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On February 23, 2018, PubMed Central Canada (PMC Canada) will be taken offline permanently. No author manuscripts will be deleted, and the approximately 2,900 manuscripts authored by Canadian Institutes of Health Research (CIHR)-funded researchers currently in the archive will be copied to the National Research Council’s (NRC) Digital Repository over the coming months. These manuscripts along with all other content will also remain publicly searchable on PubMed Central (US) and Europe PubMed Central, meaning such manuscripts will continue to be compliant with the Tri-Agency Open Access Policy on Publications.

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1.  Prognostic value of lncRNA SOX2OT for Chinese cancer patients: A meta-analysis 
PLoS ONE  2017;12(5):e0176889.
SOX2OT has been demonstrated to be aberrantly expressed in several types of cancer and maybe serve as a prognostic marker for cancer patients. However, most individual studies have been limited by small sample sizes and controversial results. Therefore, the present meta-analysis was conducted to analyze available data to reveal the potential clinical application of SOX2OT on cancer prognosis, tumor progression, distance metastasis and lymph node metastasis. Up to February 20, 2017, literature collections were conducted by comprehensive searching electronic databases, including Cochrane Library, PubMed, Embase, BioMed Central, Springer, ScienceDirect, ISI Web of Knowledge, together with three Chinese databases: China National Knowledge Internet (CNKI), Weipu and Wanfang. The hazard ratios (HR) with 95% confidence interval (95% CI) were calculated to assess the strength of the association. Five studies with a total of 481 cancer patients were included in the present meta-analysis. The results indicated that elevated SOX2OT significantly predicted unfavorable overall survival (OS) (HR = 2.44, 95% CI: 1.75–3.39, P<0.0001) and tumor progression (III/IV vs. I/II: HR 1.62, 95%CI: 1.30–2.02, P<0.0001), but failed to predict distant metastasis (HR: 3.30, 95%CI: 0.74–14.61, P = 0.12) and lymph node metastasis (HR: 1.29, 95% CI: 0.87–1.91, P = 0.21). The results revealed that SOX2OT expression level was an independent prognostic biomarker for OS and tumor progression in Chinese cancer patients.
doi:10.1371/journal.pone.0176889
PMCID: PMC5425198  PMID: 28489861
2.  Innate immune cell response upon Candida albicans infection 
Virulence  2016;7(5):512-526.
abstract
Candida albicans is a polymorphic fungus which is the predominant cause of superficial and deep tissue fungal infections. This microorganism has developed efficient strategies to invade the host and evade host defense systems. However, the host immune system will be prepared for defense against the microbe by recognition of receptors, activation of signal transduction pathways and cooperation of immune cells. As a consequence, C. albicans could either be eliminated by immune cells rapidly or disseminate hematogenously, leading to life-threatening systemic infections. The interplay between Candida albicans and the host is complex, requiring recognition of the invaded pathogens, activation of intricate pathways and collaboration of various immune cells. In this review, we will focus on the effects of innate immunity that emphasize the first line protection of host defense against invaded C. albicans including the basis of receptor-mediated recognition and the mechanisms of cell-mediated immunity.
doi:10.1080/21505594.2016.1138201
PMCID: PMC5026795  PMID: 27078171
Candida albicans; immune cells; innate immunity; receptor-mediated recognition; signal transduction
3.  Prostate-specific IL-6 transgene autonomously induce prostate neoplasm through amplifying inflammation in the prostate and peri-prostatic adipose tissue 
Background
The causative role of the pro-inflammatory cytokine IL-6 in prostate cancer progression has been well established at molecular level. However, whether and how IL-6 may play a role in prostate cancer risk and development is not well defined. One limitation factor to acquiring this knowledge is the lack of appropriate animal models.
Methods
We generated a novel line of prostate-specific IL-6 transgenic mouse model. We compared the prostate pathology, tumorigenic signaling components, and prostate tumor microenvironment of the IL-6 transgenic mice with wild type littermates.
Results
With this model, we demonstrate that IL-6 induces prostate neoplasm autonomously. We further demonstrate that transgenic expression of IL-6 in the prostate activates oncogenic pathways, induces autocrine IL-6 secretion and steadily-state of STAT3 activation in the prostate tissue, upregulates paracrine insulin-like growth factor (IGF) signaling axis, reprograms prostate oncogenic gene expression, and more intriguingly, amplifies inflammation in the prostate and peri-prostatic adipose tissue.
Conclusions
The pro-inflammatory IL-6 is autonomous oncogene for the prostate. IL-6 induces prostate oncogenesis through amplifying local inflammation. We also presented a valuable animal model to study inflammation and prostate cancer development.
Electronic supplementary material
The online version of this article (doi:10.1186/s13045-016-0386-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s13045-016-0386-7
PMCID: PMC5225646  PMID: 28077171
IL-6; Prostate neoplasm; Transgenic mouse; Inflammation
4.  Pilot study of the prevalence of binge eating disorder in non-alcoholic fatty liver disease patients 
Annals of Gastroenterology  2017;30(6):664-669.
Background:
Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the United States. Binge eating disorder (BED) is the most common form of eating disorder. NAFLD and BED have similar risk factors, including obesity, insulin resistance, and metabolic syndrome. The aim of our study was to examine prevalence of BED in NAFLD patients.
Methods:
We administered the Binge Eating Scale (BES), a questionnaire validated to screen for BED, to NAFLD patients at our Fatty Liver Center. Demographics were retrieved retrospectively from our electronic medical record.
Results:
Of the total 95 NAFLD patients screened, 22 (23.1%) had binge eating tendencies; 6 of the 22 (6.3%) scored 27 or more points, suggestive of severe binge eating. Patient demographics included 59 females and 36 males (14 females and 8 males positive for BED). Liver disease severity and of metabolic syndrome presence were similar in both groups: 45 patients had steatosis, 25 steatohepatitis, and 24 cirrhosis, of which 10 steatosis, 5 steatohepatitis, and 7 cirrhosis patients screened positive for BED. Of the NAFLD patients with BED, 50.0% had insulin resistance, 68.2% hypertension, and 50.0% hyperlipidemia, whereas among non-BED NAFLD patients 58.9% had insulin resistance, 63.0% hypertension, and 67.1% hyperlipidemia.
Conclusions:
This pilot study suggests that BED may have a higher prevalence among NAFLD patients than in the general population. Based on these preliminary results, further study into the prevalence of BED is recommended. More data is need to identify effects of BED on the progression of NAFLD and role of BED treatment.
doi:10.20524/aog.2017.0200
PMCID: PMC5670286
Non-alcoholic fatty liver disease; binge eating disorder; metabolic syndrome
5.  Quantitative Analysis in Combination with Fingerprint Technology and Chemometric Analysis Applied for Evaluating Six Species of Wild Paris Using UHPLC-UV-MS 
A fast method was developed by ultra high performance liquid chromatography (UHPLC) for simultaneous determination of polyphyllin I and polyphyllin II. Chemometric analyses including principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) based on UHPLC chromatography were used to evaluate 38 batches from six species of Paris. Variable importance of projection was applied to select important peaks. Meanwhile, similarity analysis of UHPLC fingerprint was used to evaluate the sample of Paris polyphylla yunnanensis (PPY) and P. axialis (PA). The results indicated that the total content of saponins in PPY and PA collected from Baoshan City of Yunnan Province above 8.07 mg/g was stronger than that from other areas of the rest of species. PLS-DA showed better performance than PCA with regard to classifying the samples. Retention time during 20–27 minutes of UHPLC was screened as significant peak for distinguishing Paris of different species and original geography. All of PPY and PA with similarity value were more than 0.80. It indicated that quantitative analysis combined with chemometric and similarity analyses could evaluate the different species of Paris effectively and comprehensively.
doi:10.1155/2016/3182796
PMCID: PMC5209620  PMID: 28097038
6.  ER Stress-induced Inflammasome Activation Contributes to Hepatic Inflammation and Steatosis 
Endoplasmic reticulum (ER) stress functions as a protein folding and quality control mechanism to maintain cell homeostasis. Emerging evidence indicates that ER stress is also involved in metabolic and inflammatory diseases. However, the link between ER stress and inflammation remains not well characterized. In this study, we have demonstrated that ER stress-induced inflammasome activation plays a critical role in the pathogenesis of hepatic steatosis. By utilizing genetic and pharmacological agent-induced hepatic steatosis animal models, we found that hepatic steatosis was associated with inflammasome activation and ER stress. Our results show that caspase-1 ablation alleviated liver inflammation and injury. Liver tissues from caspase-1 KO mice had significantly reduced production of IL-1β under ER stress conditions. We also found that ER stress promoted inflammasome activation and IL-1β processing in both hepatocytes and Kupffer cells/macrophages. Moreover, lack of caspase-1 ameliorated cell death or pyropoptosis of hepatocytes induced by ER stress. Taken together, our findings suggest that ER stress-induced inflammasome activation and IL-1β production generate a positive feedback loop to amplify inflammatory response, eventually leading to liver steatosis and injury.
doi:10.4172/2155-9899.1000457
PMCID: PMC5146989  PMID: 27942420
Endoplasmic reticulum; Inflammasome; Steatosis; Liver
7.  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.
doi:10.1186/s40425-016-0172-7
PMCID: PMC5123387
8.  Non-blocking monoclonal antibody targeting soluble MIC revamps endogenous innate and adaptive anti-tumor responses and eliminates primary and metastatic tumors 
Purpose
The human tumor-derived soluble MHC I-chain related molecule (sMIC) is highly immune suppressive in cancer patients and correlates with poor prognosis. However, the therapeutic effect of targeting sMIC has not been determined, due to the limitation that mice do not express homologs of human MIC. This study is to evaluate the therapeutic effect of a monoclonal antibody targeting sMIC in a clinically relevant transgenic animal model.
Experimental Design
We treated the engineered MIC-expressing “humanized” TRAMP/MIC bi-transgenic mice at advanced disease stages with a sMIC-neutralizing non-blocking anti-MIC monoclonal antibody (mAb) and assessed the therapeutic efficacy and associated mechanisms.
Results
A sMIC-neutralizing non-blocking anti-MIC mAb effectively induced regression of primary tumors and eliminated metastasis without inducing systemic toxicity. The therapeutic effect is conferred by revamping endogenous anti-tumor immune responses, exemplified by restoring NK cell homeostasis and function, enhancing susceptibility of MIC+-tumor cells to NK cell killing, reviving and sustaining antigen-specific CD8 T cell responses, augmenting CD4 T cells to Th1 responses, priming dendritic cells for antigen presentation, and remodeling tumor microenvironment to be more immune reactive.
Conclusions
Therapy with a sMIC-neutralizing non-blocking anti-MIC mAb can effectuate anti-tumor immune responses against advanced MIC+ tumors. Our study provided strong rationale for translating sMIC-neutralizing therapeutic mAb into clinics, either alone or in combination with current ongoing standard immunotherapies.
doi:10.1158/1078-0432.CCR-15-0845
PMCID: PMC4631684  PMID: 26106076
soluble MIC; Cancer Immunotherapy; neutralizing antibody
9.  Targeting inflammasome/IL-1 pathways for cancer immunotherapy 
Scientific Reports  2016;6:36107.
The inflammatory microenvironment has been shown to play important roles in various stages of tumor development including initiation, growth, and metastasis. The inflammasome is a critical innate immune pathway for the production of active IL-1β, a potent inflammatory cytokine. Although inflammasomes are essential for host defense against pathogens and contribute to autoimmune diseases, their role in tumor progression remains controversial. Here, our results demonstrate that the inflammasome and IL-1β pathway promoted tumor growth and metastasis in animal and human breast cancer models. We found that tumor progression was associated with the activation of inflammasome and elevated levels of IL-1β at primary and metastatic sites. Mice deficient for inflammasome components exhibited significantly reduced tumor growth and lung metastasis. Furthermore, inflammasome activation promoted the infiltration of myeloid cells such as myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) into tumor microenvironments. Importantly, blocking IL-1R with IL-1R antagonist (IL-Ra) inhibited tumor growth and metastasis accompanied by decreased myeloid cell accumulation. Our results suggest that targeting the inflammasome/IL-1 pathway in tumor microenvironments may provide a novel approach for the treatment of cancer.
doi:10.1038/srep36107
PMCID: PMC5082376  PMID: 27786298
10.  Deep-submicron Graphene Field-Effect Transistors with State-of-Art fmax 
Scientific Reports  2016;6:35717.
In order to conquer the short-channel effects that limit conventional ultra-scale semiconductor devices, two-dimensional materials, as an option of ultimate thin channels, receive wide attention. Graphene, in particular, bears great expectations because of its supreme carrier mobility and saturation velocity. However, its main disadvantage, the lack of bandgap, has not been satisfactorily solved. As a result, maximum oscillation frequency (fmax) which indicates transistors’ power amplification ability has been disappointing. Here, we present submicron field-effect transistors with specially designed low-resistance gate and excellent source/drain contact, and therefore significantly improved fmax. The fabrication was assisted by the advanced 8-inch CMOS back-end-of-line technology. A 200-nm-gate-length GFET achieves fT/fmax = 35.4/50 GHz. All GFET samples with gate lengths ranging from 200 nm to 400 nm possess fmax 31–41% higher than fT, closely resembling Si n-channel MOSFETs at comparable technology nodes. These results re-strengthen the promise of graphene field-effect transistors in next generation semiconductor electronics.
doi:10.1038/srep35717
PMCID: PMC5075922  PMID: 27775009
11.  Candida albicans triggers the expression of inflammatory genes in human umbilical vein endothelial cells 
The aim of the present study was to investigate the pathogenesis of Candida albicans in human umbilical vein endothelial cells (HUVECs) and to screen for aberrantly expressed genes during the process of infection. GSE7355 (accession no.) was downloaded from the National Center of Biotechnology Information Gene Expression Omnibus database and used to identify the differentially-expressed genes (DEGs) between the two groups, which included 4 samples from an untreated HUVEC control group, and 4 samples from HUVECs exposed to C. albicans. Subsequently, the gene ontology (GO) function package was used to perform GO and pathway enrichment analysis, prior to the extraction of DEG correlations in the Kyoto Encyclopedia of Genes and Genomes. A protein-protein interaction (PPI) network was constructed using the String database. In total, 77 DEGs were identified, including 69 upregulated and 8 downregulated DEGs in the C. albicans-infected HUVEC samples. DEGs were significantly enriched in response to external stimuli and chemokine activity. In addition, DEG FBJ murine osteosarcoma viral oncogene homolog (FOS) and interleukin (IL)-6 were significantly enriched in the Toll-like receptor signaling pathway. Nuclear factor κ light polypeptide gene enhancer in B cells 2 (NFKB2) was significantly enriched in the mitogen-activated protein kinase signaling pathway. In the interaction network of DEGs, according data included in the KEGG database, FOS and NFKB2 had higher connectivity degrees. Notably, FOS, IL-6 and intercellular adhesion molecule 1 were demonstrated to have higher connectivity degrees in the PPI network. FOS, IL-6 and NFKB2 may be important genes for C. albicans infection in HUVECs, and these genes may act as therapeutic targets to treat patients infected with C. albicans.
doi:10.3892/etm.2016.3464
PMCID: PMC4998159  PMID: 27602073
Candida albicans; human umbilical vein endothelial cells; differentially-expressed genes; protein-protein interaction network
12.  Increased Levels of β-catenin, LEF-1, and HPA-1 Correlate with Poor Prognosis for Acral Melanoma with Negative BRAF and NRAS Mutation in BRAF Exons 11 and 15 and NRAS Exons 1 and 2 
DNA and Cell Biology  2015;34(1):69-77.
To determine the expression of β-catenin, lymphoid enhancer-binding protein-1 (LEF-1), and heparanase-1 (HPA-1) and to evaluate these proteins' potential prognostic values in malignant acral melanoma without mutations in BRAF exons 11 and 15 and NRAS exons 1 and 2, specimens from 90 patients with wild-type BRAF and NRAS were assessed and analyzed by immunohistochemistry and western blotting. The positive expression of β-catenin, lymphoid enhancer-binding protein-1, and heparanase-1 was observed in 36 (72%), 31 (62%), and 32 (64%) of the detected acral melanomas, respectively. The expression of β-catenin, lymphoid enhancer-binding protein-1, and heparanase-1 was not correlated with gender, age, or diseased body parts (p>0.05), but was significantly positively correlated with the tumor node metastasis (TNM) stage and metastasis (correlation=0.406 and 0.716, 0.397 and 0.582, 0.353 and 0.579; p=0.040 and 0.0001, 0.0040 and 0.0001, 0.0120 and 0.0001, respectively). We also observed that the increased expression of β-catenin, lymphoid enhancer-binding protein-1, and heparanase-1 was significantly correlated with decreased survival and poor prognosis (p=0.001, 0.010, and 0.023, respectively). A multifactorial analysis using Cox's regression model revealed that β-catenin, lymphoid enhancer-binding protein-1, heparanase-1, and the TNM stage were all independent factors in malignant melanoma (risk ratios were 7.294, 5.550, 5.622, and 4.794; p-values were 0.007, 0.018, 0.018, and 0.029, respectively). This study may provide the basis for the use of β-catenin, lymphoid enhancer-binding protein-1, and heparanase-1 as novel targets in the treatment of malignant invasion and metastasis in acral melanoma cancer. The expression of β-catenin, LEF-1, and HPA-1 was assessed and compared in malignant melanoma with that of peritumoral tissue and benign nevus in the patients with negative mutations in BRAF exons 11 and 15 and NRAS exons 1 and 2. The study may provide the basis for β-catenin, LEF-1, and HPA-1 as new targets in the treatment of malignant invasion and metastasis in melanoma cancer.
doi:10.1089/dna.2014.2590
PMCID: PMC4281839  PMID: 25343173
13.  Identification of Two bZIP Transcription Factors Interacting with the Promoter of Soybean Rubisco Activase Gene (GmRCAα) 
Rubisco activase (RCA), a key photosynthetic protein, catalyses the activation of Rubisco and thus plays an important role in photosynthesis. Although the RCA gene has been characterized in a variety of species, the molecular mechanism regulating its transcription remains unclear. Our previous studies on RCA gene expression in soybean suggested that expression of this gene is regulated by trans-acting factors. In the present study, we verified activity of the GmRCAα promoter in both soybean and Arabidopsis and used a yeast one-hybrid (Y1H) system for screening a leaf cDNA expression library to identify transcription factors (TFs) interacting with the GmRCAα promoter. Four basic leucine zipper (bZIP) TFs, GmbZIP04g, GmbZIP07g, GmbZIP1, and GmbZIP71, were isolated, and GmbZIP04g and GmbZIP07g were confirmed as able to bind to a 21-nt G-box-containing sequence. Additionally, the expression patterns of GmbZIP04g, GmbZIp07g, and GmRCAα were analyzed in response to abiotic stresses and during a 24-h period. Our study will help to advance elucidation of the network regulating GmRCAα transcription.
doi:10.3389/fpls.2016.00628
PMCID: PMC4868853  PMID: 27242832
Rubisco activase; promoter; basic leucine zipper; soybean; transcription factor
14.  Protoporphyrin Treatment Modulates Susceptibility to Experimental Autoimmune Encephalomyelitis in miR-155-Deficient Mice 
PLoS ONE  2015;10(12):e0145237.
We previously identified heme oxygenase 1 (HO-1) as a specific target of miR-155, and inhibition of HO-1 activity restored the capacity of miR-155-/- CD4+ T cells to promote antigen-driven inflammation after adoptive transfer in antigen-expressing recipients. Protoporphyrins are molecules recognized for their modulatory effect on HO-1 expression and function. In the present study, we investigated the effect of protoporphyrin treatment on the development of autoimmunity in miR-155-deficient mice. MiR-155-mediated control of HO-1 expression in promoting T cell-driven chronic autoimmunity was confirmed since HO-1 inhibition restored susceptibility to experimental autoimmune encephalomyelitis (EAE) in miR-155-deficient mice. The increased severity of the disease was accompanied by an enhanced T cell infiltration into the brain. Taken together, these results underline the importance of miR-155-mediated control of HO-1 expression in regulating the function of chronically-stimulated T cells in EAE.
doi:10.1371/journal.pone.0145237
PMCID: PMC4684403  PMID: 26670809
15.  Graphene Distributed Amplifiers: Generating Desirable Gain for Graphene Field-Effect Transistors 
Scientific Reports  2015;5:17649.
Ever since its discovery, graphene bears great expectations in high frequency electronics due to its irreplaceably high carrier mobility. However, it has long been blamed for the weakness in generating gains, which seriously limits its pace of development. Distributed amplification, on the other hand, has successfully been used in conventional semiconductors to increase the amplifiers’ gain-bandwidth product. In this paper, distributed amplification is first applied to graphene. Transmission lines phase-synchronize paralleled graphene field-effect transistors (GFETs), combining the gain of each stage in an additive manner. Simulations were based on fabricated GFETs whose fT ranged from 8.5 GHz to 10.5 GHz and fmax from 12 GHz to 14 GHz. A simulated four-stage graphene distributed amplifier achieved up to 4 dB gain and 3.5 GHz bandwidth, which could be realized with future IC processes. A PCB level graphene distributed amplifier was fabricated as a proof of circuit concept.
doi:10.1038/srep17649
PMCID: PMC4669444  PMID: 26634442
16.  Inflammasome activation plays an important role in the development of spontaneous colitis 
Mucosal immunology  2014;7(5):1139-1150.
Inflammatory bowel diseases (IBD) are characterized for dysregulated intestinal inflammation. Conflicting reports have shown that activation of inflammasome could promote or decrease intestinal inflammation in an acute colitis model, whereas the involvement of inflammasome activation in chronic colitis is poorly understood. In this study, we investigated the role of inflammasome activation in the development of chronic intestinal inflammation by utilizing IL-10 knockout (KO) mouse as an animal model, which develops chronic colitis resembling human IBD. We demonstrate the causative link between inflammasome activation and the development of chronic intestinal inflammation. Our results show that mature IL-1β protein levels were significantly increased in all colon sections from IL-10 deficient mice compared with that of wild type mice. We found that inhibition of inflammasome activities with IL-1 receptor antagonist or caspase 1 inhibitors suppressed IL-1β and IL-17 production from inflamed colon explants. Furthermore, blocking inflammasome activation with caspase-1 inhibitor in vivo significantly ameliorated the spontaneous colitis in IL-10 KO mice. Together, these observations demonstrate that inflammasome activation promotes the development of chronic intestinal inflammation.
doi:10.1038/mi.2014.1
PMCID: PMC4115056  PMID: 24472848
IBD; colitis; inflammasome; IL-10; IL-1β; IL-17
17.  PUFA diets alter the microRNA expression profiles in an inflammation rat model 
Molecular Medicine Reports  2015;11(6):4149-4157.
Omega-3 and -6 polyunsaturated fatty acids (PUFAs) can directly or indirectly regulate immune homeostasis via inflammatory pathways, and components of these pathways are crucial targets of microRNAs (miRNAs). However, no study has examined the changes in the miRNA transcriptome during PUFA-regulated inflammatory processes. Here, we established PUFA diet-induced autoimmune-prone (AP) and autoimmune-averse (AA) rat models, and studied their physical characteristics and immune status. Additionally, miRNA expression patterns in the rat models were compared using microarray assays and bioinformatic methods. A total of 54 miRNAs were differentially expressed in common between the AP and the AA rats, and the changes in rno-miR-19b-3p, -146b-5p and -183-5p expression were validated using stem-loop reverse transcription-quantitative polymerase chain reaction. To better understand the mechanisms underlying PUFA-regulated miRNA changes during inflammation, computational algorithms and biological databases were used to identify the target genes of the three validated miRNAs. Furthermore, Gene Ontology (GO) term annotation and KEGG pathway analyses of the miRNA targets further allowed to explore the potential implication of the miRNAs in inflammatory pathways. The predicted PUFA-regulated inflammatory pathways included the Toll-like receptor (TLR), T cell receptor (TCR), NOD-like receptor (NLR), RIG-I-like receptor (RLR), mitogen-activated protein kinase (MAPK) and the transforming growth factor-β (TGF-β) pathway. This study is the first report, to the best of our knowledge, on in vivo comparative profiling of miRNA transcriptomes in PUFA diet-induced inflammatory rat models using a microarray approach. The results provide a useful resource for future investigation of the role of PUFA-regulated miRNAs in immune homeostasis.
doi:10.3892/mmr.2015.3318
PMCID: PMC4394972  PMID: 25672643
microRNA; polyunsaturated fatty acids; immune homeostasis; microRNA target gene prediction; functional enrichment analysis
18.  NKG2D Ligands in Tumor Immunity: Two Sides of a Coin 
The activating/co-stimulatory receptor NKG2D (natural-killer group 2, member D) is expressed on the surface of all human NK, NKT, CD8+ T, and subsets of γδ+ T cells. The significance of NKG2D function in tumor immunity has been well demonstrated in experimental animal models. However, the role of human NKG2D ligands in regulating tumor immunity and cancer prognosis had been controversial in the literature. In this review, we summarize the latest advancement, discuss the controversies, and present evidence that membrane-bound and soluble NKG2D ligands oppositely regulate tumor immunity. We also discuss new perspectives of targeting NKG2D ligands for cancer immunotherapy.
doi:10.3389/fimmu.2015.00097
PMCID: PMC4349182  PMID: 25788898
NKG2D ligands; cancer; NK cells; T cells; tumor immunity
19.  Variation in Rubisco activase (RCAβ) gene promoters and expression in soybean [Glycine max (L.) Merr.] 
Journal of Experimental Botany  2013;65(1):47-59.
Variation in Rubisco activase gene promoters (RCAβ) could affect diversity of expression level, which provided a new approach for enhancing soybean productivity by altering the expression level of RCAβ
Understanding the genetic basis of Rubisco activase (RCA) gene regulation and altering its expression levels to optimize Rubisco activation may provide an approach to enhance plant productivity. However, the genetic mechanisms and the effect of RCA expression on phenotype are still unknown in soybean. This work analysed the expression of RCA genes and demonstrated that two RCA isoforms presented different expression patterns. Compared with GmRCAα, GmRCAβ was expressed at higher mRNA and protein levels. In addition, GmRCAα and GmRCAβ were positively correlated with chlorophyll fluorescence parameters and seed yield, suggesting that changes in expression of RCA has a potential applicability in breeding for enhanced soybean productivity. To identify the genetic factors that cause expression level variation of GmRCAβ, expression quantitative trait loci (eQTL) mapping was combined with allele mining in a natural population including 219 landraces. The eQTL mapping showed that a combination of both cis- and trans-acting eQTLs might control GmRCAβ expression. As promoters can affect both cis- and trans-acting eQTLs by altering cis-acting regulatory elements or transcription factor binding sites, this work subsequently focused on the promoter region of GmRCAβ. Single-nucleotide polymorphisms in the GmRCAβ promoter were identified and shown to correlate with expression level diversity. These SNPs were classified into two groups, A and B. Further transient expression showed that GUS expression driven by the group A promoter was stronger than that by the group B promoter, suggesting that promoter sequence types could influence gene expression levels. These results would improve understanding how variation within promoters affects gene expression and, ultimately, phenotypic diversity in natural populations.
doi:10.1093/jxb/ert346
PMCID: PMC3883283  PMID: 24170743
Allele mining; eQTL; photosynthesis; promoter; Rubisco activase; seed yield; soybean [Glycine max (L.) Merr.]
20.  Gene transfer of Chlorella vulgaris n-3 fatty acid desaturase optimizes the fatty acid composition of human breast cancer cells 
Chlorella vulgaris has the gene of n-3 fatty acid desaturase (CvFad3), which can synthesize the precursor of n-3 polyunsaturated fatty acids (PUFAs) or convert n-6 to n-3 PUFAs. The objective of the present study was to examine whether the CvFad3 gene from C. vulgaris can be functionally and efficiently expressed in human breast cancer cells and whether its expression can exert a significant effect on cell fatty acid composition. We inserted the CvFad3 gene into the plasmid pEGFP-C3 to construct the eukaryotic expression vector pEGFP-C3-n-3 and to express the n-3 Fad gene in human breast cancer cells (MCF-7 cells). Transfection of MCF-7 cells with the recombinant vector resulted in a high expression of n-3 fatty acid desaturase. Lipid analysis indicated that the ratio of n-6/n-3 PUFAs was decreased from 6:1 in the control cells to about 1:1 in the cells expressing the n-3 fatty acid desaturase. Accordingly, the CvFad3 gene significantly decreased the ratio of n-6/n-3 PUFAs of the MCF-7 cell membrane. The expression of the CvFad3 gene can decrease cell proliferation and promote cell apoptosis. This study demonstrates that the CvFad3 gene can dramatically balance the ratio of n-6/n-3 PUFAs and may provide an effective approach to the modification of the fatty acid composition of mammalian cells, also providing a basis for potential applications of its transfer in experimental and clinical settings.
PMCID: PMC3854232  PMID: 22983174
Chlorella vulgaris; CvFad3 gene; Fatty acid desaturase; Recombinant expression vector; Fatty acid composition; Breast cancer cells
21.  Anticancer Properties and Mechanisms of Fucoidan on Mouse Breast Cancer In Vitro and In Vivo 
PLoS ONE  2012;7(8):e43483.
Background
Fucoidan is a sulfated polysaccharide derived from brown algae that has been reported to perform multiple biological activities, including antitumor activity. In this study, we examined the influence of crude fucoidan on mouse breast cancer in vitro and in vivo.
Materials and Methods
In vitro, fluorescent staining, flow cytometry and Western blot were performed to analyze apoptosis and vascular endothelial growth factor (VEGF) expression of mouse breast cancer 4T1 cells. In vivo, therapy experiments were conducted on Babl/c mice bearing breast cancer. The tumor volume and weight were measured. The number of apoptotic cells and microvascular density (MVD) in tumor tissues were assessed by TUNEL and CD34 immunostaining. Immunohistochemical assays and ELISA assay were used to detect the expression of VEGF in tissues.
Results
In vitro studies showed that crude fucoidan significantly decreased the viable number of 4T1 cells, induced apoptosis and down-regulated the expression of VEGF. The expression of Bcl-2 was decreased, and the ratio of Bcl-2 to Bax was significantly decreased. The expression of Survivin and phosphorylated extracellular signal regulated protein kinases (ERKs) was decreased. Cytochrome C was released from mitochondria into cytosol, and the cleaved Caspase-3 protein rose after fucoidan treatment. Intraperitoneal injection of fucoidan in breast cancer models reduced the tumor volume and weight. The enhanced antitumor efficacy was associated with decreased angiogenesis and increased induction of apoptosis.
Conclusion
These findings indicated that crude fucoidan inhibited mouse breast cancer growth in vitro and in vivo. These data suggest that fucoidan may serve as a potential therapeutic agent for breast cancer.
doi:10.1371/journal.pone.0043483
PMCID: PMC3423341  PMID: 22916270
22.  Altered microRNA expression profile with miR-146a upregulation in CD4+ T cells from patients with rheumatoid arthritis 
Introduction
Increasing evidence indicates that microRNAs (miRNAs) play a critical role in the pathogenesis of inflammatory diseases. The aim of the study was to investigate the expression pattern and function of miRNAs in CD4+ T cells from patients with rheumatoid arthritis (RA).
Methods
The expression profile of miRNAs in CD4+ T cells from synovial fluid (SF) and peripheral blood of 33 RA patients was determined by microarray assay and validated by qRT-PCR analysis. The correlation between altered expression of miRNAs and cytokine levels was determined by linear regression analysis. The role of miR-146a overexpression in regulating T cell apoptosis was evaluated by flow cytometry. A genome-wide gene expression analysis was further performed to identify miR-146a-regulated genes in T cells.
Results
miRNA expression profile analysis revealed that miR-146a expression was significantly upregulated while miR-363 and miR-498 were downregulated in CD4+ T cells of RA patients. The level of miR-146a expression was positively correlated with levels of tumor necrosis factor-alpha (TNF-α), and in vitro studies showed TNF-α upregulated miR-146a expression in T cells. Moreover, miR-146a overexpression was found to suppress Jurkat T cell apoptosis. Finally, transcriptome analysis of miR-146a overexpression in T cells identified Fas associated factor 1 (FAF1) as a miR-146a-regulated gene, which was critically involved in modulating T cell apoptosis.
Conclusions
We have detected increased miR-146a in CD4+ T cells of RA patients and its close correlation with TNF-α levels. Our findings that miR-146a overexpression suppresses T cell apoptosis indicate a role of miR-146a in RA pathogenesis and provide potential novel therapeutic targets.
doi:10.1186/ar3006
PMCID: PMC2911863  PMID: 20459811

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