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2. Ibrutinib plus rituximab and mini-CHOP in older patients with newly diagnosed DLBCL: a phase 2 ALLG study

Author

Lenton, Douglas, Taper, John, Presgrave, Peter, Butler, Jason, Mollee, Peter, Kannourakis, George, Steer, Christopher, Verner, Emma, Johnston, Amanda, Pati, Nalini, Hawkes, Eliza A., Lee, Hui-Peng, Cochrane, Tara, Cheah, Chan Yoon, Filshie, Robin, Purtill, Duncan, Sia, Hanlon, Enjeti, Anoop K., Brown, Christina, Murphy, Nicholas, Curnow, Jennifer, Lee, Kenneth, Gandhi, Maher K., Walia, Mannu, Butcher, Belinda E., and Trotman, Judith

Published
2024
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3. Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer

Author

Sevelda, Paul, Haslbauer, Ferdinand, Penzinger, Monika, Öhler, Leopold, Tinchon, Christoph, Greil, Richard, Heibl, Sonja, Bartsch, Rupert, Wette, Viktor, Singer, Christian F., Pasterk, Claudia, Helfgott, Ruth, Pristauz-Telsnigg, Gunda, Stöger, Herbert, Weltermann, Angsar, Egle, Daniel, Thiel, Irene, Fuchs, David, Rumpold, Holger, Strasser-Weippl, Kathrin, Rautenberg, Beate, Müller, Volkmar, Schmidt, Marcus, Paepke, Stefan, Aydogdu, Mustafa, Thomssen, Christoph, Rom, Joachim, Mau, Christine, Fasching, Peter, Göhring, Uwe-Jochen, Kühn, Thorsten, Noeding, Stefanie, Kümmel, Sherko, Hackmann, John, Stickeler, Elmar, Joshi, Abhishek, Dewar, Joanna, Friedlander, Michael, Phillips, Kelly-Anne, Antill, Yoland, Woodward, Natasha, Abdi, Ehtesham, Tiley, Susan, George, Mathew, Boadle, David, Goodwin, Annabel, van der Westhuizen, Andre, Kannourakis, George, Murray, Nicholas, McCarthy, Nicole, Kroep, Judith, de Boer, Maaike, Heijns, Joan, Jager, Agnes, Erdkamp, Franciscus, Bakker, Sandra, Sonke, Gabe S., Sami, Amer, Mackey, John, Prady, Catherine, Eisen, Andrea, Desbiens, Christine, Patocskai, Erica, Ferrario, Cristiano, Gelmon, Karen, Bordeleau, Louise, Chalchal, Haji, Niraula, Saroj, ido wolf, Senkus, Elżbieta, Duhoux, François, Randal d’Hondt, Luce, Sylvie, Roodenbeke, Daphné t’Kint de, Papadimitriou, Konstantinos, Borms, Marleen, Quaghebeur, Claire, Jacot, William, Brain, Etienne, Venat-Bouvet, Laurence, Lortholary, Alain, Nowecki, Zbigniew, Cardoso, Fátima, Hayward, Richard, Bella, Santiago, Lazzaro, Mauricio Fernández, Pilnik, Norma, Fein, Luis E., Blajman, Cesar, Lerzo, Guillermo, Varela, Mirta, Zarba, Juan Jose, Kaen, Diego, Constanzo, Maria Victoria, Tio, Joke, Siggelkow, Wulf, Jackisch, Christian, Grischke, Eva Maria, Zahm, Dirk, Tato-Varela, Sara, Schmatloch, Sabine, Klare, Peter, Stefek, Andrea, Rhiem, Kerstin, Hoffmann, Oliver, Deryal, Mustafa, Gröll, Isolde, Ledwon, Peter, Uleer, Christoph, Krabisch, Petra, Potenberg, Jochem, Darsow, Maren, Park-Simon, Tjoung-Won, Höffkes, Heinz-Gert, Emde, Till-Oliver, Graffunder, Gerd, Tomé, Oliver, Forstmeyer, Dirk, Terhaag, Jürgen, Salat, Christoph, Kast, Karin, Weniger, Steffi, Schreiber, Carsten, Heinrich, Bernhard, Dieterich, Max, Wüllner, Michaela Penelope, Conejero, Raquel Andrés, García Sáenz, José Ángel, Martinez, Lourdes Calvo, Lanza, Angels Arcusa, Murillo, Serafín Morales, Carrasco, Fernando Henao, Tormo, Salvador Blanch, López, Isabel Álvarez, Delgado Mingorance, Juan Ignacio, Gomez, Elena Álvarez, Santisteban, Marta, Jurado, Josefina Cruz, Quiroga, Vanesa, Borrego, Manuel Ruiz, Martínez de Dueñas, Eduardo, Alés Martínez, Jose Enrique, De la Haba, Juan, Jañez, Noelia Martínez, Lescure, Álvaro Rodríguez, Torres, Antonio Antón, Crusades, Gema Llort, González-Santiago, Santiago, Aragones, Antonia Marquez, Ortega, Ana Laura, Molins, Agusti Barnadas, Chacón López-Muñiz, José Ignacio, Jiménez, Miguel Martín, Bertrán, Ana Santaballa, Rodríguez, César, Cortijo, Lucía González, Cretella, Elisabetta, Cortesi, Laura, Ruggeri, Enzo Maria, Verusio, Claudio, Gori, Stefania, Bonetti, Andrea, Mosconi, Anna Maria, Johannsson, Oskar, Jerusalem, Guy, Neven, Patrick, Nagy, Tünde, Pinotti, Graziella, Colleoni, Marco A., Bernardo, Antonio, Gianni, Lorenzo, Bucci, Eraldo, Biganzoli, Laura, Dedes, Konstantin, Novak, Urban, Zaman, Khalil, Braybrooke, Jeremy, Winter, Matthew, Rea, Daniel, Kelleher, Muireann, Barrett, Sophie, Chan, Stephen, Hickish, Tamas, Hurwitz, Jane, Conibear, John, Jegannathen, Apurna, Parton, Marina, Tutt, Andrew, Allerton, Rozenn, Borley, Annabel, Armstrong, Anne, Copson, Ellen, Levitt, Nicola, Abraham, Jean, Perren, Timothy, Roylance, Rebecca, Ishida, Kazushige, Toyama, Tatsuya, Masuda, Norikazu, Watanabe, Junichiro, Tokunaga, Eriko, Kinoshita, Takayuki, Rai, Yoshiaki, Takada, Masahiro, Yanagita, Yasuhiro, Nakamura, Rikiya, Nakayama, Takahiro, Naoi, Yasuto, Iwata, Hiroji, Nakamura, Seigo, Takahashi, Masato, Aogi, Kenjiro, Tsugawa, Koichiro, Mukai, Hirofumi, Takano, Toshimi, Osaki, Akihiko, Sato, Nobuaki, Yamauchi, Hideko, Tokuda, Yutaka, Ito, Mitsuya, Sugimoto, Takeki, Bahadur, Shakeela W., Ganz, Patricia A., Lu, Min J., Mita, Monica M., Waisman, James, Polikoff, Jonathan A., Telli, Melinda L., Seaward, Samantha A., Suga, J. Marie, Durna, Lara N., Carney, Jennifer Fu, Menter, Alex, Puthillath, Ajithkumar, Rohatgi, Nitin, Feusner, James H., Bobolis, Kristie A., Eisenberg, Peter D., Wong, Derrick, Borges, Virginia F., Urquhart, Alexander T., Hofstatter, Erin W., McCarron, Edward C., Isaacs, Claudine, Herbolsheimer, Pia, Varadarajan, Ramya, Raben, Adam, Deveras, Ruby Anne E., Valdes-Albini, Frances, Mahtani, Reshma L., Meisel, Jane L., Sumrall, Bradley T., Jones, Cheryl F., Ofori, Samuel N., Sumida, Kenneth N.M., Karwal, Mark, Wilbur, Deborah W., Singh, (Joe), Spector, David M., Schallenkamp, John, Merkel, Douglas E., Lo, Shelly S., Khosla, Pam G., Cristofanilli, Massimo, Flaum, Lisa, Hoskins, Kent F., Cobleigh, Melody A., Lambiase, Elyse A., Hahn, Olwen M., Oliff, Ira A., Faller, Bryan A., Wade, James L., Burhani, Nafisa D., Gil, Amaryllis, Einhorn, Harvey E., Storniolo, Anna M.V., Chang, Brian K., Kalra, Maitri, Robin, Erwin L., Ansari, Bilal, Sharma, Priyanka, Dakhil, Shaker R., Deming, Richard L., Cole, John T., Hanson, David S., Ochoa, Augusto C., Garber, Judy E., Zimbler, Harvey, Armstrong, Deborah K., Tkaczuk, Katherine H.R., Riseberg, David A., O'Connor, Brian M., Openshaw, Thomas H., Zakalik, Dana, Vakhariya, Cynthia M., Schott, Anne F., Simon, Michael S., Doyle, Thomas J., Al Baghdadi, Tareq, VanderWoude, Amy, Flynn, Patrick J., Zera, Richard T., Friday, Bret E.B., Ruddy, Kathryn J., Smith, Ron, Ademuyiwa, Olabisi, Foluso, Ellis, Robert, Carlson, Jay W., Marchello, T, Benjamin, Levine, Edward A., Marcom, Paul K., Harkness, Cameron B., Tan, Antoinette R., Charles, William J., Kuzma, Charles S., Asaad, Shonda, Radford, James E., Steen, Preston D., Unnikrishnan, Madhu, Seeger, Grant R., Leu, Kirsten M.H., Copur, Mehmet S., Hauke, Ralph J., Soori, Gamini S., Arrick, Bradley A., Reeder, Jennifer G., Toppmeyer, Deborah L., Dayao, Zoneddy R., Adams, Sylvia, Andreopoulou, Eleni, Allison, Magnuson, Anampa Mesias, Jesus D., Sharma, Ruby, Ramaswamy, Bhuvaneswari, Gerds, Aaron T., Shenk, Robert R., Gross, Howard M., Trehan, Shruti, Razaq, Wajeeha, Mansoor, Abdul H., Hilton, Christie J., Brufsky, Adam M., Huynh, Chanh, Chowdhury, Nabila, Domchek, Susan M., Sigurdson, Elin R., Cescon, Terrence P., Rovito, Marc A., DeNittis, Albert S., Vogel, Victor G., Julian, Thomas B., Boyle, L.E., Baez-Diaz, Luis, Brescia, Frank J., Doster, John E., Siegel, Robert D., Wong, Lucas, Patel, Tejal, Nangia, Julie R., Jones, Catherine A., Cannon, George M., Bear, Harry D., Vachhani, Hetal, Wilkinson, Mary, Wood, Marie E., Yan, Fengting, Sui, Xingwei, van Haelst, Carol M., Specht, Jennifer M., Zhuo, Ying, Qamar, Rubina, Ryan, Matthew L., Stockham, Abigail, Virani, Shamsuddin, Gayle, Arlene A., Jubelirer, Steven J., Kurian, Sobha, Salkeni, Mohamad A., Loman, Niklas, Linderholm, Barbro, Silander, Gustav, Hallbeck, Anna-Lotta, von Wachenfeldt Väppling, Anna, Curtit, Elsa, Cardoso, Catarina, Braga, Sofia, Abreu, Miguel, Casa-Nova, Mafalda, Nave, Mónica, Ciruelos Gil, Eva María, Gelpi, Judith Balmaña, Ortega, Adela Fernández, Padró, Josep Gumà, Bermejo de las Heras, Begoña, Cao, María González, Bañuelos, Juan Cueva, Company, Jesús Alarcon, Villaró, Gemma Viñas, Estevez, Laura García, Huober, Jens, Busch, Steffi, Fehm, Tanja, Hahn, Antje, Grafe, Andrea, Noesselt, Thomas, Dewitz, Thomas, Wagner, Harald, Bechtner, Christina, Weigel, Michael, Kolberg, Hans-Christian, Decker, Thomas, Thomalla, Jörg, Hesse, Tobias, Harbeck, Nadia, Jens-Uwe Blohmer, Jan Schröder, Wolf Sütterlin, Marc, Altena, Renske, Chiu, Chang-Fang, Chen, Shin-Cheh, Hou, Ming-Feng, Chang, Yuan-Ching, Chen, Shang-Hung, Chen, Shou-Tung, Huang, Chiun-Sheng, Yeh, Dah-Cherng, Yu, Jyh-Cherng, Tseng, Ling-Ming, Chung, Wei-Pang, Mailliez, Audrey, Petit, Thierry, Delaloge, Suzette, Lévy, Christelle, Dalivoust, Philippe, Extra, Jean-Marc, Mouret-Reynier, Marie-Ange, Hardy-Bessard, Anne-Claire, Simon, Hélène, L'Haridon, Tiffenn, Mege, Alice, Giacchetti, Sylvie, Chakiba-Brugere, Camille, Gratet, Alain, Pottier, Virginie, Ferrero, Jean-Marc, Tennevet, Isabelle, Perrin, Christophe, Canon, Jean-Luc, Joris, Sofie, Shao, Zhimin, Xu, Binghe, Jiang, ZeFei, Sun, Qiang, Shen, Kunwei, Pang, Da, Zhang, Jin, Wang, Shui, Yang, Hongjian, Liao, Ning, Zheng, Hong, Fu, Peifen, Song, Chuangui, Wang, Yongsheng, Fan, Zhimin, Geng, Cuizhi, Tredan, Olivier, Landherr, László, Kaufman, Bella, Yerushalmi, Rinat, Uziely, Beatrice, Conte, Pierfranco, Zamagni, Claudio, Bianchini, Giampaolo, De Laurentiis, Michelino, Tondini, Carlo, Gebbia, Vittorio, Ciccarese, Mariangela, Sarosiek, Tomasz, Mackiewicz, Jacek, Słowińska, Anna, Kalinka, Ewa, Huzarski, Tomasz, Im, Seock-Ah, Jung, Kyung Hae, Sohn, Joo Hyuk, Kim, Jee Hyun, Lee, Keun Seok, Park, Yeon Hee, Lee, Kyoung Eun, Chae, Yee Soo, Cho, Eun Kyung, Geyer, C.E., Jr., Garber, J.E., Gelber, R.D., Yothers, G., Taboada, M., Ross, L., Rastogi, P., Cui, K., Arahmani, A., Aktan, G., Armstrong, A.C., Arnedos, M., Balmaña, J., Bergh, J., Bliss, J., Delaloge, S., Domchek, S.M., Eisen, A., Elsafy, F., Fein, L.E., Fielding, A., Ford, J.M., Friedman, S., Gelmon, K.A., Gianni, L., Gnant, M., Hollingsworth, S.J., Im, S.-A., Jager, A., Jóhannsson, Ó. Þ, Lakhani, S.R., Janni, W., Linderholm, B., Liu, T.-W., Loman, N., Korde, L., Loibl, S., Lucas, P.C., Marmé, F., Martinez de Dueñas, E., McConnell, R., Phillips, K.-A., Piccart, M., Rossi, G., Schmutzler, R., Senkus, E., Shao, Z., Sharma, P., Singer, C.F., Španić, T., Stickeler, E., Toi, M., Traina, T.A., Viale, G., Zoppoli, G., Park, Y.H., Yerushalmi, R., Yang, H., Pang, D., Jung, K.H., Mailliez, A., Fan, Z., Tennevet, I., Zhang, J., Nagy, T., Sonke, G.S., Sun, Q., Parton, M., Colleoni, M.A., Schmidt, M., Brufsky, A.M., Razaq, W., Kaufman, B., Cameron, D., Campbell, C., and Tutt, A.N.J.

Published
2022
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4. Plakin Expression in Serous Epithelial Ovarian Cancer Has the Potential to Impede Metastatic Spread and Epithelial–Mesenchymal Transition: A Comparative Expression Analysis of Immunohistochemical and In Silico Datasets.

Author

Wesley, Tamsin, Escalona, Ruth M., Kannourakis, George, and Ahmed, Nuzhat

Subjects
STATISTICAL correlation, PEARSON correlation (Statistics), EPITHELIAL-mesenchymal transition, ASCITES, T-test (Statistics), RESEARCH funding, CYTOSKELETAL proteins, DESCRIPTIVE statistics, METASTASIS, GENE expression, CELL lines, IMMUNOHISTOCHEMISTRY, MESSENGER RNA, KAPLAN-Meier estimator, ONE-way analysis of variance, OVARIAN epithelial cancer, STAINS & staining (Microscopy), CANCER genes, COMPARATIVE studies, DISEASE progression
Abstract

Simple Summary: Approximately 60% of patients diagnosed with epithelial ovarian cancer (EOC) die within the first five years due to disease recurrence. Identification of cytoskeletal proteins that may be involved in the epithelial-to-mesenchymal transition (EMT) may guide the accurate treatment and follow-up of patients with advanced EOC. The aim of this study was to evaluate whether there is a correlation between the expression of these cytoskeletal proteins and EMT as EOC progresses using primary EOC biopsies. We suggest that the expression of specific cytoskeletal proteins (plakins) is enhanced in early stages/grades of EOC but diminished as EOC progresses. However, the EMT marker proteins have a mixed expression, suggesting that plakin expression in primary tumours could impact the clinical progression and survival of patients with EOC. Epithelial ovarian cancer is aggressive and causes high mortality among women worldwide. Members of the plakin family are essential to maintain cytoskeletal integrity and key cellular processes. In this study we characterised the expression of plakins, particularly plectin (PLEC), periplakin (PPL), envoplakin (EVPL), and EMT-related proteins by immunohistochemistry in n = 48 patients' samples to evaluate a potential correlation of plakin expression with EMT as EOC progresses. These tissue plakin and EMT expression analyses were further evaluated by in vitro cell line expression and correlated with the expression of these molecules using publicly available datasets such as Cancer Genome Atlas (TCGA) and Clinical Proteome Tumour Analysis Consortium (CPTAC) datasets. We demonstrate that the expression of PPL and PLEC plakins is decreased in high-grade compared to low-grade EOCs with mixed EMT marker protein expression. This is supported by the correlation of high PPL and PLEC expression with an epithelial rather than mesenchymal phenotype. Our data suggest a partial loss of plakin expression as EOC tumours progress. This may impact the connections of plakins with membrane-bound receptors, which impede the downstream signalling required for the initiation of EMT as the tumours progress. [ABSTRACT FROM AUTHOR]

Published
2024
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6. Reduced T and NK Cell Activity in Glioblastoma Patients Correlates with TIM-3 and BAT3 Dysregulation.

Author

Ahmady, Farah, Curpen, Peter, Perriman, Louis, Fonseca Teixeira, Adilson, Wu, Siqi, Zhu, Hong-Jian, Poddar, Arpita, Jayachandran, Aparna, Kannourakis, George, and Luwor, Rodney B.

Subjects
T-cell exhaustion, KILLER cells, T cells, CELL physiology, HEPATITIS A virus cellular receptors
Abstract

Inhibitory receptors are critical for regulating immune cell function. In cancer, these receptors are often over-expressed on the cell surface of T and NK cells, leading to reduced anti-tumor activity. Here, through the analysis of 11 commonly studied checkpoint and inhibitory receptors, we discern that only HAVCR2 (TIM3) and ENTPD1 (CD39) display significantly greater gene expression in glioblastoma compared to normal brain and lower grade glioma. Cell surface TIM-3, but not ENTPD1, was also elevated on activated CD4+ and CD8+ T cells, as well as on NK cells from glioblastoma patients compared to healthy donor T and NK cells. A subsequent analysis of molecules known to co-ordinate TIM-3 function and regulation was performed, which revealed that BAT3 expression was significantly reduced in CD4+ and CD8+ T cells, as well as NK cells from glioblastoma patients compared to counterparts from healthy donors. These pro-inhibitory changes are also correlated with reduced levels of the activation marker CD69 and the pro-inflammatory cytokine IFNγ in CD4+ and CD8+ T cells, as well as NK cells from glioblastoma patients. Collectively, these data reveal that glioblastoma-mediated CD4+ and CD8+ T cell and NK cell suppression is due, at least in part, to dysregulated TIM-3 and BAT3 expression and the associated downstream immunoregulatory and dysfunctional effects. [ABSTRACT FROM AUTHOR]

Published
2024
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9. Ibrutinib plus rituximab and mini-CHOP in older patients with newly diagnosed DLBCL: a phase 2 ALLG study

Author

Verner, Emma, Johnston, Amanda, Pati, Nalini, Hawkes, Eliza A., Lee, Hui-Peng, Cochrane, Tara, Cheah, Chan Yoon, Filshie, Robin, Purtill, Duncan, Sia, Hanlon, Enjeti, Anoop K., Brown, Christina, Murphy, Nicholas, Curnow, Jennifer, Lee, Kenneth, Gandhi, Maher K., Walia, Mannu, Butcher, Belinda E., Trotman, Judith, Lenton, Douglas, Taper, John, Presgrave, Peter, Butler, Jason, Mollee, Peter, Kannourakis, George, and Steer, Christopher

Abstract

•Ibrutinib–R-mini-CHOP was a deliverable combination in patients with DLBCL aged ≥75 years.•Ibrutinib–R-mini-CHOP improves PFS compared with historical rates reported for R-mini-CHOP, but this study did not demonstrate a superior OS.

Published
2024
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21. Divergent molecular networks program functionally distinct CD8+ skin-resident memory T cells.

Author

Park, Simone L., Christo, Susan N., Wells, Alexandria C., Gandolfo, Luke C., Zaid, Ali, Alexandre, Yannick O., Burn, Thomas N., Schröder, Jan, Collins, Nicholas, Seong-Ji Han, Guillaume, Stéphane M., Evrard, Maximilien, Castellucci, Clara, Davies, Brooke, Osman, Maleika, Obers, Andreas, McDonald, Keely M., Huimeng Wang, Mueller, Scott N., and Kannourakis, George

Published
2023
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22. The Interleukin-11/IL-11 Receptor Promotes Glioblastoma Survival and Invasion under Glucose-Starved Conditions through Enhanced Glutaminolysis

Author

Stuart, Sarah F., primary, Bezawork-Geleta, Ayenachew, additional, Areeb, Zammam, additional, Gomez, Juliana, additional, Tsui, Vanessa, additional, Zulkifli, Ahmad, additional, Paradiso, Lucia, additional, Jones, Jordan, additional, Nguyen, Hong P. T., additional, Putoczki, Tracy L., additional, Licciardi, Paul V., additional, Kannourakis, George, additional, Morokoff, Andrew P., additional, Achuthan, Adrian A., additional, and Luwor, Rodney B., additional

Published
2023
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24. Additional file 1 of Knock down of TIMP-2 by siRNA and CRISPR/Cas9 mediates diverse cellular reprogramming of metastasis and chemosensitivity in ovarian cancer

Author

Escalona, Ruth M., Chu, Simon, Kadife, Elif, Kelly, Jason K., Kannourakis, George, Findlay, Jock K., and Ahmed, Nuzhat

Abstract

Additional file 1: Figure S1. siRNA suppression of TIMP-2 in the OVCAR5 cell line. Diagram showing the location of single siRNA duplexes A, B, C in the TIMP-2 gene. Figure S2. CRISPR/Cas9 editing of the TIMP-2 gene in the OVCAR5 cell line. A Diagram showing the configuration of TIMP-2 CRISPR/Cas9 plasmid. The TIMP-2 linear donor plasmid is ~ 2.74 kb and incorporates the donor GFP and puromycin (under the EF1a promoter). The transfection involves integration of Cas9/gRNA and the linear donor plasmid (GFP and puromycin) genes into cells. The Cas9 targets the TIMP-2 gene in exon1, guided by two gRNA sequences [the gRNA1 (yellow) and gRNA2 (pink)]. The donor genes can be inserted in the cells by transcription in the forward or reverse directions. In both situations, interruption of TIMP-2 expression coinciding with puromycin resistance and GFP expression should occur. (Figure adapted from https://www.origene.com/catalog/gene-expression/knockout-kits-crispr/kn409796/timp2-human-gene-knockout-kit-crispr ). B Puromycin “death” curve in the OVCAR5 cell line. The OVCAR5 cell line was incubated with puromycin concentrations ranging from 0 to 320 µg/mL followed by an MTT assay of OVCAR5 cells after 48 h. The concentration of 3 µg/mL (indicated by red arrow) was used for puromycin selection. Values are mean ± SEM and graph is representative of three experiments done in triplicate. C CRISPR transfected OVCAR5 cells after puromycin selection and GFP sorting. OVCAR5 cells were transfected with CRISPR/Cas9 vectors plus the donor plasmid containing puromycin and GFP genes. After puromycin selection, cells were GFP sorted and visualized under a confocal microscope. After a second GFP sorting, GFP fluorescence was only seen in gRNA2 cells but not in gRNA1 cells. 20× magnification; scale bar 1000 µM. D MTT assay of OVCAR5 TIMP-2 CRISPR/Cas9 transfected and Control cells. After 48 h of incubation the concentration of puromycin that killed 50% of cells was determined (IC50 values). Values are mean ± SEM and the graph is representative of three experiments done in triplicate. Figure S3. Expression of cellular TIMP-2 and corresponding GAPDH by Western blot. Representative full image of a Western blot of TIMP-2 and GAPDH proteins on the cell lysates of parental, CRISPR/Cas9 treated control, gRNA1 and gRNA2 cell lines. Figure S4. Quantification of EdU stained OVCAR5 parental, CRISPR control, and TIMP-2 knocked down gRNA2 and gRNA1 cells. The cells were stained with EdU and propidium iodide (PI) as described in “Methods”. A Flow cytometer representation of percentage of EdU stained cells in S-phase of the cycle for CRISPR transfected cell lines. B Flow cytometer representation of negative controls used to calculate the percentage of EdU stained cells in S-phase of the cycle for the OVCAR5 parental cell line. Red rectangles indicate the areas analysed for EdU positive cells. Table S1. Primers used in the study.

Published
2023
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26. Effects of Ker-050 on Iron Metabolism: Exploratory Analyses from an Ongoing Phase 2 Study in Patients with Myelodysplastic Syndromes

Author

Chee, Lynette C.Y., primary, Ross, David M, additional, Tan, Shuh Ying, additional, Wight, Joel, additional, Kannourakis, George, additional, Ross, Miranda, additional, Feng, Wei, additional, Jiang, Ying, additional, Natarajan, Harveen Dhillon, additional, Graham, Christine, additional, Rovaldi, Christopher, additional, Cooper, Simon, additional, and Salstrom, Jen L., additional

Published
2022
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27. Modulation of TGF-β Superfamily Signaling to Treat Myelofibrosis and Mitigate JAK Inhibitor Toxicity: A Report on the Phase 2 Study of Ker-050 in Participants with Myelofibrosis

Author

Harrison, Claire, primary, Tan, Shuh Ying, additional, Ross, David M, additional, Kannourakis, George, additional, McGinty, Allie, additional, Feng, Wei, additional, Jiang, Ying, additional, Graham, Christine, additional, Rovaldi, Chris, additional, Cooper, Simon, additional, and Salstrom, Jen L., additional

Published
2022
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30. A three-stage developmental pathway for human Vγ9Vδ2 T cells within the postnatal thymus.

Author

Perriman, Louis, Tavakolinia, Naeimeh, Jalali, Sedigheh, Li, Shuo, Hickey, Peter F., Amann-Zalcenstein, Daniela, Ho, William Wing Ho, Baldwin, Tracey M., Piers, Adam T., Konstantinov, Igor E., Anderson, Jeremy, Stanley, Edouard G., Licciardi, Paul V., Kannourakis, George, Naik, Shalin H., Koay, Hui-Fern, Mackay, Laura K., Berzins, Stuart P., and Pellicci, Daniel G.

Abstract

Vγ9Vδ2 T cells are the largest population of γδ T cells in adults and can play important roles in providing effective immunity against cancer and infection. Many studies have suggested that peripheral Vγ9Vδ2 T cells are derived from the fetal liver and thymus and that the postnatal thymus plays little role in the development of these cells. More recent evidence suggested that these cells may also develop postnatally in the thymus. Here, we used high-dimensional flow cytometry, transcriptomic analysis, functional assays, and precursor-product experiments to define the development pathway of Vγ9Vδ2 T cells in the postnatal thymus. We identify three distinct stages of development for Vγ9Vδ2 T cells in the postnatal thymus that are defined by the progressive acquisition of functional potential and major changes in the expression of transcription factors, chemokines, and other surface markers. Furthermore, our analysis of donor-matched thymus and blood revealed that the molecular requirements for the development of functional Vγ9Vδ2 T cells are delivered predominantly by the postnatal thymus and not in the periphery. Tbet and Eomes, which are required for IFN-γ and TNFα expression, are up-regulated as Vγ9Vδ2 T cells mature in the thymus, and mature thymic Vγ9Vδ2 T cells rapidly express high levels of these cytokines after stimulation. Similarly, the postnatal thymus programs Vγ9Vδ2 T cells to express the cytolytic molecules, perforin, granzyme A, and granzyme K. This study provides a greater understanding of how Vγ9Vδ2 T cells develop in humans and may lead to opportunities to manipulate these cells to treat human diseases. Editor's summary: Unconventional T cells play an important role in protective immunity; however, the development of these distinctive cell populations is poorly understood. Using tissues donated from children undergoing heart surgery, Perriman et al. investigated the development of Vγ9Vδ2 T cells, a large population of unconventional γδ T cells found in adults, addressing the uncertainty about the role of the postnatal thymus in their maturation. This work identified three distinct populations of Vγ9Vδ2 T cells, distinguished by their transcriptional profiles and functional ability to produce cytokines, consistent with a three-stage developmental transition in the thymus before egress of functionally mature cells into the periphery. The identification of precursor Vγ9Vδ2 T cells extends understanding of factors potentially involved in the differentiation of these cells in humans. —Sarah H. Ross [ABSTRACT FROM AUTHOR]

Published
2023
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31. Efficacy and safety of maintenance therapy with pamiparib versus placebo for advanced gastric cancer responding to first‐line platinum‐based chemotherapy: Phase 2 study results.

Author

Ciardiello, Fortunato, Bang, Yung‐Jue, Cervantes, Andrés, Dvorkin, Mikhail, Lopez, Charles D., Metges, Jean‐Philippe, Sánchez Ruiz, Antonio, Calvo, Mariona, Strickland, Andrew H., Kannourakis, George, Muro, Kei, Kawakami, Hisato, Wei, Jia, Borg, Christophe, Zhu, Zhaoyin, Gupta, Neal, Pelham, Robert J., and Shen, Lin

Subjects
STOMACH cancer, PEMETREXED, TERMINATION of treatment, PLACEBOS, RECOMBINANT DNA, DNA repair, GASTRIC outlet obstruction
Abstract

Background: Poly (ADP‐ribose) polymerase (PARP) inhibitors (PARPi) are approved for the treatment of various solid tumors. In gastric cancer, genes commonly harbor mutations in the homologous recombination DNA repair pathway, potentially increasing sensitivity to PARPi. Pamiparib (BGB‐290) is a small molecule inhibitor of PARP1 and PARP2. Methods: The PARALLEL‐303 study (NCT03427814) investigated the efficacy and safety of pamiparib 60 mg orally (PO) twice daily (BID) versus placebo PO BID as maintenance therapy in patients with inoperable locally advanced or metastatic gastric cancer that responded to platinum‐based first‐line chemotherapy. The primary endpoint of this double‐blind, randomized, global phase 2 study was progression‐free survival (PFS) (RECIST version 1.1; per investigator assessment). Secondary endpoints included overall survival (OS) and safety. Results: In total, 136 patients were randomized 1:1 to receive pamiparib (n = 71) or placebo (n = 65). Median PFS was numerically longer with pamiparib versus placebo but did not reach statistical significance (3.7 months [95% confidence interval (CI): 1.9, 5.3] vs. 2.1 months [95% CI: 1.9, 3.8]; hazard ratio 0.8 [95% CI: 0.5, 1.2]; p = 0.1428). Median OS was 10.2 months (95% CI: 8.7, 16.3) in the pamiparib arm versus 12.0 months (95% CI: 8.2, not estimable) in the placebo arm. Overall, 8 patients (11.3%) in the pamiparib arm and 2 patients (3.1%) in the placebo arm experienced ≥1 TEAE leading to treatment discontinuation. Conclusions: Maintenance pamiparib did not meet statistical significance for superiority versus placebo for PFS, but was well tolerated with few treatment discontinuations; no unexpected safety signals were identified. [ABSTRACT FROM AUTHOR]

Published
2023
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39. A Phase 2, Open-Label, Ascending Dose Study of Ker-050 for the Treatment of Anemia in Patients with Very Low, Low, or Intermediate Risk Myelodysplastic Syndromes

Author

Ross, David M, primary, Arbelaez, Alejandro, additional, Chee, Lynette C.Y., additional, Fong, Chun Yew, additional, Hiwase, Devendra, additional, Kannourakis, George, additional, Kwan, John, additional, Liang, James, additional, Puliyayil, Anish, additional, Rose, Hannah, additional, Tan, Shuhying, additional, Teh, Tse-Chieh, additional, Westerman, David Alan, additional, Wight, Joel, additional, Rovaldi, Chris, additional, Furutani, Elissa M., additional, Gaggi, Adrienne, additional, Jiang, Ying, additional, Lachey, Jenn, additional, Natarajan, Harveen Dhillon, additional, and Ordonez, Claudia, additional

Published
2021
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41. Sphingosine 1-phosphate receptor 5 (S1PR5) regulates the peripheral retention of tissue-resident lymphocytes

Author

Evrard, Maximilien, primary, Wynne-Jones, Erica, additional, Peng, Changwei, additional, Kato, Yu, additional, Christo, Susan N., additional, Fonseca, Raissa, additional, Park, Simone L., additional, Burn, Thomas N., additional, Osman, Maleika, additional, Devi, Sapna, additional, Chun, Jerold, additional, Mueller, Scott N., additional, Kannourakis, George, additional, Berzins, Stuart P., additional, Pellicci, Daniel G., additional, Heath, William R., additional, Jameson, Stephen C., additional, and Mackay, Laura K., additional

Published
2021
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43. PARALLEL 303: Phase 2 randomized study of pamiparib vs placebo as maintenance therapy in patients (pts) with inoperable locally advanced or metastatic gastric cancer that responded to platinum-based first-line (1L) chemotherapy.

Author

Ciardiello, Fortunato, primary, Bang, Yung-Jue, additional, Bendell, Johanna C., additional, Cervantes, Andres, additional, Dvorkin, Mikhail, additional, Lopez, Charles D., additional, Metges, Jean-Philippe, additional, Sanchez, Antonio, additional, Calvo, Mariona, additional, Strickland, Andrew, additional, Kannourakis, George, additional, Muro, Kei, additional, Kawakami, Hisato, additional, Wei, Jia, additional, Borg, Christophe, additional, Mu, Song, additional, Zhang, Kathy, additional, Zhang, Maggie, additional, and Shen, Lin, additional

Published
2021
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47. Patients with both Langerhans cell histiocytosis and Crohn’s disease highlight a common role of interleukin‐23

Author

Kvedaraite, Egle, primary, Lourda, Magda, additional, Han, HongYa, additional, Tesi, Bianca, additional, Mitchell, Jenée, additional, Ideström, Maja, additional, Mouratidou, Natalia, additional, Rassidakis, George, additional, von Bahr Greenwood, Tatiana, additional, Cohen‐Aubart, Fleur, additional, Jädersten, Martin, additional, Åkefeldt, Selma Olsson, additional, Svensson, Mattias, additional, Kannourakis, George, additional, Bryceson, Yenan T., additional, Haroche, Julien, additional, and Henter, Jan‐Inge, additional

Published
2020
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