.85 Gy per fraction to 38.5 Gy. Clinical follow-up was conducted at regular intervals that included history, physical exam, and mammography. The overall cosmesis was graded using the Harvard scale and toxicity was graded according to the Common Toxicity Criteria (v4.0), including hyperpigmentation, edema, telangiectasia, mastalgia, surgical defect, fibrosis, and fat necrosis. Dose-volume histogram and treatment parameters were collected and analyzed.

Results: At a mean follow-up of 44.3 months (range, 2-94 months), there were 4 cases of grade 3-4 toxicity (7%): 1 patient with mastalgia; 1 patient with mastalgia and fat necrosis; 1 patient with telangiectasia; and 1 patient with fibrosis. There was no statistical correlate between dosimetric parameters and cosmetic outcome. Overall cosmetic outcome was good or excellent in 58 breasts (95%) and "fair to poor" in 3 (5%). There were no local-regional failures; 3 patients failed distantly (5%).

Conclusions: Accelerated partial breast irradiation using 3D-CRT is safe and the risk of serious chronic side effect is low and acceptable.
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http://dx.doi.org/10.1016/j.prro.2013.07.004DOI Listing
January 2015

The human oncoprotein MDM2 induces replication stress eliciting early intra-S-phase checkpoint response and inhibition of DNA replication origin firing.

Nucleic Acids Res 2014 Jan 24;42(2):926-40. Epub 2013 Oct 24.

Division of Hematology, Oncology and Palliative Care, Department of Medicine, The Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA, Department of Biochemistry and Molecular Biology, The Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA, Department of Biostatistics, The Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA and Department of Medicinal Chemistry, The Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.

Conventional paradigm ascribes the cell proliferative function of the human oncoprotein mouse double minute2 (MDM2) primarily to its ability to degrade p53. Here we report that in the absence of p53, MDM2 induces replication stress eliciting an early S-phase checkpoint response to inhibit further firing of DNA replication origins. Partially synchronized lung cells cultured from p53-/-:MDM2 transgenic mice enter S phase and induce S-phase checkpoint response earlier than lung cells from p53-/- mice and inhibit firing of DNA replication origins. MDM2 activates chk1 phosphorylation, elevates mixed lineage lymphoma histone methyl transferase levels and promotes checkpoint-dependent tri-methylation of histone H3 at lysine 4, known to prevent firing of late replication origins at the early S phase. In the absence of p53, a condition that disables inhibition of cyclin A expression by MDM2, MDM2 increases expression of cyclin D2 and A and hastens S-phase entry of cells. Consistently, inhibition of cyclin-dependent kinases, known to activate DNA replication origins during firing, inhibits MDM2-mediated induction of chk1 phosphorylation indicating the requirement of this activity in MDM2-mediated chk1 phosphorylation. Our data reveal a novel pathway, defended by the intra-S-phase checkpoint, by which MDM2 induces unscheduled origin firing and accelerates S-phase entry of cells in the absence of p53.
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http://dx.doi.org/10.1093/nar/gkt944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3902934PMC
January 2014

Novel role of MDA-9/syntenin in regulating urothelial cell proliferation by modulating EGFR signaling.

Clin Cancer Res 2013 Sep 19;19(17):4621-33. Epub 2013 Jul 19.

Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA 23298, USA.

Purpose: Urothelial cell carcinoma (UCC) rapidly progresses from superficial to muscle-invasive tumors. The key molecules involved in metastatic progression and its early detection require clarification. The present study defines a seminal role of the metastasis-associated gene MDA-9/Syntenin in UCC progression.

Experimental Design: Expression pattern of MDA-9/Syntenin was examined in 44 primary UCC and the impact of its overexpression and knockdown was examined in multiple cells lines and key findings were validated in primary tumors.

Results: Significantly higher (P=0.002-0.003) expression of MDA-9/Syntenin was observed in 64% (28 of 44) of primary tumors and an association was evident with stage (P=0.01), grade (P=0.03), and invasion status (P=0.02). MDA-9/Syntenin overexpression in nontumorigenic HUC-1 cells increased proliferation (P=0.0012), invasion (P=0.0001), and EGF receptor (EGFR), AKT, phosphoinositide 3-kinase (PI3K), and c-Src expression. Alteration of β-catenin, E-cadherin, vimentin, claudin-1, ZO-1, and T-cell factor-4 (TCF4) expression was also observed. MDA-9/Syntenin knockdown in three UCC cell lines reversed phenotypic and molecular changes observed in the HUC-1 cells and reduced in vivo metastasis. Key molecular changes observed in the cell lines were confirmed in primary tumors. A physical interaction and colocalization of MDA-9/Syntenin and EGFR was evident in UCC cell lines and primary tumors. A logistic regression model analysis revealed a significant correlation between MDA-9/Syntenin:EGFR and MDA-9/Syntenin:AKT expressions with stage (P=0.04, EGFR; P=0.01, AKT). A correlation between MDA-9/Syntenin:β-catenin coexpression with stage (P=0.03) and invasion (P=0.04) was also evident.

Conclusions: Our findings indicate that MDA-9/Syntenin might provide an attractive target for developing detection, monitoring, and therapeutic strategies for managing UCC.
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http://dx.doi.org/10.1158/1078-0432.CCR-13-0585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3872137PMC
September 2013

ATM kinase inhibition preferentially sensitizes p53-mutant glioma to ionizing radiation.

Clin Cancer Res 2013 Jun 25;19(12):3189-200. Epub 2013 Apr 25.

Department of Radiation Oncology, Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia 23112, USA.

Purpose: Glioblastoma multiforme (GBM) is the most lethal form of brain cancer with a median survival of only 12 to 15 months. Current standard treatment consists of surgery followed by chemoradiation. The poor survival of patients with GBM is due to aggressive tumor invasiveness, an inability to remove all tumor tissue, and an innate tumor chemo- and radioresistance. Ataxia-telangiectasia mutated (ATM) is an excellent target for radiosensitizing GBM because of its critical role in regulating the DNA damage response and p53, among other cellular processes. As a first step toward this goal, we recently showed that the novel ATM kinase inhibitor KU-60019 reduced migration, invasion, and growth, and potently radiosensitized human glioma cells in vitro.

Experimental Design: Using orthotopic xenograft models of GBM, we now show that KU-60019 is also an effective radiosensitizer in vivo. Human glioma cells expressing reporter genes for monitoring tumor growth and dispersal were grown intracranially, and KU-60019 was administered intratumorally by convection-enhanced delivery or osmotic pump.

Results: Our results show that the combined effect of KU-60019 and radiation significantly increased survival of mice 2- to 3-fold over controls. Importantly, we show that glioma with mutant p53 is much more sensitive to KU-60019 radiosensitization than genetically matched wild-type glioma.

Conclusions: Taken together, our results suggest that an ATM kinase inhibitor may be an effective radiosensitizer and adjuvant therapy for patients with mutant p53 brain cancers.
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http://dx.doi.org/10.1158/1078-0432.CCR-12-3408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3687028PMC
June 2013

An inferential framework for biological network hypothesis tests.

BMC Bioinformatics 2013 Mar 14;14:94. Epub 2013 Mar 14.

Pfizer Global Research and Development, Groton, CT, USA.

Background: Networks are ubiquitous in modern cell biology and physiology. A large literature exists for inferring/proposing biological pathways/networks using statistical or machine learning algorithms. Despite these advances a formal testing procedure for analyzing network-level observations is in need of further development. Comparing the behaviour of a pharmacologically altered pathway to its canonical form is an example of a salient one-sample comparison. Locating which pathways differentiate disease from no-disease phenotype may be recast as a two-sample network inference problem.

Results: We outline an inferential method for performing one- and two-sample hypothesis tests where the sampling unit is a network and the hypotheses are stated via network model(s). We propose a dissimilarity measure that incorporates nearby neighbour information to contrast one or more networks in a statistical test. We demonstrate and explore the utility of our approach with both simulated and microarray data; random graphs and weighted (partial) correlation networks are used to form network models. Using both a well-known diabetes dataset and an ovarian cancer dataset, the methods outlined here could better elucidate co-regulation changes for one or more pathways between two clinically relevant phenotypes.

Conclusions: Formal hypothesis tests for gene- or protein-based networks are a logical progression from existing gene-based and gene-set tests for differential expression. Commensurate with the growing appreciation and development of systems biology, the dissimilarity-based testing methods presented here may allow us to improve our understanding of pathways and other complex regulatory systems. The benefit of our method was illustrated under select scenarios.
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http://dx.doi.org/10.1186/1471-2105-14-94DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3621801PMC
March 2013

Contura Multi-Lumen Balloon breast brachytherapy catheter: comparative dosimetric findings of a phase 4 trial.

Int J Radiat Oncol Biol Phys 2013 Jun 20;86(2):264-9. Epub 2013 Feb 20.

Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia, USA.

Purpose: Final dosimetric findings of a completed, multi-institutional phase 4 registry trial using the Contura Multi-Lumen Balloon (MLB) breast brachytherapy catheter to deliver accelerated partial breast irradiation (APBI) in patients with early-stage breast cancer are presented.

Methods And Materials: Three dosimetric plans with identical target coverage were generated for each patient for comparison: multilumen multidwell (MLMD); central-lumen multidwell (CLMD); and central-lumen single-dwell (CLSD) loading of the Contura catheter. For this study, a successful treatment plan achieved ideal dosimetric goals and included the following: ≥ 95% of the prescribed dose (PD) covering ≥ 95% of the target volume (TV); maximum skin dose ≤ 125% of the PD; maximum rib dose ≤ 145% of the PD; and V150 ≤50 cc and V200 ≤ 10 cc.

Results: Between January 2008 and February 2011, 23 institutions participated. A total of 318 patients were available for dosimetric review. Using the Contura MLB, all dosimetric criteria were met in 78.93% of cases planned with MLMD versus 55.38% with the CLMD versus 37.66% with the CLSD (P ≤.0001). Evaluating all patients with the full range of skin to balloon distance represented, median maximum skin dose was reduced by 12% and median maximum rib dose by 13.9% when using MLMD-based dosimetric plans compared to CLSD. The dosimetric benefit of MLMD was further demonstrated in the subgroup of patients where skin thickness was <5 mm, where MLMD use allowed a 38% reduction in median maximum skin dose over CLSD. For patients with rib distance <5 mm, the median maximum rib dose reduction was 27%.

Conclusions: Use of the Contura MLB catheter produced statistically significant improvements in dosimetric capabilities between CLSD and CLMD treatments. This device approach demonstrates the ability not only to overcome the barriers of limited skin thickness and close rib proximity, but to consistently achieve a higher standard of dosimetric planning goals.
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http://dx.doi.org/10.1016/j.ijrobp.2013.01.005DOI Listing
June 2013

SH3GL2 is frequently deleted in non-small cell lung cancer and downregulates tumor growth by modulating EGFR signaling.

J Mol Med (Berl) 2013 Mar 12;91(3):381-93. Epub 2012 Sep 12.

Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, USA.

The purpose of this study was to identify key genetic pathways involved in non-small cell lung cancer (NSCLC) and understand their role in tumor progression. We performed a genome wide scanning using paired tumors and corresponding 16 mucosal biopsies from four follow-up lung cancer patients on Affymetrix 250K-NSpI array platform. We found that a single gene SH3GL2 located on human chromosome 9p22 was most frequently deleted in all the tumors and corresponding mucosal biopsies. We further validated the alteration pattern of SH3GL2 in a substantial number of primary NSCLC tumors at DNA and protein level. We also overexpressed wild-type SH3GL2 in three NSCLC cell lines to understand its role in NSCLC progression. Validation in 116 primary NSCLC tumors confirmed frequent loss of heterozygosity of SH3GL2 in overall 51 % (49/97) of the informative cases. We found significantly low (p = 0.0015) SH3GL2 protein expression in 71 % (43/60) primary tumors. Forced overexpression of wild-type (wt) SH3GL2 in three NSCLC cell lines resulted in a marked reduction of active epidermal growth factor receptor (EGFR) expression and an increase in EGFR internalization and degradation. Significantly decreased in vitro (p = 0.0015-0.030) and in vivo (p = 0.016) cellular growth, invasion (p = 0.029-0.049), and colony formation (p = 0.023-0.039) were also evident in the wt-SH3GL2-transfected cells accompanied by markedly low expression of activated AKT(Ser(473)), STAT3 (Tyr(705)), and PI3K. Downregulation of SH3GL2 interactor USP9X and activated ß-catenin was also evident in the SH3GL2-transfected cells. Our results indicate that SH3GL2 is frequently deleted in NSCLC and regulates cellular growth and invasion by modulating EGFR function.
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http://dx.doi.org/10.1007/s00109-012-0955-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3691869PMC
March 2013
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