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1.  Differential effects of patient-related factors on the outcome of radiation therapy for rectal cancer 
Journal of radiation oncology  2016;5(3):279-286.
The objective of this study was to investigate whether cancer specific survival in rectal cancer patients is affected by patient-related factors, conditional on radiation treatment.
359 invasive rectal cancer patients who consented and provided questionnaire data for a population-based case-control study of colorectal cancer in Metropolitan Detroit were included in this study. Their vital status was ascertained through to the population-based cancer registry. Hazard ratios (HR) for cancer specific and other deaths and 95% confidence intervals (CIs) were calculated according to selected patients' characteristics, stratified by radiation status, using joint Cox proportional hazards models.
A total of 159 patients were found to be deceased after the median follow-up of 9.2 years, and 70% of them were considered to be cancer specific. Smoking and a history of diabetes were associated with an increased probability of deaths from other causes (HR 3.20, 95% CI 1.72–5.97 and HR 2.02, 95% CI 0.98–4.16, respectively), while regular use of non-steroidal anti-inflammatory drugs (NSAIDs) was inversely correlated with cancer-specific mortality (HR 0.50, 95% CI 0.30–0.81). Furthermore, the associations of smoking and NSAIDs with the two different types of deaths (cancer vs others) significantly varied with radiation status (P-values for the interactions= 0.014 for both). In addition, we observed a marginally significantly reduced risk of cancer specific deaths in the patients who had the relative ketogenic diet overall (HR=0.49, 95% 0.23–1.02).
Further research is warranted to confirm these results in order to develop new interventions to improve outcome from radiation treatment.
PMCID: PMC5061458  PMID: 27746859
Non-steroidal anti-inflammatory drugs; smoking; diet; rectal cancer; survival
2.  Outcomes of Elderly Patients Who Receive Combined Modality Therapy for Locally Advanced Non–Small-Cell Lung Cancer 
Clinical lung cancer  2016;18(1):e21-e26.
Our objective was to determine the significance of age in patients treated with sequential or concurrent chemoradiotherapy for locally advanced non–small-cell lung cancer (LA-NSCLC). Ninety-eight patients were 70 years of age or younger and 25 were older than 70 years. In multivariable analysis, there was no difference in the progression-free survival (hazard ratio [HR], 1.15; P = .64) or overall survival (HR, 1.18; P = .65) of older versus younger patients. Chemoradiotherapy is an effective treatment in elderly patients with LA-NSCLC, with outcomes similar to that in younger patients.
The objective of this study was to review our institution’s experience among patients with locally advanced non–small-cell lung cancer (LA-NSCLC) treated with chemotherapy and radiation and to determine the prognostic significance of age.
Patients and Methods
Patients were included if they underwent sequential or concurrent chemoradiotherapy from 2006 to 2014 for LA-NSCLC. Patients were stratified according to age ≤70 and >70 years. Kaplan–Meier and Cox regression methods were performed to evaluate overall survival (OS) and progression-free survival (PFS).
One hundred twenty-three patients were identified. Ninety-eight patients were 70 years of age or younger and 25 patients were older than 70 years of age. The median radiotherapy dose was 6660 cGy (range, 3780–7600 cGy). A greater percentage of elderly patients were men, 72% (18 patients) versus 39% (38 patients) (P = .006) and received carboplatin/paclitaxel-based chemotherapy, 60% (15 patients) versus 21% (20 patients) (P < .001). Median follow-up for OS was 25.9 (95% confidence interval [CI], 21.3–33.9) months. There was no difference in the PFS of older patients versus younger patients (hazard ratio [HR], 1.15; P = .64), adjusted for significant covariates. The 1-year PFS rate for patients 70 years of age or younger was 51% (95% CI, 42%–63%) versus 45% (95% CI, 28%–71%) in patients older than 70 years. After adjusting for significant covariates, there was no difference in the OS of older patients compared with younger patients (HR, 1.18; P = .65). The 1-year OS rate for patients 70 years of age or younger was 77% (95% CI, 68%–86%) versus 56% (95% CI, 39%–81%) in patients younger than 70 years.
Chemoradiotherapy is an effective treatment in elderly patients with LA-NSCLC, with outcomes similar to that in younger patients. Appropriately selected elderly patients should be considered for chemoradiation.
PMCID: PMC5576136  PMID: 27567356
Chemotherapy; Radiation; Geriatric; Oncology; Retrospective study
3.  An essential role of maspin in embryogenesis and tumor suppression 
Cancer research  2016;77(4):886-896.
Maspin (SerpinB5) is an epithelial-specific tumor suppressor gene product that displays context-dependent cellular functions. Maspin-deficient mouse models created to date have not definitively established maspin functions critical for cancer suppression. In this study, we generated a mouse strain in which exon 4 of the Maspin gene was deleted, confirming its essential role in development but also enabling a breeding scheme to bypass embryonic lethality. Phenotypic characterization of this viable strain established that maspin deficiency was associated with a reduction in maximum body weight and a variety of context-dependent epithelial abnormalities. Specifically, maspin-deficient mice exhibited pulmonary adenocarcinoma, myoepithelial hyperplasia of the mammary gland, hyperplasia of luminal cells of dorsolateral and anterior prostate, and atrophy of luminal cells of ventral prostate and stratum spinosum of epidermis. These cancer phenotypes were accompanied by increased inflammatory stroma. These mice also displayed the autoimmune disorder alopecia aerate. Overall, our findings defined context-specific tumor suppressor roles for maspin in a clinically relevant model to study maspin functions in cancer and other pathologies.
PMCID: PMC5313336  PMID: 27923833
tumor suppressor; Zp3-Cre recombinase; embryonic lethality; epithelial differentiation; hyperplasia; adenocarcinoma
4.  HPV-associated differential regulation of tumor metabolism in oropharyngeal head and neck cancer 
Oncotarget  2017;8(31):51530-51541.
HPV-positive oropharyngeal cancer patients experience significantly lower locoregional recurrence and higher overall survival in comparison with HPV-negative patients, especially among those who received radiation therapy. The goal of the present study is to investigate the molecular mechanisms underlying the differential radiation sensitivity between HPV-negative and HPV-positive head and neck squamous cell carcinoma (HNSCC). Here, we show that HPV-negative HNSCC cells exhibit increased glucose metabolism as evidenced by increased production of lactate, while HPV-positive HNSCC cells effectively utilize mitochondrial respiration as evidenced by increased oxygen consumption. HPV-negative cells express HIF1α and its downstream mediators of glucose metabolism such as hexokinase II (HKII) and carbonic anhydrase IX (CAIX) at higher levels, while the expression level of cytochrome c oxidase (COX) was noticeably higher in HPV-positive HNSCC. In addition, the expression levels of pyruvate dehydrogenase kinases (PDKs), which inhibit pyruvate dehydrogenase activity, thereby preventing entry of pyruvate into the mitochondrial tricarboxylic acid (TCA) cycle, were much higher in HPV-negative HNSCC compared to those in HPV-positive cells. Importantly, a PDK inhibitor, dichloroacetate, effectively sensitized HPV-negative cells to irradiation. Lastly, we found positive interactions between tonsil location and HPV positivity for COX intensity and COX/HKII index ratio as determined by immunohistochemical analysis. Overall survival of patients with HNSCC at the tonsil was significantly improved with an increased COX expression. Taken together, the present study provides molecular insights into the mechanistic basis for the differential responses to radiotherapy between HPV-driven vs. spontaneous or chemically induced oropharyngeal cancer.
PMCID: PMC5584266
head and neck squamous cell carcinoma; human papillomavirus; radiation; glucose metabolism; mitochondrial respiration
5.  Targeting ERK enhances the cytotoxic effect of the novel PI3K and mTOR dual inhibitor VS-5584 in preclinical models of pancreatic cancer 
Oncotarget  2017;8(27):44295-44311.
Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease in urgent need of newer therapeutic modalities. Majority of patients with PDAC have mutations in KRAS, which unfortunately remains an ineffectual target. Our strategy here is to target KRAS downstream effectors PI3K and mTOR. In this study, we investigated the antitumor efficacy of the novel PI3K and mTOR dual inhibitor VS-5584 in PDAC. Our data shows that PI3K/mTOR dual inhibition causes ERK activation in all tested PDAC cell lines. Although the MEK inhibitor GSK1120212 could abrogate VS-5584-induced ERK activation, it did not substantially enhance cell death in all the cell lines tested. However, combination with ERK inhibitor SCH772984 not only mitigated VS-5584-induced ERK activation but also enhanced VS-5584-induced cell death. In a xenograft model of PDAC, we observed 28% and 44% tumor inhibition for individual treatment with VS-5584 and SCH772984, respectively, while the combined treatment showed superior tumor inhibition (80%) compared to vehicle control treatment. Our findings support the clinical development of VS-5584 and ERK inhibitor combination for PDAC treatment.
PMCID: PMC5546481  PMID: 28574828
pancreatic cancer; PI3K/mTOR; ERK; VS-5584; SCH772984
6.  Reanalysis of BRCA1/2 negative high risk ovarian cancer patients reveals novel germline risk loci and insights into missing heritability 
PLoS ONE  2017;12(6):e0178450.
While up to 25% of ovarian cancer (OVCA) cases are thought to be due to inherited factors, the majority of genetic risk remains unexplained. To address this gap, we sought to identify previously undescribed OVCA risk variants through the whole exome sequencing (WES) and candidate gene analysis of 48 women with ovarian cancer and selected for high risk of genetic inheritance, yet negative for any known pathogenic variants in either BRCA1 or BRCA2. In silico SNP analysis was employed to identify suspect variants followed by validation using Sanger DNA sequencing. We identified five pathogenic variants in our sample, four of which are in two genes featured on current multi-gene panels; (RAD51D, ATM). In addition, we found a pathogenic FANCM variant (R1931*) which has been recently implicated in familial breast cancer risk. Numerous rare and predicted to be damaging variants of unknown significance were detected in genes on current commercial testing panels, most prominently in ATM (n = 6) and PALB2 (n = 5). The BRCA2 variant p.K3326*, resulting in a 93 amino acid truncation, was overrepresented in our sample (odds ratio = 4.95, p = 0.01) and coexisted in the germline of these women with other deleterious variants, suggesting a possible role as a modifier of genetic penetrance. Furthermore, we detected loss of function variants in non-panel genes involved in OVCA relevant pathways; DNA repair and cell cycle control, including CHEK1, TP53I3, REC8, HMMR, RAD52, RAD1, POLK, POLQ, and MCM4. In summary, our study implicates novel risk loci as well as highlights the clinical utility for retesting BRCA1/2 negative OVCA patients by genomic sequencing and analysis of genes in relevant pathways.
PMCID: PMC5462348  PMID: 28591191
7.  ALKBH7 Variant Related to Prostate Cancer Exhibits Altered Substrate Binding 
PLoS Computational Biology  2017;13(2):e1005345.
The search for prostate cancer biomarkers has received increased attention and several DNA repair related enzymes have been linked to this dysfunction. Here we report a targeted search for single nucleotide polymorphisms (SNPs) and functional impact characterization of human ALKBH family dioxygenases related to prostate cancer. Our results uncovered a SNP of ALKBH7, rs7540, which is associated with prostate cancer disease in a statistically significantly manner in two separate cohorts, and maintained in African American men. Comparisons of molecular dynamics (MD) simulations on the wild-type and variant protein structures indicate that the resulting alteration in the enzyme induces a significant structural change that reduces ALKBH7’s ability to bind its cosubstrate. Experimental spectroscopy studies with purified proteins validate our MD predictions and corroborate the conclusion that this cancer-associated mutation affects productive cosubstrate binding in ALKBH7.
Author Summary
Improvements in personalized DNA sequencing have led to an increased interest in targeted biomarkers for therapeutic and diagnostic purposes. In this work, we report on a new biomarker for prostate cancer found through a targeted search for single nucleotide polymorphisms (SNPs) of the genes encoding human ALKBH family dioxygenases. Our results uncovered rs7540, which leads to a missense mutation in ALKBH7. Comparative molecular dynamics simulations on the wild type and SNP variant of the protein show that the mutation elicits a structural change that dramatically decreases ALKBH7’s affinity for its cosubstrate. This prediction is confirmed by experimental UV-Vis spectroscopy. Taken together, these results give important insights into a novel prostate-cancer related SNP and its impact on the structure and function of ALKBH7.
PMCID: PMC5322872  PMID: 28231280
8.  31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016): part one 
Lundqvist, Andreas | van Hoef, Vincent | Zhang, Xiaonan | Wennerberg, Erik | Lorent, Julie | Witt, Kristina | Sanz, Laia Masvidal | Liang, Shuo | Murray, Shannon | Larsson, Ola | Kiessling, Rolf | Mao, Yumeng | Sidhom, John-William | Bessell, Catherine A. | Havel, Jonathan | Schneck, Jonathan | Chan, Timothy A. | Sachsenmeier, Eliot | Woods, David | Berglund, Anders | Ramakrishnan, Rupal | Sodre, Andressa | Weber, Jeffrey | Zappasodi, Roberta | Li, Yanyun | Qi, Jingjing | Wong, Philip | Sirard, Cynthia | Postow, Michael | Newman, Walter | Koon, Henry | Velcheti, Vamsidhar | Callahan, Margaret K. | Wolchok, Jedd D. | Merghoub, Taha | Lum, Lawrence G. | Choi, Minsig | Thakur, Archana | Deol, Abhinav | Dyson, Gregory | Shields, Anthony | Haymaker, Cara | Uemura, Marc | Murthy, Ravi | James, Marihella | Wang, Daqing | Brevard, Julie | Monaghan, Catherine | Swann, Suzanne | Geib, James | Cornfeld, Mark | Chunduru, Srinivas | Agrawal, Sudhir | Yee, Cassian | Wargo, Jennifer | Patel, Sapna P. | Amaria, Rodabe | Tawbi, Hussein | Glitza, Isabella | Woodman, Scott | Hwu, Wen-Jen | Davies, Michael A. | Hwu, Patrick | Overwijk, Willem W. | Bernatchez, Chantale | Diab, Adi | Massarelli, Erminia | Segal, Neil H. | Ribrag, Vincent | Melero, Ignacio | Gangadhar, Tara C. | Urba, Walter | Schadendorf, Dirk | Ferris, Robert L. | Houot, Roch | Morschhauser, Franck | Logan, Theodore | Luke, Jason J. | Sharfman, William | Barlesi, Fabrice | Ott, Patrick A. | Mansi, Laura | Kummar, Shivaani | Salles, Gilles | Carpio, Cecilia | Meier, Roland | Krishnan, Suba | McDonald, Dan | Maurer, Matthew | Gu, Xuemin | Neely, Jaclyn | Suryawanshi, Satyendra | Levy, Ronald | Khushalani, Nikhil | Wu, Jennifer | Zhang, Jinyu | Basher, Fahmin | Rubinstein, Mark | Bucsek, Mark | Qiao, Guanxi | MacDonald, Cameron | Hylander, Bonnie | Repasky, Elizabeth | Chatterjee, Shilpak | Daenthanasanmak, Anusara | Chakraborty, Paramita | Toth, Kyle | Meek, Megan | Garrett-Mayer, Elizabeth | Nishimura, Michael | Paulos, Chrystal | Beeson, Craig | Yu, Xuezhong | Mehrotra, Shikhar | Zhao, Fei | Evans, Kathy | Xiao, Christine | Holtzhausen, Alisha | Hanks, Brent A. | Scharping, Nicole | Menk, Ashley V. | Moreci, Rebecca | Whetstone, Ryan | Dadey, Rebekah | Watkins, Simon | Ferris, Robert | Delgoffe, Greg M. | Peled, Jonathan | Devlin, Sean | Staffas, Anna | Lumish, Melissa | Rodriguez, Kori Porosnicu | Ahr, Katya | Perales, Miguel | Giralt, Sergio | Taur, Ying | Pamer, Eric | van den Brink, Marcel R. M. | Jenq, Robert | Annels, Nicola | Pandha, Hardev | Simpson, Guy | Mostafid, Hugh | Harrington, Kevin | Melcher, Alan | Grose, Mark | Davies, Bronwyn | Au, Gough | Karpathy, Roberta | Shafren, Darren | Ricca, Jacob | Merghoub, Taha | Wolchok, Jedd D. | Zamarin, Dmitriy | Batista, Luciana | Marliot, Florence | Vasaturo, Angela | Carpentier, Sabrina | Poggionovo, Cécile | Frayssinet, Véronique | Fieschi, Jacques | Van den Eynde, Marc | Pagès, Franck | Galon, Jérôme | Hermitte, Fabienne | Smith, Sean G. | Nguyen, Khue | Ravindranathan, Sruthi | Koppolu, Bhanu | Zaharoff, David | Schvartsman, Gustavo | Bassett, Roland | McQuade, Jennifer L. | Haydu, Lauren E. | Davies, Michael A. | Tawbi, Hussein | Glitza, Isabella | Kline, Douglas | Chen, Xiufen | Fosco, Dominick | Kline, Justin | Overacre, Abigail | Chikina, Maria | Brunazzi, Erin | Shayan, Gulidanna | Horne, William | Kolls, Jay | Ferris, Robert L. | Delgoffe, Greg M. | Bruno, Tullia C. | Workman, Creg | Vignali, Dario | Adusumilli, Prasad S. | Ansa-Addo, Ephraim A | Li, Zihai | Gerry, Andrew | Sanderson, Joseph P. | Howe, Karen | Docta, Roslin | Gao, Qian | Bagg, Eleanor A. L. | Tribble, Nicholas | Maroto, Miguel | Betts, Gareth | Bath, Natalie | Melchiori, Luca | Lowther, Daniel E. | Ramachandran, Indu | Kari, Gabor | Basu, Samik | Binder-Scholl, Gwendolyn | Chagin, Karen | Pandite, Lini | Holdich, Tom | Amado, Rafael | Zhang, Hua | Glod, John | Bernstein, Donna | Jakobsen, Bent | Mackall, Crystal | Wong, Ryan | Silk, Jonathan D. | Adams, Katherine | Hamilton, Garth | Bennett, Alan D. | Brett, Sara | Jing, Junping | Quattrini, Adriano | Saini, Manoj | Wiedermann, Guy | Gerry, Andrew | Jakobsen, Bent | Binder-Scholl, Gwendolyn | Brewer, Joanna | Duong, MyLinh | Lu, An | Chang, Peter | Mahendravada, Aruna | Shinners, Nicholas | Slawin, Kevin | Spencer, David M. | Foster, Aaron E. | Bayle, J. Henri | Bergamaschi, Cristina | Ng, Sinnie Sin Man | Nagy, Bethany | Jensen, Shawn | Hu, Xintao | Alicea, Candido | Fox, Bernard | Felber, Barbara | Pavlakis, George | Chacon, Jessica | Yamamoto, Tori | Garrabrant, Thomas | Cortina, Luis | Powell, Daniel J. | Donia, Marco | Kjeldsen, Julie Westerlin | Andersen, Rikke | Westergaard, Marie Christine Wulff | Bianchi, Valentina | Legut, Mateusz | Attaf, Meriem | Dolton, Garry | Szomolay, Barbara | Ott, Sascha | Lyngaa, Rikke | Hadrup, Sine Reker | Sewell, Andrew Kelvin | Svane, Inge Marie | Fan, Aaron | Kumai, Takumi | Celis, Esteban | Frank, Ian | Stramer, Amanda | Blaskovich, Michelle A. | Wardell, Seth | Fardis, Maria | Bender, James | Lotze, Michael T. | Goff, Stephanie L. | Zacharakis, Nikolaos | Assadipour, Yasmine | Prickett, Todd D. | Gartner, Jared J. | Somerville, Robert | Black, Mary | Xu, Hui | Chinnasamy, Harshini | Kriley, Isaac | Lu, Lily | Wunderlich, John | Robbins, Paul F. | Rosenberg, Steven | Feldman, Steven A. | Trebska-McGowan, Kasia | Kriley, Isaac | Malekzadeh, Parisa | Payabyab, Eden | Sherry, Richard | Rosenberg, Steven | Goff, Stephanie L. | Gokuldass, Aishwarya | Blaskovich, Michelle A. | Kopits, Charlene | Rabinovich, Brian | Lotze, Michael T. | Green, Daniel S. | Kamenyeva, Olena | Zoon, Kathryn C. | Annunziata, Christina M. | Hammill, Joanne | Helsen, Christopher | Aarts, Craig | Bramson, Jonathan | Harada, Yui | Yonemitsu, Yoshikazu | Helsen, Christopher | Hammill, Joanne | Mwawasi, Kenneth | Denisova, Galina | Bramson, Jonathan | Giri, Rajanish | Jin, Benjamin | Campbell, Tracy | Draper, Lindsey M. | Stevanovic, Sanja | Yu, Zhiya | Weissbrich, Bianca | Restifo, Nicholas P. | Trimble, Cornelia L. | Rosenberg, Steven | Hinrichs, Christian S. | Tsang, Kwong | Fantini, Massimo | Hodge, James W. | Fujii, Rika | Fernando, Ingrid | Jochems, Caroline | Heery, Christopher | Gulley, James | Soon-Shiong, Patrick | Schlom, Jeffrey | Jing, Weiqing | Gershan, Jill | Blitzer, Grace | Weber, James | McOlash, Laura | Johnson, Bryon D. | Kiany, Simin | Gangxiong, Huang | Kleinerman, Eugenie S. | Klichinsky, Michael | Ruella, Marco | Shestova, Olga | Kenderian, Saad | Kim, Miriam | Scholler, John | June, Carl H. | Gill, Saar | Moogk, Duane | Zhong, Shi | Yu, Zhiya | Liadi, Ivan | Rittase, William | Fang, Victoria | Dougherty, Janna | Perez-Garcia, Arianne | Osman, Iman | Zhu, Cheng | Varadarajan, Navin | Restifo, Nicholas P. | Frey, Alan | Krogsgaard, Michelle | Landi, Daniel | Fousek, Kristen | Mukherjee, Malini | Shree, Ankita | Joseph, Sujith | Bielamowicz, Kevin | Byrd, Tiara | Ahmed, Nabil | Hegde, Meenakshi | Lee, Sylvia | Byrd, David | Thompson, John | Bhatia, Shailender | Tykodi, Scott | Delismon, Judy | Chu, Liz | Abdul-Alim, Siddiq | Ohanian, Arpy | DeVito, Anna Marie | Riddell, Stanley | Margolin, Kim | Magalhaes, Isabelle | Mattsson, Jonas | Uhlin, Michael | Nemoto, Satoshi | Villarroel, Patricio Pérez | Nakagawa, Ryosuke | Mule, James J. | Mailloux, Adam W. | Mata, Melinda | Nguyen, Phuong | Gerken, Claudia | DeRenzo, Christopher | Spencer, David M. | Gottschalk, Stephen | Mathieu, Mélissa | Pelletier, Sandy | Stagg, John | Turcotte, Simon | Minutolo, Nicholas | Sharma, Prannda | Tsourkas, Andrew | Powell, Daniel J. | Mockel-Tenbrinck, Nadine | Mauer, Daniela | Drechsel, Katharina | Barth, Carola | Freese, Katharina | Kolrep, Ulrike | Schult, Silke | Assenmacher, Mario | Kaiser, Andrew | Mullinax, John | Hall, MacLean | Le, Julie | Kodumudi, Krithika | Royster, Erica | Richards, Allison | Gonzalez, Ricardo | Sarnaik, Amod | Pilon-Thomas, Shari | Nielsen, Morten | Krarup-Hansen, Anders | Hovgaard, Dorrit | Petersen, Michael Mørk | Loya, Anand Chainsukh | Junker, Niels | Svane, Inge Marie | Rivas, Charlotte | Parihar, Robin | Gottschalk, Stephen | Rooney, Cliona M. | Qin, Haiying | Nguyen, Sang | Su, Paul | Burk, Chad | Duncan, Brynn | Kim, Bong-Hyun | Kohler, M. Eric | Fry, Terry | Rao, Arjun A. | Teyssier, Noam | Pfeil, Jacob | Sgourakis, Nikolaos | Salama, Sofie | Haussler, David | Richman, Sarah A. | Nunez-Cruz, Selene | Gershenson, Zack | Mourelatos, Zissimos | Barrett, David | Grupp, Stephan | Milone, Michael | Rodriguez-Garcia, Alba | Robinson, Matthew K. | Adams, Gregory P. | Powell, Daniel J. | Santos, João | Havunen, Riikka | Siurala, Mikko | Cervera-Carrascón, Víctor | Parviainen, Suvi | Antilla, Marjukka | Hemminki, Akseli | Sethuraman, Jyothi | Santiago, Laurelis | Chen, Jie Qing | Dai, Zhimin | Wardell, Seth | Bender, James | Lotze, Michael T. | Sha, Huizi | Su, Shu | Ding, Naiqing | Liu, Baorui | Stevanovic, Sanja | Pasetto, Anna | Helman, Sarah R. | Gartner, Jared J. | Prickett, Todd D. | Robbins, Paul F. | Rosenberg, Steven A. | Hinrichs, Christian S. | Bhatia, Shailender | Burgess, Melissa | Zhang, Hui | Lee, Tien | Klingemann, Hans | Soon-Shiong, Patrick | Nghiem, Paul | Kirkwood, John M. | Rossi, John M. | Sherman, Marika | Xue, Allen | Shen, Yueh-wei | Navale, Lynn | Rosenberg, Steven A. | Kochenderfer, James N. | Bot, Adrian | Veerapathran, Anandaraman | Gokuldass, Aishwarya | Stramer, Amanda | Sethuraman, Jyothi | Blaskovich, Michelle A. | Wiener, Doris | Frank, Ian | Santiago, Laurelis | Rabinovich, Brian | Fardis, Maria | Bender, James | Lotze, Michael T. | Waller, Edmund K. | Li, Jian-Ming | Petersen, Christopher | Blazar, Bruce R. | Li, Jingxia | Giver, Cynthia R. | Wang, Ziming | Grossenbacher, Steven K. | Sturgill, Ian | Canter, Robert J. | Murphy, William J. | Zhang, Congcong | Burger, Michael C. | Jennewein, Lukas | Waldmann, Anja | Mittelbronn, Michel | Tonn, Torsten | Steinbach, Joachim P. | Wels, Winfried S. | Williams, Jason B. | Zha, Yuanyuan | Gajewski, Thomas F. | Williams, LaTerrica C. | Krenciute, Giedre | Kalra, Mamta | Louis, Chrystal | Gottschalk, Stephen | Xin, Gang | Schauder, David | Jiang, Aimin | Joshi, Nikhil | Cui, Weiguo | Zeng, Xue | Menk, Ashley V. | Scharping, Nicole | Delgoffe, Greg M. | Zhao, Zeguo | Hamieh, Mohamad | Eyquem, Justin | Gunset, Gertrude | Bander, Neil | Sadelain, Michel | Askmyr, David | Abolhalaj, Milad | Lundberg, Kristina | Greiff, Lennart | Lindstedt, Malin | Angell, Helen K. | Kim, Kyoung-Mee | Kim, Seung-Tae | Kim, Sung | Sharpe, Alan D. | Ogden, Julia | Davenport, Anna | Hodgson, Darren R. | Barrett, Carl | Lee, Jeeyun | Kilgour, Elaine | Hanson, Jodi | Caspell, Richard | Karulin, Alexey | Lehmann, Paul | Ansari, Tameem | Schiller, Annemarie | Sundararaman, Srividya | Lehmann, Paul | Hanson, Jodi | Roen, Diana | Karulin, Alexey | Lehmann, Paul | Ayers, Mark | Levitan, Diane | Arreaza, Gladys | Liu, Fang | Mogg, Robin | Bang, Yung-Jue | O’Neil, Bert | Cristescu, Razvan | Friedlander, Philip | Wassman, Karl | Kyi, Chrisann | Oh, William | Bhardwaj, Nina | Bornschlegl, Svetlana | Gustafson, Michael P. | Gastineau, Dennis A. | Parney, Ian F. | Dietz, Allan B. | Carvajal-Hausdorf, Daniel | Mani, Nikita | Velcheti, Vamsidhar | Schalper, Kurt | Rimm, David | Chang, Serena | Levy, Ronald | Kurland, John | Krishnan, Suba | Ahlers, Christoph Matthias | Jure-Kunkel, Maria | Cohen, Lewis | Maecker, Holden | Kohrt, Holbrook | Chen, Shuming | Crabill, George | Pritchard, Theresa | McMiller, Tracee | Pardoll, Drew | Pan, Fan | Topalian, Suzanne | Danaher, Patrick | Warren, Sarah | Dennis, Lucas | White, Andrew M. | D’Amico, Leonard | Geller, Melissa | Disis, Mary L. | Beechem, Joseph | Odunsi, Kunle | Fling, Steven | Derakhshandeh, Roshanak | Webb, Tonya J. | Dubois, Sigrid | Conlon, Kevin | Bryant, Bonita | Hsu, Jennifer | Beltran, Nancy | Müller, Jürgen | Waldmann, Thomas | Duhen, Rebekka | Duhen, Thomas | Thompson, Lucas | Montler, Ryan | Weinberg, Andrew | Kates, Max | Early, Brandon | Yusko, Erik | Schreiber, Taylor H. | Bivalacqua, Trinity J. | Ayers, Mark | Lunceford, Jared | Nebozhyn, Michael | Murphy, Erin | Loboda, Andrey | Kaufman, David R. | Albright, Andrew | Cheng, Jonathan | Kang, S. Peter | Shankaran, Veena | Piha-Paul, Sarina A. | Yearley, Jennifer | Seiwert, Tanguy | Ribas, Antoni | McClanahan, Terrill K. | Cristescu, Razvan | Mogg, Robin | Ayers, Mark | Albright, Andrew | Murphy, Erin | Yearley, Jennifer | Sher, Xinwei | Liu, Xiao Qiao | Nebozhyn, Michael | Lunceford, Jared | Joe, Andrew | Cheng, Jonathan | Plimack, Elizabeth | Ott, Patrick A. | McClanahan, Terrill K. | Loboda, Andrey | Kaufman, David R. | Forrest-Hay, Alex | Guyre, Cheryl A. | Narumiya, Kohei | Delcommenne, Marc | Hirsch, Heather A. | Deshpande, Amit | Reeves, Jason | Shu, Jenny | Zi, Tong | Michaelson, Jennifer | Law, Debbie | Trehu, Elizabeth | Sathyanaryanan, Sriram | Hodkinson, Brendan P. | Hutnick, Natalie A. | Schaffer, Michael E. | Gormley, Michael | Hulett, Tyler | Jensen, Shawn | Ballesteros-Merino, Carmen | Dubay, Christopher | Afentoulis, Michael | Reddy, Ashok | David, Larry | Fox, Bernard | Jayant, Kumar | Agrawal, Swati | Agrawal, Rajendra | Jeyakumar, Ghayathri | Kim, Seongho | Kim, Heejin | Silski, Cynthia | Suisham, Stacey | Heath, Elisabeth | Vaishampayan, Ulka | Vandeven, Natalie | Viller, Natasja Nielsen | O’Connor, Alison | Chen, Hui | Bossen, Bolette | Sievers, Eric | Uger, Robert | Nghiem, Paul | Johnson, Lisa | Kao, Hsiang-Fong | Hsiao, Chin-Fu | Lai, Shu-Chuan | Wang, Chun-Wei | Ko, Jenq-Yuh | Lou, Pei-Jen | Lee, Tsai-Jan | Liu, Tsang-Wu | Hong, Ruey-Long | Kearney, Staci J. | Black, Joshua C. | Landis, Benjamin J. | Koegler, Sally | Hirsch, Brooke | Gianani, Roberto | Kim, Jeffrey | He, Ming-Xiao | Zhang, Bingqing | Su, Nan | Luo, Yuling | Ma, Xiao-Jun | Park, Emily | Kim, Dae Won | Copploa, Domenico | Kothari, Nishi | doo Chang, Young | Kim, Richard | Kim, Namyong | Lye, Melvin | Wan, Ee | Kim, Namyong | Lye, Melvin | Wan, Ee | Kim, Namyong | Lye, Melvin | Wan, Ee | Knaus, Hanna A. | Berglund, Sofia | Hackl, Hubert | Karp, Judith E. | Gojo, Ivana | Luznik, Leo | Hong, Henoch S. | Koch, Sven D. | Scheel, Birgit | Gnad-Vogt, Ulrike | Kallen, Karl-Josef | Wiegand, Volker | Backert, Linus | Kohlbacher, Oliver | Hoerr, Ingmar | Fotin-Mleczek, Mariola | Billingsley, James M. | Koguchi, Yoshinobu | Conrad, Valerie | Miller, William | Gonzalez, Iliana | Poplonski, Tomasz | Meeuwsen, Tanisha | Howells-Ferreira, Ana | Rattray, Rogan | Campbell, Mary | Bifulco, Carlo | Dubay, Christopher | Bahjat, Keith | Curti, Brendan | Urba, Walter | Vetsika, E-K | Kallergi, G. | Aggouraki, Despoina | Lyristi, Z. | Katsarlinos, P. | Koinis, Filippos | Georgoulias, V. | Kotsakis, Athanasios | Martin, Nathan T. | Aeffner, Famke | Kearney, Staci J. | Black, Joshua C. | Cerkovnik, Logan | Pratte, Luke | Kim, Rebecca | Hirsch, Brooke | Krueger, Joseph | Gianani, Roberto | Martínez-Usatorre, Amaia | Jandus, Camilla | Donda, Alena | Carretero-Iglesia, Laura | Speiser, Daniel E. | Zehn, Dietmar | Rufer, Nathalie | Romero, Pedro | Panda, Anshuman | Mehnert, Janice | Hirshfield, Kim M. | Riedlinger, Greg | Damare, Sherri | Saunders, Tracie | Sokol, Levi | Stein, Mark | Poplin, Elizabeth | Rodriguez-Rodriguez, Lorna | Silk, Ann | Chan, Nancy | Frankel, Melissa | Kane, Michael | Malhotra, Jyoti | Aisner, Joseph | Kaufman, Howard L. | Ali, Siraj | Ross, Jeffrey | White, Eileen | Bhanot, Gyan | Ganesan, Shridar | Monette, Anne | Bergeron, Derek | Amor, Amira Ben | Meunier, Liliane | Caron, Christine | Morou, Antigoni | Kaufmann, Daniel | Liberman, Moishe | Jurisica, Igor | Mes-Masson, Anne-Marie | Hamzaoui, Kamel | Lapointe, Rejean | Mongan, Ann | Ku, Yuan-Chieh | Tom, Warren | Sun, Yongming | Pankov, Alex | Looney, Tim | Au-Young, Janice | Hyland, Fiona | Conroy, Jeff | Morrison, Carl | Glenn, Sean | Burgher, Blake | Ji, He | Gardner, Mark | Mongan, Ann | Omilian, Angela R. | Conroy, Jeff | Bshara, Wiam | Angela, Omilian | Burgher, Blake | Ji, He | Glenn, Sean | Morrison, Carl | Mongan, Ann | Obeid, Joseph M. | Erdag, Gulsun | Smolkin, Mark E. | Deacon, Donna H. | Patterson, James W. | Chen, Lieping | Bullock, Timothy N. | Slingluff, Craig L. | Obeid, Joseph M. | Erdag, Gulsun | Deacon, Donna H. | Slingluff, Craig L. | Bullock, Timothy N. | Loffredo, John T. | Vuyyuru, Raja | Beyer, Sophie | Spires, Vanessa M. | Fox, Maxine | Ehrmann, Jon M. | Taylor, Katrina A. | Korman, Alan J. | Graziano, Robert F. | Page, David | Sanchez, Katherine | Ballesteros-Merino, Carmen | Martel, Maritza | Bifulco, Carlo | Urba, Walter | Fox, Bernard | Patel, Sapna P. | De Macedo, Mariana Petaccia | Qin, Yong | Reuben, Alex | Spencer, Christine | Guindani, Michele | Bassett, Roland | Wargo, Jennifer | Racolta, Adriana | Kelly, Brian | Jones, Tobin | Polaske, Nathan | Theiss, Noah | Robida, Mark | Meridew, Jeffrey | Habensus, Iva | Zhang, Liping | Pestic-Dragovich, Lidija | Tang, Lei | Sullivan, Ryan J. | Logan, Theodore | Khushalani, Nikhil | Margolin, Kim | Koon, Henry | Olencki, Thomas | Hutson, Thomas | Curti, Brendan | Roder, Joanna | Blackmon, Shauna | Roder, Heinrich | Stewart, John | Amin, Asim | Ernstoff, Marc S. | Clark, Joseph I. | Atkins, Michael B. | Kaufman, Howard L. | Sosman, Jeffrey | Weber, Jeffrey | McDermott, David F. | Weber, Jeffrey | Kluger, Harriet | Halaban, Ruth | Snzol, Mario | Roder, Heinrich | Roder, Joanna | Asmellash, Senait | Steingrimsson, Arni | Blackmon, Shauna | Sullivan, Ryan J. | Wang, Chichung | Roman, Kristin | Clement, Amanda | Downing, Sean | Hoyt, Clifford | Harder, Nathalie | Schmidt, Guenter | Schoenmeyer, Ralf | Brieu, Nicolas | Yigitsoy, Mehmet | Madonna, Gabriele | Botti, Gerardo | Grimaldi, Antonio | Ascierto, Paolo A. | Huss, Ralf | Athelogou, Maria | Hessel, Harald | Harder, Nathalie | Buchner, Alexander | Schmidt, Guenter | Stief, Christian | Huss, Ralf | Binnig, Gerd | Kirchner, Thomas | Sellappan, Shankar | Thyparambil, Sheeno | Schwartz, Sarit | Cecchi, Fabiola | Nguyen, Andrew | Vaske, Charles | Hembrough, Todd
Journal for Immunotherapy of Cancer  2016;4(Suppl 1):1-106.
PMCID: PMC5123387
9.  Role of cancer stem cells in racial disparity in colorectal cancer 
Cancer Medicine  2016;5(6):1268-1278.
Although African‐Americans (AAs) have a higher incidence of colorectal cancer (CRC) than White people, the underlying biochemical mechanisms for this increase are poorly understood. The current investigation was undertaken to examine whether differences in self‐renewing cancer stem/stem‐like cells (CSCs) in the colonic mucosa, whose stemness is regulated by certain microRNAs (miRs), could partly be responsible for the racial disparity in CRC. The study contains 53 AAs and 47 White people. We found the number of adenomas and the proportion of CD44+ CD166−   CSC phenotype in the colon to be significantly higher in AAs than White people. MicroRNAs profile in CSC‐enriched colonic mucosal cells, expressed as ratio of high‐risk (≥3 adenomas) to low‐risk (no adenoma) CRC patients revealed an 8‐fold increase in miR‐1207‐5p in AAs, compared to a 1.2‐fold increase of the same in White people. This increase in AA was associated with a marked rise in lncRNA PVT1 (plasmacytoma variant translocation 1), a host gene of miR‐1207‐5p. Forced expression of miR‐1207‐5p in normal human colonic epithelial cells HCoEpiC and CCD841 produced an increase in stemness, as evidenced by morphologically elongated epithelial mesenchymal transition( EMT) phenotype and significant increases in CSC markers (CD44, CD166, and CD133) as well as TGF‐β, CTNNB1, MMP2, Slug, Snail, and Vimentin, and reduction in Twist and N‐Cadherin. Our findings suggest that an increase in CSCs, specifically the CD44+ CD166− phenotype in the colon could be a predisposing factor for the increased incidence of CRC among AAs. MicroRNA 1207‐5p appears to play a crucial role in regulating stemness in colonic epithelial cells in AAs.
PMCID: PMC4924385  PMID: 26990997
Adenoma; African‐Americans; cancer stem cells; colorectal cancer; lncRNA; microRNA; miR‐1207‐5p; White Americans
10.  Targeting the Nuclear Export Protein XPO1/CRM1 Reverses Epithelial to Mesenchymal Transition 
Scientific Reports  2015;5:16077.
Here we demonstrate for the first time that targeted inhibition of nuclear exporter protein exportin 1 (XPO1) also known as chromosome maintenance region 1 (CRM1) by Selective Inhibitor of Nuclear Export (SINE) compounds results in reversal of EMT in snail-transduced primary human mammary epithelial cells (HMECs). SINE compounds selinexor (KPT-330) and KPT-185, leptomycin B (LMB as +ve control) but not KPT-301 (–ve control) reverse EMT, suppress mesenchymal markers and consequently induce growth inhibition, apoptosis and prevent spheroid formation. SINE treatment resulted in nuclear retention of snail regulator FBXL5 that was concurrent with suppression of snail and down-regulation of mesenchymal markers. FBXL5 siRNA or transfection with cys528 mut-Xpo1 (lacking SINE binding site) markedly abrogated SINE activity highlighting an XPO1 and FBXL5 mediated mechanism of action. Silencing XPO1 or snail caused re-expression of FBXL5 as well as EMT reversal. Pathway analysis on SINE treated HMECs further verified the involvement of additional F-Box family proteins and confirmed the suppression of snail network. Oral administration of selinexor (15 mg/kg p.o. QoDx3/week for 3weeks) resulted in complete cures (no tumor rebound at 120 days) of HMLER-Snail xenografts. These findings raise the unique possibility of blocking EMT at the nuclear pore.
PMCID: PMC4633607  PMID: 26536918
11.  Omega-3 fatty acid is a potential preventive agent for recurrent colon cancer 
Increasing evidence supports the contention that many malignancies, including sporadic colorectal cancer (CRC), are driven by the self-renewing, chemotherapy-resistant cancer stem/stem-like cells (CSCs/CSLCs) underscoring the need for improved preventive and therapeutic strategies targeting CSCs/CSLCs. Omega-3 polyunsaturated fatty acids (ω-3 PUFA), have been reported to inhibit the growth of primary tumors, but their potential as a preventive agent for recurring cancers is un-explored. The primary objectives of this investigation are to examine whether eicosapentaenoic acid (EPA; one of the ω-3 PUFA) synergizes with FuOx (5-FU+Oxaliplatin), the backbone of colon cancer chemotherapy, and (b) whether EPA by itself or in combination with conventional chemotherapy prevents the recurrence of colon cancer via eliminating/suppressing CSCs/CSLCs. FuOx-resistant (chemo-resistant; CR) colon cancer cells, highly enriched in CSCs, were utilized for this study. While EPA alone was effective, combination of EPA and FuOx was more potent in (a) inhibiting cell growth, colonosphere formation and sphere-forming frequency, (b) increasing sphere disintegration, (c) suppressing the growth of SCID mice xenografts of CR colon cancer cells, and (d) decreasing pro-inflammatory metabolites in mice. Additionally, EPA + FuOx caused a reduction in CSC/CSLC population. The growth reduction by this regimen is the result of increased apoptosis as evidenced by PARP cleavage. Furthermore, increased pPTEN, decreased pAkt, normalization of β-catenin expression, localization and transcriptional activity by EPA suggests a role for PTEN/Akt axis and Wnt signaling in regulating this process. Our data suggest that EPA by itself or in combination with FuOx could be an effective preventive strategy for recurring CRC.
PMCID: PMC4221533  PMID: 25193342
12.  A Single Nucleotide Polymorphism in Catalase Is Strongly Associated with Ovarian Cancer Survival 
PLoS ONE  2015;10(8):e0135739.
Ovarian cancer is the deadliest of all gynecologic cancers. Recent evidence demonstrates an association between enzymatic activity altering single nucleotide polymorphisms (SNP) with human cancer susceptibility. We sought to evaluate the association of SNPs in key oxidant and antioxidant enzymes with increased risk and survival in epithelial ovarian cancer. Individuals (n = 143) recruited were divided into controls, (n = 94): healthy volunteers, (n = 18), high-risk BRCA1/2 negative (n = 53), high-risk BRCA1/2 positive (n = 23) and ovarian cancer cases (n = 49). DNA was subjected to TaqMan SNP genotype analysis for selected oxidant and antioxidant enzymes. Of the seven selected SNP studied, no association with ovarian cancer risk (Pearson Chi-square) was found. However, a catalase SNP was identified as a predictor of ovarian cancer survival by the Cox regression model. The presence of this SNP was associated with a higher likelihood of death (hazard ratio (HR) of 3.68 (95% confidence interval (CI): 1.149–11.836)) for ovarian cancer patients. Kaplan-Meier survival analysis demonstrated a significant median overall survival difference (108 versus 60 months, p<0.05) for those without the catalase SNP as compared to those with the SNP. Additionally, age at diagnosis greater than the median was found to be a significant predictor of death (HR of 2.78 (95% CI: 1.022–7.578)). This study indicates a strong association with the catalase SNP and survival of ovarian cancer patients, and thus may serve as a prognosticator.
PMCID: PMC4547699  PMID: 26301412
13.  Hydrazinobenzoylcurcumin inhibits androgen receptor activity and growth of castration-resistant prostate cancer in mice 
Oncotarget  2015;6(8):6136-6150.
There is a critical need for therapeutic agents that can target the amino-terminal domain (NTD) of androgen receptor (AR) for the treatment of castration-resistant prostate cancer (CRPC). Calmodulin (CaM) binds to the AR NTD and regulates AR activity. We discovered that Hydrazinobenzoylcurcumin (HBC), which binds exclusively to CaM, inhibited AR activity. HBC abrogated AR interaction with CaM, suppressed phosphorylation of AR Serine81, and blocked the binding of AR to androgen-response elements. RNA-Seq analysis identified 57 androgen-regulated genes whose expression was significantly (p ≤ 0.002) altered in HBC treated cells as compared to controls. Oncomine analysis revealed that genes repressed by HBC are those that are usually overexpressed in prostate cancer (PCa) and genes stimulated by HBC are those that are often down-regulated in PCa, suggesting a reversing effect of HBC on androgen-regulated gene expression associated with PCa. Ingenuity Pathway Analysis revealed a role of HBC affected genes in cellular functions associated with proliferation and survival. HBC was readily absorbed into the systemic circulation and inhibited the growth of xenografted CRPC tumors in nude mice. These observations demonstrate that HBC inhibits AR activity by targeting the AR NTD and suggest potential usefulness of HBC for effective treatment of CRPC.
PMCID: PMC4467427  PMID: 25704883
Androgen receptor; calmodulin; Hydrazinobenzoylcurcumin; CTK7A; castration-resistant prostate cancer
14.  Incidence, Risk Factors, and Outcome of Cytomegalovirus Viremia and Gastroenteritis in Patients with Gastrointestinal Graft-versus-Host Disease 
Gastrointestinal (GI) graft-versus-host disease (GVHD) is 1 of the most common causes of morbidity and mortality after allogeneic stem cell transplantation. In addition, cytomegalovirus (CMV) infection of the gastrointestinal tract can complicate the post-transplantation course of these patients and it can be difficult to differentiate the 2 diagnoses given that they can present with similar symptoms. We retrospectively analyzed 252 patients who were diagnosed with GI GVHD to evaluate the incidence, risk factors, and outcomes of CMV viremia and CMV gastroenteritis in these patients. The median age at the time of transplantation was 51 years, 35% were related donor transplantations, and 65% were unrelated donor transplantations. A total of 114 (45%) patients developed CMV viremia a median of 34 days (range, 14 to 236 days) after transplantation. Only recipient CMV IgG serostatus was significantly associated with development of CMV viremia (P < .001). The incidence of CMV viremia with relation to donor (D) and recipient (R) CMV serostatus subgroups was as follows: D+/R+, 73%; D−/R+, 67%; D+/R−, 19%; and D−/R−, 0. A total of 31 patients were diagnosed with a biopsy-proven CMV gastroenteritis; 2 patients had evidence of CMV gastroenteritis and GVHD on the first biopsy and 29 on the second biopsy. Median time to development of CMV gastroenteritis was 52 days (range, 19 to 236 days) after transplantation. Using death as a competing risk, the cumulative incidence of CMV gastroenteritis at 1 year was 16.4%. The incidence of CMV gastroenteritis in relation to the donor/recipient serostatus was as follows: D+/R+, 22%; D−/R+, 31%; D+/R−, 12%; and D−/R−, 0. Median overall survival of the 252 patients was 35.4 (range, 23.8 to 44.8) months. The estimated overall survival rate at 1 and 2 years was .45 (95% confidence interval [CI], .39 to .52) and .39 (95% CI, .33 to .46), respectively. Of the examined variables, those related to the overall survival were maximal clinical GVHD grade (P < .001) and development of CMV gastroenteritis (P = .008). Development of CMV viremia was not associated with increased mortality. In conclusion, CMV gastroenteritis is common complication in patients with GI GVHD and can adversely affect the prognosis.
PMCID: PMC4283200  PMID: 25445637
Allogeneic stem cell; transplantation; Graft-versus-host disease; Cytomegalovirus viremia; Cytomegalovirus; gastroenteritis
15.  Considering race and the potential for ERG expression as a biomarker for prostate cancer 
Personalized medicine  2014;11(4):409-412.
Genomic rearrangement and overexpression of the ERG oncogene (also known as v-ets avian erythroblastosis virus E26 oncogene homolog) is estimated to occur at a rate of 40–50% in prostate cancer. Early evidence suggests that ERG overexpression may be associated with disease progression, and the utilization of ERG levels as a biomarker for prostate cancer is being strongly considered. However, the evidence is incomplete because it relies on studies that primarily focused on men of European ancestry, giving little consideration to African–American men even though African–American men bear a greater disease burden in the form of significantly greater incidence and worse outcomes. In this perspective article we bring to light the issue that the potential use of ERG expression as a biomarker is yet to be solidly established and may have limited utility or varied applicably for African–American men as compared with European–American men.
PMCID: PMC4276316  PMID: 25544850
African–American; biomarker; ERG; prostate cancer
16.  Hypothesis driven single nucleotide polymorphism search (HyDn-SNP-S) 
DNA repair  2013;12(9):733-740.
The advent of complete-genome genotyping across phenotype cohorts has provided a rich source of information for bioinformaticians. However the search for SNPs from this data is generally performed on a study-by-study case without any specific hypothesis of the location for SNPs that are predictive for the phenotype. We have designed a method whereby very large SNP lists (several gigabytes in size), combining several genotyping studies at once, can be sorted and traced back to their ultimate consequence in protein structure. Given a working hypothesis, researchers are able to easily search whole genome genotyping data for SNPs that link genetic locations to phenotypes. This allows a targeted search for correlations between phenotypes and potentially relevant systems, rather than utilizing statistical methods only. HyDn-SNP-S returns results that are less data dense, allowing more thorough analysis, including haplotype analysis. We have applied our method to correlate DNA polymerases to cancer phenotypes using four of the available cancer databases in dbGaP. Logistic regression and derived haplotype analysis indicates that ~80 SNPs, previously overlooked, are statistically significant. Derived haplotypes from this work link POLL to breast cancer and POLG to prostate cancer with an increase in incidence of 3.01- and 9.6-fold, respectively. Molecular dynamics simulations on wild-type and one of the SNP mutants from the haplotype of POLL provide insights at the atomic level on the functional impact of this cancer related SNP. Furthermore, HyDn-SNP-S has been designed to allow application to any system. The program is available upon request from the authors.
PMCID: PMC3916134  PMID: 23830898
SNP search; Biomarkers; Molecular dynamics; DNA polymerases; Cancer
17.  Axitinib Improves Radiotherapy in Murine Xenograft Lung Tumors 
Translational Oncology  2014;7(3):400-409.
A third of patients with non-small cell lung cancer (NSCLC) present with un-resectable stage III locally advanced disease and are currently treated by chemo-radiotherapy but the median survival is only about 21 months. Using an orthotopic xenograft model of lung carcinoma, we have investigated the combination of radiotherapy with the anti-angiogenic drug axitinib (AG-013736, Pfizer), which is a small molecule receptor tyrosine kinase inhibitor that selectively targets the signal transduction induced by VEGF binding to VEGFR receptors. We have tested the combination of axitinib with radiotherapy in nude mice bearing human NSCLC A549 lung tumors. The therapy effect was quantitatively evaluated in lung tumor nodules. The modulation of radiation-induced pneumonitis, vascular damage and fibrosis by axitinib was assessed in lung tissue. Lung irradiation combined with long-term axitinib treatment was safe resulting in minimal weight loss and no vascular injury in heart, liver and kidney tissues. A significant decrease in the size of lung tumor nodules was observed with either axitinib or radiation, associated with a decrease in Ki-67 staining and a heavy infiltration of inflammatory cells in tumor nodules. The lungs of mice treated with radiation and axitinib showed a complete response with no detectable residual tumor nodules. A decrease in pneumonitis, vascular damage and fibrosis were observed in lung tissues from mice treated with radiation and axitinib. Our studies suggest that axitinib is a potent and safe drug to use in conjunction with radiotherapy for lung cancer that could also act as a radioprotector for lung tissue by reducing pneumonitis and fibrosis.
PMCID: PMC4145357  PMID: 24862536
18.  Evaluation of the effect of genetic variation on the relationship between statins, cardiovascular disease and cancer 
Statins are a class of medications that are competitive inhibitors of Hydroxy Methyl Glutaryl Co-enzyme A (HMG-CoA) reductase which is the rate-limiting enzyme in the cholesterol bio-synthesis pathway. As a result, statins lower total cholesterol and low density lipoprotein (LDL) cholesterol thus impacting cardiovascular mortality. The downstream effects of statins are not limited to inhibition of cholesterol synthesis alone. Statins have anti-inflammatory effects thought to be important in the setting of acute myocardial infarction which also may be a mechanism involved in anti-carcinogenic properties of statins. Furthermore, statin inhibition of the mevalonate pathway may impact Ras and RhoGTPases that are important in cell proliferation, migration and apoptosis. These alterations may also play a role in the anti-cancer effect of statins. In this article we will review the literature on how genetic variation modifies the effect of statins on the risk of cardiovascular disease and how genetic variation may impact the relationship between statins and the risk of a number of different cancers.
PMCID: PMC3852638  PMID: 24319534
Statins; blood lipids; cancer risk; cardiovascular disease; genetic variation
19.  Association between COX-2 Expression and Effectiveness of COX-2 Inhibitors in Phase II Trial in Patients with Metastatic Colorectal Adenocarcinoma 
Anticancer research  2012;32(8):3559-3563.
The role for the cyclooxygenase-2 (COX-2) pathway in colorectal carcinogenesis has been suggested in pre-clinical models. In a previously reported phase II trial, the addition of COX-2 inhibitor celecoxib to irinotecan and capecitabine did not appear to significantly increase the activity of chemotherapy in patients with metastatic colorectal carcinoma (mCRC). We evaluated COX-2 expression in the available tumors from patients enrolled by immunohistochemistry and its correlation with clinical outcome.
Patients and Methods
Fifty-one patients with mCRC were enrolled in the phase II study between June 2002 and November 2005. Patients received a combination of irinotecan 70 mg/m2 over 30 min i.v. on days 1 and 8, capecitabine 1,000 mg/m2 twice per day orally on days 1-14 and the COX-2 inhibitor celecoxib at a daily dose of 800 mg continuously. Cycles were repeated every 21 days. Formalin-fixed paraffin-embedded tumor tissue samples were available for 17 patients enrolled on that study. COX-2 expression was evaluated by immunohistochemistry and correlated with clinical outcome.
In the phase II study, the objective response rate was 41%. The median time to progression was 7.7 months and median survival time was 21.2 months. Tumor COX-2 expression by immunohistochemistry was assessed for 17 patients enrolled in that same phase II study. While not statistically significant, the response rate was better for patients in the low COX-2 expression group, while time to progression and overall survival was longer in patients in the high COX-2 expression group. This discrepancy can be partially attributed to the small sample size.
In the previously published phase II study, the addition of celecoxib to irinotecan and capecitabine did not appear to significantly increase the activity of chemotherapy. COX-2 expression by immunohistochemistry was neither prognostic nor predictive for response.
PMCID: PMC3807874  PMID: 22843946
COX-2; metastatic colorectal cancer; celecoxib
20.  Radiographic Parameters in Predicting Outcome of Patients with Hepatocellular Carcinoma Treated with Yttrium-90 Microsphere Radioembolization 
ISRN Oncology  2013;2013:538376.
Background. In patients with hepatocellular carcinoma, selection criteria for transarterial hepatic selective internal radiotherapy are imprecise. Additionally, radiographic parameters to predict outcome of transarterial hepatic selective internal radiotherapy have not been fully characterized. Patients and methods. Computed tomography (CT) scans of 23 patients with unresectable primary hepatocellular carcinoma before and after transarterial hepatic selective internal radiotherapy with yttrium-90 microspheres were retrospectively reviewed. Selected radiographic parameters were evaluated and correlated with progression-free survival and overall survival. Response to treatment was assessed with Response RECIST 1.1 and Morphology, Attenuation, Size, and Structure (MASS) criteria. Results. On the post-SIRT CT, 68% of tumors demonstrated decreased size (median decrease of 0.8 cm, P = 0.3); 64% had decreased attenuation (median decrease 5.7 HU, P = 0.06), and 48% demonstrated increased tumor necrosis (P < 0.001). RECIST-defined partial response was seen in 10% patients, stable disease in 80%, and 10% had disease progression. Median progression-free survival was 3.9 months (range, 3.3 to 7.3), and median overall survival was 11.2 months (7.1 to 31.1). Pretreatment lower hepatopulmonary shunt fraction, central hypervascularity, and well-defined tumor margins were associated with improved progression-free survival. Conclusion. In patients with unresectable hepatocellular carcinoma, pretreatment CT parameters may predict favorable response to SIRT and improve patient selection.
PMCID: PMC3791818  PMID: 24167742
21.  Systems analysis reveals a transcriptional reversal of the mesenchymal phenotype induced by SNAIL-inhibitor GN-25 
BMC Systems Biology  2013;7:85.
HMLEs (HMLE-SNAIL and Kras-HMLE, Kras-HMLE-SNAIL pairs) serve as excellent model system to interrogate the effect of SNAIL targeted agents that reverse epithelial-to-mesenchymal transition (EMT). We had earlier developed a SNAIL-p53 interaction inhibitor (GN-25) that was shown to suppress SNAIL function. In this report, using systems biology and pathway network analysis, we show that GN-25 could cause reversal of EMT leading to mesenchymal-to-epithelial transition (MET) in a well-recognized HMLE-SNAIL and Kras-HMLE-SNAIL models.
GN-25 induced MET was found to be consistent with growth inhibition, suppression of spheroid forming capacity and induction of apoptosis. Pathway network analysis of mRNA expression using microarrays from GN-25 treated Kras-HMLE-SNAIL cells showed an orchestrated global re-organization of EMT network genes. The expression signatures were validated at the protein level (down-regulation of mesenchymal markers such as TWIST1 and TWIST2 that was concurrent with up-regulation of epithelial marker E-Cadherin), and RNAi studies validated SNAIL dependent mechanism of action of the drug. Most importantly, GN-25 modulated many major transcription factors (TFs) such as inhibition of oncogenic TFs Myc, TBX2, NR3C1 and led to enhancement in the expression of tumor suppressor TFs such as SMAD7, DD1T3, CEBPA, HOXA5, TFEB, IRF1, IRF7 and XBP1, resulting in MET as well as cell death.
Our systems and network investigations provide convincing pre-clinical evidence in support of the clinical application of GN-25 for the reversal of EMT and thereby reducing cancer cell aggressiveness.
PMCID: PMC3848843  PMID: 24004452
SNAIL; EMT; MET; Snail inhibitor; Systems biology; Network analysis; Pathway analysis
22.  Epigenetic deregulation of miR-29a and miR-1256 by isoflavone contributes to the inhibition of prostate cancer cell growth and invasion 
Epigenetics  2012;7(8):940-949.
The epigenetic regulation of genes has long been recognized as one of the causes of prostate cancer (PCa) development and progression. Recent studies have shown that a number of microRNAs (miRNAs) are also epigenetically regulated in different types of cancers including PCa. In this study, we found that the DNA sequence of the promoters of miR-29a and miR-1256 are partly methylated in PCa cells, which leads to their lower expression both in PCa cells and in human tumor tissues compared with normal epithelial cells and normal human prostate tissues. By real-time PCR, Western Blot analysis and miRNA mimic and 3′-UTR-Luc transfection, we found that TRIM68 is a direct target of miR-29a and miR-1256 and that the downregulation of miR-29a and miR-1256 in PCa cells leads to increased expression of TRIM68 and PGK-1 in PCa cells and in human tumor tissue specimens. Interestingly, we found that a natural agent, isoflavone, could demethylate the methylation sites in the promoter sequence of miR-29a and miR-1256, leading to the upregulation of miR-29a and miR-1256 expression. The increased levels of miR-29a and miR-1256 by isoflavone treatment resulted in decreased expression of TRIM68 and PGK-1, which is mechanistically linked with inhibition of PCa cell growth and invasion. The selective demethylation activity of isoflavone on miR-29a and miR-1256 leading to the suppression of TRIM68 and PGK-1 expression is an important biological effect of isoflavone, suggesting that isoflavone could be a useful non-toxic demethylating agent for the prevention of PCa development and progression.
PMCID: PMC3427289  PMID: 22805767
DNA methylation; PGK-1; TRIM68; isoflavone; miR-1256; miR-29a
23.  ER-tethered Transcription Factor CREBH Regulates Hepatic Lipogenesis, Fatty Acid Oxidation, and Lipolysis upon Metabolic Stress 
Hepatology (Baltimore, Md.)  2012;55(4):1070-1082.
CREBH is a liver-specific transcription factor that is localized in the endoplasmic reticulum (ER) membrane. Our previous work demonstrated that CREBH is activated by ER stress or inflammatory stimuli to induce an acute-phase hepatic inflammation. Here we demonstrate that CREBH is a key metabolic regulator of hepatic lipogenesis, fatty acid (FA) oxidation, and lipolysis under metabolic stress. Saturated FA, insulin signals, or an atherogenic high-fat diet can induce CREBH activation in the liver. Under the normal chow diet, CrebH knockout mice display a modest decrease in hepatic lipid contents but an increase in plasma triglycerides (TG). After feeding an atherogenic high-fat diet, massive accumulation of hepatic lipid metabolites and significant increase in plasma TG levels were observed in the CrebH knockout mice. Along with the hypertriglyceridemia phenotype, the CrebH null mice displayed significantly reduced body weight gain, diminished abdominal fat, and increased non-alcoholic steatohepatitis (NASH) activities under the atherogenic high-fat diet. Gene expression analysis and chromatin-immunoprecipitation (ChIP) assay indicated that CREBH is required to activate expression of the genes encoding functions involved in de novo lipogenesis, TG and cholesterol biosynthesis, FA elongation and oxidation, lipolysis, and lipid transport. Supporting the role of CREBH in lipogenesis and lipolysis, forced expression of an activated form of CREBH protein in the liver significantly increases accumulation of hepatic lipids but reduces plasma TG levels in mice. All together our study shows that CREBH plays a key role in maintaining lipid homeostasis by regulating expression of the genes involved in hepatic lipogenesis, FA oxidation, and lipolysis under metabolic stress. The identification of CREBH as a stress-inducible metabolic regulator has important implications in the understanding and treatment of metabolic disease.
PMCID: PMC3319338  PMID: 22095841
24.  Comprehensive molecular oncogenomic profiling and miRNA analysis of prostate cancer 
This study was focused on molecular profiling of prostate cancer (PCa) using scant amounts of both frozen and formalin-fixed paraffin-embedded (FFPE) PCa tissue specimens. DNA and RNA were extracted and interrogated for: (1) whole-genome gene expression profiling, (2) miRNA expression analysis, (3) SNP analysis, and (4) mutation analysis. Data was statistically analyzed and correlated with clinical and pathologic variables. Expression profiling of 47,224 genes revealed 74 genes that were significant in predicting high tumor grade in PCa (p<0.0001). These were involved in many cellular processes as analyzed by Ingenuity Pathway Analysis (IPA). Using novel high throughput technologies, we identified a specific oncogenomic and miRNA signatures showing loss of miR-34 expression. Interestingly, p53 was at the center hub of the signaling pathways, and the loss of miR-34a expression was consistent with the central role of p53 in PCa. Analysis of 731,442 SNP’s, revealed 638 SNP’s that were significant in predicting high tumor grade (p<0.0001; logistic regression analysis). We also found, for the first time, a novel hot spot mutation in MET oncogene, variant T992I, suggesting that our findings would be useful in further defining the role of specific regulatory genes and miRNAs in the pathological evolution of PCa, and could also have potential clinical utility in improving diagnostic accuracy, refining prognostic and predictive capabilities and may serve as therapeutic targets.
PMCID: PMC3612515  PMID: 23573364
Molecular; oncogenomic; miRNA; profiling; prostate cancer
25.  Maspin Reprograms the Gene Expression Profile of Prostate Carcinoma Cells for Differentiation 
Genes & Cancer  2011;2(11):1009-1022.
Maspin is an epithelial-specific tumor suppressor gene. Previous data suggest that maspin expression may redirect poorly differentiated tumor cells to better differentiated phenotypes. Further, maspin is the first and only endogenous polypeptide inhibitor of histone deacetylase 1 (HDAC1) identified thus far. In the current study, to address what central program of tumor cell redifferentiation is regulated by maspin and how tumor microenvironments further define the effects of maspin, we conducted a systematic and extensive comparison of prostate tumor cells grown in 2-dimensional culture, in 3-dimensional collagen I culture, and as in vivo bone tumors. We showed that maspin was sufficient to drive prostate tumor cells through a spectrum of temporally and spatially polarized cellular processes of redifferentiation, a reversal of epithelial-to-mesenchymal transition (EMT). Genes commonly regulated by maspin were a small subset of HDAC target genes that are closely associated with epithelial differentiation and TGFβ signaling. These results suggest that a specific endogenous HDAC inhibitor may regulate one functionally related subset of HDAC target genes, although additional maspin-induced changes of gene expression may result from tumor interaction with its specific microenvironments. Currently, EMT is recognized as a critical step in tumor progression. To this end, our current study uncovered a link between maspin and a specific mechanism of prostate epithelial differentiation that can reverse EMT.
PMCID: PMC3379563  PMID: 22737267
cell differentiation; organotypic model; microarray analysis

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