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1. Multi-region sampling with paired sample sequencing analyses reveals sub-groups of patients with novel patient-specific dysregulation in Hepatocellular Carcinoma

Author

Jeon, Ah-Jung, Teo, Yue-Yang, Sekar, Karthik, Chong, Shay Lee, Wu, Lingyan, Chew, Sin-Chi, Chen, Jianbin, Kendarsari, Raden Indah, Lai, Hannah, Ling, Wen Huan, Kaya, Neslihan Arife, Lim, Jia Qi, Ramasamy, Adaikalavan, Oguz, Gokce, Chung, Alexander Yaw-Fui, Chan, Chung Yip, Cheow, Peng-Chung, Kam, Juinn Huar, Madhavan, Krishnakumar, Kow, Alfred, Ganpathi, Iyer Shridhar, Lim, Tony Kiat Hon, Leow, Wei-Qiang, Loong, Shihleone, Loh, Tracy Jiezhen, Wan, Wei Keat, Soon, Gwyneth Shook Ting, Pang, Yin Huei, Yoong, Boon Koon, Ong, Diana Bee-Lan, Lim, Jasmine, de Villa, Vanessa H., Cruz, Rouchelle D.dela, Chanwat, Rawisak, Thammasiri, Jidapa, Bonney, Glenn K., Goh, Brian K. P., Tucker-Kellogg, Greg, Foo, Roger Sik Yin, and Chow, Pierce K. H.

Published
2023
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2. Biliary complications after adult-to-adult living-donor liver transplantation: An international multicenter study of 3633 cases

Author

Li, Zhihao, Rammohan, Ashwin, Gunasekaran, Vasanthakumar, Hong, Suyoung, Chih-Yi Chen, Itsuko, Kim, Jongman, Hervera Marquez, Kris Ann, Hsu, Shih-Chao, Kirimker, Elvan Onur, Akamatsu, Nobuhisa, Shaked, Oren, Finotti, Michele, Yeow, Marcus, Genedy, Lara, Dutkowski, Philipp, Nadalin, Silvio, Boehnert, Markus U., Polak, Wojciech G., Bonney, Glenn K., Mathur, Abhishek, Samstein, Benjamin, Emond, Jean C., Testa, Giuliano, Olthoff, Kim M., Rosen, Charles B., Heimbach, Julie K., Taner, Timucin, Wong, Tiffany CL., Lo, Chung-Mau, Hasegawa, Kiyoshi, Balci, Deniz, Cattral, Mark, Sapisochin, Gonzalo, Selzner, Nazia, Jeng, Long-Bin, Broering, Dieter, Joh, Jae-Won, Chen, Chao-Long, Suh, Kyung-Suk, Rela, Mohamed, and Clavien, Pierre-Alain

Published
2024
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3. Novel Benchmark for Adult-to-Adult Living-donor Liver Transplantation: Integrating Eastern and Western Experiences

Author

Li, Zhihao, Rammohan, Ashwin, Gunasekaran, Vasanthakumar, Hong, Suyoung, Chen, Itsuko Chih-Yi, Kim, Jongman, Hervera Marquez, Kris Ann, Hsu, Shih Chao, Kirimker, Elvan Onur, Akamatsu, Nobuhisa, Shaked, Oren, Finotti, Michele, Yeow, Marcus, Genedy, Lara, Dutkowski, Philipp, Nadalin, Silvio, Boehnert, Markus U., Polak, Wojciech G., Bonney, Glenn K., Mathur, Abhishek, Samstein, Benjamin, Emond, Jean C., Testa, Giuliano, Olthoff, Kim M., Rosen, Charles B., Heimbach, Julie K., Taner, Timucin, Wong, Tiffany CL., Lo, Chung-Mau, Hasegawa, Kiyoshi, Balci, Deniz, Cattral, Mark, Sapisochin, Gonzalo, Selzner, Nazia, Bin Jeng, Long, Broering, Dieter, Joh, Jae-Won, Chen, Chao-Long, Suk, Kyung-Suh, Rela, Mohamed, and Clavien, Pierre-Alain

Published
2023
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4. A genomic enhancer signature associates with hepatocellular carcinoma prognosis

Author

Jeon, Ah-Jung, Anene-Nzelu, Chukwuemeka George, Teo, Yue-Yang, Chong, Shay Lee, Sekar, Karthik, Wu, Lingyan, Chew, Sin-Chi, Chen, Jianbin, Kendarsari, Raden Indah, Lai, Hannah, Ling, Wen Huan, Kaya, Neslihan Arife, Lim, Jia Qi, Chung, Alexander Yaw Fui, Cheow, Peng-Chung, Kam, Juinn Huar, Madhavan, Krishnakumar, Kow, Alfred, Ganpathi, Iyer Shridhar, Lim, Tony Kiat Hon, Leow, Wei-Qiang, Loong, Shihleone, Loh, Tracy Jiezhen, Wan, Wei Keat, Soon, Gwyneth Shook Ting, Pang, Yin Huei, Yoong, Boon Koon, Bee-Lan Ong, Diana, Lim, Jasmine, de Villa, Vanessa H., dela Cruz, Rouchelle D., Chanwat, Rawisak, Thammasiri, Jidapa, Bonney, Glenn K., Goh, Brian K.P., Foo, Roger Sik Yin, and Chow, Pierce Kah-Hoe

Published
2023
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5. UNOS Down-Staging Criteria for Liver Transplantation of Hepatocellular Carcinoma: Systematic Review and Meta-Analysis of 25 Studies

Author

Tan, Darren Jun Hao, Lim, Wen.Hui, Yong, Jie Ning, Ng, Cheng Han, Muthiah, Mark D., Tan, Eunice X., Xiao, Jieling, Lim, Snow Yunni, Pin Tang, Ansel Shao, Pan, Xin Hui, Kabir, Tousif, Bonney, Glenn K., Sundar, Raghav, Syn, Nicholas, Kim, Beom Kyung, Dan, Yock Young, Noureddin, Mazen, Loomba, Rohit, and Huang, Daniel Q.

Published
2023
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8. Trajectory of immune evasion and cancer progression in hepatocellular carcinoma

Author

Nguyen, Phuong H. D., Wasser, Martin, Tan, Chong Teik, Lim, Chun Jye, Lai, Hannah L. H., Seow, Justine Jia Wen, DasGupta, Ramanuj, Phua, Cheryl Z. J., Ma, Siming, Yang, Jicheng, Suthen, Sheena D/O, Tam, Wai Leong, Lim, Tony K. H., Yeong, Joe, Leow, Wei Qiang, Pang, Yin Huei, Soon, Gwyneth, Loh, Tracy Jiezhen, Wan, Wei Keat, Chan, Chung Yip, Cheow, Peng Chung, Toh, Han Chong, Kow, Alfred, Dan, Yock Young, Kam, Juinn Huar, Iyer, Shridhar, Madhavan, Krishnakumar, Chung, Alexander, Bonney, Glenn K., Goh, Brian K. P., Fu, Naiyang, Yu, Victor C., Zhai, Weiwei, Albani, Salvatore, Chow, Pierce K. H., and Chew, Valerie

Published
2022
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10. Liver transplantation for non-resectable colorectal liver metastases: the International Hepato-Pancreato-Biliary Association consensus guidelines

Author

Bonney, Glenn K, Chew, Claire Alexandra, Lodge, Peter, Hubbard, Joleen, Halazun, Karim J, Trunecka, Pavel, Muiesan, Paolo, Mirza, Darius F, Isaac, John, Laing, Richard W, Iyer, Shridhar Ganpathi, Chee, Cheng Ean, Yong, Wei Peng, Muthiah, Mark Dhinesh, Panaro, Fabrizio, Sanabria, Juan, Grothey, Axel, Moodley, Keymanthri, Chau, Ian, Chan, Albert C Y, Wang, Chih Chi, Menon, Krishna, Sapisochin, Gonzalo, Hagness, Morten, Dueland, Svein, Line, Pål-Dag, and Adam, René

Published
2021
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13. Ethnic disparities in waitlist outcomes of patients with nonalcoholic steatohepatitis listed for liver transplantation in the US

Author

Lim, Wen Hui, primary, Yong, Jie Ning, additional, Ong, Christen En Ya, additional, Ng, Cheng Han, additional, Tan, Darren Jun Hao, additional, Zeng, Rebecca Wenling, additional, Chung, Charlotte Hui, additional, Kaewdech, Apichat, additional, Chee, Douglas, additional, Tseng, Michael, additional, Wijarnpreecha, Karn, additional, Syn, Nicholas, additional, Bonney, Glenn K., additional, Kow, Alfred, additional, Huang, Daniel Q., additional, Noureddin, Mazen, additional, Muthiah, Mark, additional, Tan, Eunice, additional, and Siddiqui, Mohammad Shadab, additional

Published
2023
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14. IFNγ−IL-17+ CD8 T cells contribute to immunosuppression and tumor progression in human hepatocellular carcinoma

Author

Lee, Yun Hua, primary, Chuah, Samuel, additional, Nguyen, Phuong H.D., additional, Lim, Chun Jye, additional, Lai, Hannah L.H., additional, Wasser, Martin, additional, Chua, Camillus, additional, Lim, Tony K.H., additional, Leow, Wei Qiang, additional, Loh, Tracy Jiezhen, additional, Wan, Wei Keat, additional, Pang, Yin Huei, additional, Soon, Gwyneth, additional, Cheow, Peng Chung, additional, Kam, Juinn Huar, additional, Iyer, Shridhar, additional, Kow, Alfred, additional, Bonney, Glenn K., additional, Chan, Chung Yip, additional, Chung, Alexander, additional, Goh, Brian K.P., additional, Zhai, Weiwei, additional, Chow, Pierce K.H., additional, Albani, Salvatore, additional, Liu, Haiyan, additional, and Chew, Valerie, additional

Published
2023
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15. Additional file 6 of Multi-region sampling with paired sample sequencing analyses reveals sub-groups of patients with novel patient-specific dysregulation in Hepatocellular Carcinoma

Author

Jeon, Ah-Jung, Teo, Yue-Yang, Sekar, Karthik, Chong, Shay Lee, Wu, Lingyan, Chew, Sin-Chi, Chen, Jianbin, Kendarsari, Raden Indah, Lai, Hannah, Ling, Wen Huan, Kaya, Neslihan Arife, Lim, Jia Qi, Ramasamy, Adaikalavan, Oguz, Gokce, Chung, Alexander Yaw-Fui, Chan, Chung Yip, Cheow, Peng-Chung, Kam, Juinn Huar, Madhavan, Krishnakumar, Kow, Alfred, Ganpathi, Iyer Shridhar, Lim, Tony Kiat Hon, Leow, Wei-Qiang, Loong, Shihleone, Loh, Tracy Jiezhen, Wan, Wei Keat, Soon, Gwyneth Shook Ting, Pang, Yin Huei, Yoong, Boon Koon, Ong, Diana Bee-Lan, Lim, Jasmine, de Villa, Vanessa H., Cruz, Rouchelle D.dela, Chanwat, Rawisak, Thammasiri, Jidapa, Bonney, Glenn K., Goh, Brian K. P., Tucker-Kellogg, Greg, Foo, Roger Sik Yin, and Chow, Pierce K. H.

Abstract

Additional file 6: Supplementary Table S7. Top 20 REACTOME and CGP gene sets from GSEA of 328 NAP genes.

Published
2023
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16. Additional file 10 of Multi-region sampling with paired sample sequencing analyses reveals sub-groups of patients with novel patient-specific dysregulation in Hepatocellular Carcinoma

Author

Jeon, Ah-Jung, Teo, Yue-Yang, Sekar, Karthik, Chong, Shay Lee, Wu, Lingyan, Chew, Sin-Chi, Chen, Jianbin, Kendarsari, Raden Indah, Lai, Hannah, Ling, Wen Huan, Kaya, Neslihan Arife, Lim, Jia Qi, Ramasamy, Adaikalavan, Oguz, Gokce, Chung, Alexander Yaw-Fui, Chan, Chung Yip, Cheow, Peng-Chung, Kam, Juinn Huar, Madhavan, Krishnakumar, Kow, Alfred, Ganpathi, Iyer Shridhar, Lim, Tony Kiat Hon, Leow, Wei-Qiang, Loong, Shihleone, Loh, Tracy Jiezhen, Wan, Wei Keat, Soon, Gwyneth Shook Ting, Pang, Yin Huei, Yoong, Boon Koon, Ong, Diana Bee-Lan, Lim, Jasmine, de Villa, Vanessa H., Cruz, Rouchelle D.dela, Chanwat, Rawisak, Thammasiri, Jidapa, Bonney, Glenn K., Goh, Brian K. P., Tucker-Kellogg, Greg, Foo, Roger Sik Yin, and Chow, Pierce K. H.

Abstract

Additional file 10: Fig. S2. A. GSEA results for up-regulated genes in tumour tissues from all-patients (AP) analysis. B: GSEA results for down-regulated genes in tumour tissues from AP analysis. Across both panels, top chart shows results including all the up-regulated genes from the AP analysis, while the bottom chart excludes the genes also detected in PP analyses.

Published
2023
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17. Additional file 8 of Multi-region sampling with paired sample sequencing analyses reveals sub-groups of patients with novel patient-specific dysregulation in Hepatocellular Carcinoma

Author

Jeon, Ah-Jung, Teo, Yue-Yang, Sekar, Karthik, Chong, Shay Lee, Wu, Lingyan, Chew, Sin-Chi, Chen, Jianbin, Kendarsari, Raden Indah, Lai, Hannah, Ling, Wen Huan, Kaya, Neslihan Arife, Lim, Jia Qi, Ramasamy, Adaikalavan, Oguz, Gokce, Chung, Alexander Yaw-Fui, Chan, Chung Yip, Cheow, Peng-Chung, Kam, Juinn Huar, Madhavan, Krishnakumar, Kow, Alfred, Ganpathi, Iyer Shridhar, Lim, Tony Kiat Hon, Leow, Wei-Qiang, Loong, Shihleone, Loh, Tracy Jiezhen, Wan, Wei Keat, Soon, Gwyneth Shook Ting, Pang, Yin Huei, Yoong, Boon Koon, Ong, Diana Bee-Lan, Lim, Jasmine, de Villa, Vanessa H., Cruz, Rouchelle D.dela, Chanwat, Rawisak, Thammasiri, Jidapa, Bonney, Glenn K., Goh, Brian K. P., Tucker-Kellogg, Greg, Foo, Roger Sik Yin, and Chow, Pierce K. H.

Abstract

Additional file 8: Supplementary Table S10. Top 20 REACTOME gene sets from GSEA of down-regulated and up-regulated genes in PG1.

Published
2023
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18. Additional file 3 of Multi-region sampling with paired sample sequencing analyses reveals sub-groups of patients with novel patient-specific dysregulation in Hepatocellular Carcinoma

Author

Jeon, Ah-Jung, Teo, Yue-Yang, Sekar, Karthik, Chong, Shay Lee, Wu, Lingyan, Chew, Sin-Chi, Chen, Jianbin, Kendarsari, Raden Indah, Lai, Hannah, Ling, Wen Huan, Kaya, Neslihan Arife, Lim, Jia Qi, Ramasamy, Adaikalavan, Oguz, Gokce, Chung, Alexander Yaw-Fui, Chan, Chung Yip, Cheow, Peng-Chung, Kam, Juinn Huar, Madhavan, Krishnakumar, Kow, Alfred, Ganpathi, Iyer Shridhar, Lim, Tony Kiat Hon, Leow, Wei-Qiang, Loong, Shihleone, Loh, Tracy Jiezhen, Wan, Wei Keat, Soon, Gwyneth Shook Ting, Pang, Yin Huei, Yoong, Boon Koon, Ong, Diana Bee-Lan, Lim, Jasmine, de Villa, Vanessa H., Cruz, Rouchelle D.dela, Chanwat, Rawisak, Thammasiri, Jidapa, Bonney, Glenn K., Goh, Brian K. P., Tucker-Kellogg, Greg, Foo, Roger Sik Yin, and Chow, Pierce K. H.

Abstract

Additional file 3: Supplementary Table S4. Top 20 gene sets from GSEA of up-regulated and down-regulated genes in all-patients analysis.

Published
2023
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20. 437: UNOS-DOWNSTAGING CRITERIA FOR LIVER TRANSPLANTATION OF HEPATOCELLULAR CARCINOMA: SYSTEMATIC REVIEW AND META-ANALYSIS OF 26 STUDIES

Author

Tan, Darren J., primary, Yong, Jie Ning, additional, Ng, Cheng Han, additional, Muthiah, Mark Dhinesh, additional, Tan, Eunice X., additional, Xiao, Jieling, additional, Lim, Wen Hui, additional, Lin, Snow Yunni, additional, Tang, Ansel S., additional, Pan, Xin-Hui, additional, Kabir, Tousif, additional, Dan, Yock Young, additional, Sundhar, Raghav, additional, Syn, Nicholas L., additional, Kim, Beom Kyung, additional, Bonney, Glenn k., additional, Noureddin, Mazen, additional, Loomba, Rohit, additional, and Huang, Daniel, additional

Published
2022
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21. Hypoxia‐driven immunosuppression by Treg and type‐2 conventional dendritic cells in HCC

Author

Suthen, Sheena, primary, Lim, Chun Jye, additional, Nguyen, Phuong H. D., additional, Dutertre, Charles‐Antoine, additional, Lai, Hannah L. H., additional, Wasser, Martin, additional, Chua, Camillus, additional, Lim, Tony K. H., additional, Leow, Wei Qiang, additional, Loh, Tracy Jiezhen, additional, Wan, Wei Keat, additional, Pang, Yin Huei, additional, Soon, Gwyneth, additional, Cheow, Peng Chung, additional, Kam, Juinn Huar, additional, Iyer, Shridhar, additional, Kow, Alfred, additional, Tam, Wai Leong, additional, Shuen, Timothy W. H., additional, Toh, Han Chong, additional, Dan, Yock Young, additional, Bonney, Glenn K., additional, Chan, Chung Yip, additional, Chung, Alexander, additional, Goh, Brian K. P., additional, Zhai, Weiwei, additional, Ginhoux, Florent, additional, Chow, Pierce K. H., additional, Albani, Salvatore, additional, and Chew, Valerie, additional

Published
2022
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22. Additional file 1 of Rational drug combination design in patient-derived avatars reveals effective inhibition of hepatocellular carcinoma with proteasome and CDK inhibitors

Author

Lim, Jhin Jieh, Hooi, Lissa, Dan, Yock Young, Bonney, Glenn K., Zhou, Lei, Chow, Pierce K.-H., Chee, Cheng Ean, Toh, Tan Boon, and Chow, Edward K.-H.

Abstract

Additional file 1: Figure S1. Annexin V/PI assay in proteasome inhibitor-treated HCC PDXOs. (A and B) Flow cytometry analysis and corresponding quantification of annexin V/PI-stained PDXO1 (A) and PDXO11 (B) after 24-hour treatment with carfilzomib and ixazomib. Data presented as mean ± SD, n = 3. **, P < 0.01; ***, P < 0.001 compared to respective controls. Black and grey asterisks indicate comparison within early and late apoptosis groups, respectively. Statistical significance was determined using two-tailed Student’s t test. Figure S2. QPOP highlights Ixa+Dina as more effective than other ixazomib-based drug combinations. (A) Cluster heatmap of all two-drug combinations ranked based on QPOP output (viabilityTHLE2 – viabilityPDXO). Highest rank indicates maximal difference in viability and vice versa. The corresponding two-drug combinations are listed in Table S4. (B) Polygonograms depicting QPOP-derived two-drug interaction effects on PDXO viability between ixazomib (IXA), dinaciclib (DINA), sorafenib (SORA), regorafenib (REGO), oxaliplatin (OXA), and 5-fluorouracil (5FU) in HCC PDXOs. (C) Parabolic response surface maps showing the effects of ixazomib and dinaciclib on the therapeutic output (viabilityTHLE2 – viabilityPDXO) in HCC PDXOs. Figure S3. Annexin V/PI assay in HCC PDXOs treated with Ixa+Dina. (A and B) Analysis of Annexin V and PI-stained PDXO1 (A) and PDXO11 (B) after ixazomib and dinaciclib treatment for 24 hours. Figure S4. JNK pathway is involved in Ixa+Dina combined effects in HCC PDXOs. (A) Immunoblot analysis of the activation status of JNK, p38 and ERK in Ixa+Dina treated HCC PDXO1 and 11. (B) Relative mRNA levels of JUN and MAPK8 (JNK) after siRNA-mediated knockdown in Ixa+Dina treated PDXO1. Data presented as mean ± SD, n = 3. *, P < 0.05; **, P < 0.01. Statistical significance was determined using two-tailed Student’s t test. (C) Immunoblot analysis of JNK and c-Jun protein expression after siRNA transfection in Ixa+Dina treated PDXO1. (D) Immunoblots showing basal levels of JNK pathway proteins in panel of HCC PDXOs and THLE-2. Figure S5. Analysis of potential toxicities associated with ixazomib and dinaciclib drug treatment in vivo. (A and B) Representative H&E images of the livers, kidneys, and spleens from drug-treated PDX1 (A) and PDX11 (B) tumor-bearing mice. Scale bar = 50 μm. Table S1. List of primary antibodies used. Table S2. List of drugs and corresponding drug identification ordered by rank as displayed in Fig. 2A. Table S3. QPOP drug combination design (OACD) consisting of 155 combinations for nine drugs at three dosage levels (− 1, 0, 1). The nine drugs include Ixazomib (Ixa), Dinaciclib (Dina), Carfilzomib (Car), Sorafenib (Sora), Lenvatinib (Len), Regorafenib (Rego), Cabozantinib (Cabo), Oxaliplatin (Oxa), and 5-Fluorouracil (5-FU). Table S4. Concentrations of drugs used for QPOP on HCC PDXOs and THLE-2 at the three dosage levels (− 1, 0, 1). Table S5. QPOP-derived two-drug combinations as shown in Fig. S2A. Values represent the concentrations (μM) used for each drug.

Published
2022
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23. UNOS Down-Staging Criteria for Liver Transplantation of Hepatocellular Carcinoma: Systematic Review and Meta-Analysis of 25 Studies

Author

Tan, Darren Jun Hao, primary, Lim, Wen.Hui, additional, Yong, Jie Ning, additional, Ng, Cheng Han, additional, Muthiah, Mark D., additional, Tan, Eunice X., additional, Xiao, Jieling, additional, Lim, Snow Yunni, additional, Pin Tang, Ansel Shao, additional, Pan, Xin Hui, additional, Kabir, Tousif, additional, Bonney, Glenn K., additional, Sundar, Raghav, additional, Syn, Nicholas, additional, Kim, Beom Kyung, additional, Dan, Yock Young, additional, Noureddin, Mazen, additional, Loomba, Rohit, additional, and Huang, Daniel Q., additional

Published
2022
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24. A Multiethnic Asian Perspective of Presumed Consent for Organ Donation: A Population-Based Perception Study

Author

Muthiah, Mark D., primary, Chua, Melissa Sin Hui, additional, Griva, Konstadina, additional, Low, Ivan, additional, Lim, Wen Hui, additional, Ng, Cheng Han, additional, Hwang, Jeff Y. F., additional, Yap, Jason C. H., additional, Iyer, Shridhar G., additional, Bonney, Glenn K., additional, Anantharaman, Vathsala, additional, Huang, Daniel Q., additional, Tan, Eunice Xiang-Xuan, additional, Lee, Guan-Huei, additional, Kow, Alfred W. C., additional, and Tai, Bee Choo, additional

Published
2021
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32. Abstract 1788: A high-throughput chemical genetic screen reveals SALL4-induced metabolic vulnerabilities in cancer

Author

Tan, Justin L., primary, Li, Feng, additional, Yeo, Joanna Z., additional, Yong, Kol Jia, additional, Bassal, Mahmoud A., additional, Ng, Guo Hao, additional, Lee, May Yin, additional, Leong, Chung Yan, additional, Tan, Hong Kee, additional, Wu, Chan-Shuo, additional, Liu, Bee Hui, additional, Chan, Hon Man, additional, Tan, Zi Hui, additional, Chan, Yun Shen, additional, Wang, Siyu, additional, Lim, Zhi Han, additional, Toh, Tan Boon, additional, Hooi, Lissa, additional, Low, Kia Ngee, additional, Ma, Siming, additional, Kong, Nikki R., additional, Stein, Alicia J., additional, Wu, Yue, additional, Thangavelu, Matan T., additional, Suzuki, Atsushi, additional, Periyasamy, Giridharan, additional, Asara, John M., additional, Dan, Yock Young, additional, Bonney, Glenn K., additional, Chow, Edward K., additional, Lu, Guo-Dong, additional, Ng, Huck Hui, additional, Kanagasundaram, Yoganathan, additional, Ng, Siew Bee, additional, Tam, Wai Leong, additional, Chai, Li, additional, and Tenen, Daniel G., additional

Published
2020
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38. Increasing the Donor Pool: Consideration of Prehospital Cardiac Arrest in Controlled Donation After Circulatory Death for Liver Transplantation

Author

Elaffandi, Ahmed H., primary, Bonney, Glenn K., additional, Gunson, Bridget, additional, Scalera, Irene, additional, Mergental, Hynek, additional, Isaac, John R., additional, Bramhall, Simon R., additional, Mirza, Darius F., additional, P.R. Perera, M. Thamara, additional, and Muiesan, Paolo, additional

Published
2013
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45. IFNγ-IL-17+ CD8 T cells contribute to immunosuppression and tumor progression in human hepatocellular carcinoma.

Author

Lee, Yun Hua, Chuah, Samuel, Nguyen, Phuong H.D., Lim, Chun Jye, Lai, Hannah L.H., Wasser, Martin, Chua, Camillus, Lim, Tony K.H., Leow, Wei Qiang, Loh, Tracy Jiezhen, Wan, Wei Keat, Pang, Yin Huei, Soon, Gwyneth, Cheow, Peng Chung, Kam, Juinn Huar, Iyer, Shridhar, Kow, Alfred, Bonney, Glenn K., Chan, Chung Yip, and Chung, Alexander

Subjects
*T cells, *HEPATOCELLULAR carcinoma, *CANCER invasiveness, *CD8 antigen, *IMMUNOSUPPRESSION, *IMMUNOLOGICAL tolerance, *INTERLEUKINS, *LIVER tumors, *INTERFERONS, *PROTEOMICS
Abstract

IL-17-producing CD8 (Tc17) T cells have been shown to play an important role in infection and chronic inflammation, however their implications in hepatocellular carcinoma (HCC) remain elusive. In this study, we performed cytometry by time-of-flight (CyTOF) and revealed the distinctive immunological phenotypes of two IFNγ+ and IFNγ- Tc17 subsets that were preferentially enriched in human HCC. Single-cell RNA-sequencing analysis further revealed regulatory circuits governing the different phenotypes of these Tc17 subsets. In particular, we discovered that IFNγ- Tc17 subset demonstrated pro-tumoral characteristics and expressed higher levels of CCL20. This corresponded to increased tumor infiltration of T regulatory cells (Treg) validated by immunohistochemistry in another independent HCC cohort, demonstrating the immunosuppressive functions of IFNγ- Tc17 subset. Most importantly, higher intra-tumoral proportions of IFNγ- Tc17 were associated with poorer prognosis in patients with HCC and this was further validated in The Cancer Genome Atlas (TCGA) HCC cohort. Taken together, this compendium of transcriptomic and proteomic data of Tc17 subsets sheds light on the immunosuppressive phenotypes of IFNγ- Tc17 and its implications in HCC progression. [ABSTRACT FROM AUTHOR]

Published
2023
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46. GATA4 downregulation enhances CCL20-mediated immunosuppression in hepatocellular carcinoma.

Author

Nasir NJM, Chuah S, Shuen T, Prawira A, Ba R, Lim MC, Chua J, Nguyen PHD, Lim CJ, Wasser M, Hazirah SN, Lim TKH, Leow WQ, Loh TJ, Wan WK, Pang YH, Soon G, Cheow PC, Kam JH, Iyer S, Kow A, Dan YY, Bonney GK, Chung A, Goh BKP, Chow PKH, Albani S, Zhai W, Ouyang JF, Toh HC, and Chew V

Subjects
Humans, Gene Expression Regulation, Neoplastic, Immune Tolerance, Myeloid-Derived Suppressor Cells immunology, Male, T-Lymphocytes, Regulatory immunology, Carcinoma, Hepatocellular immunology, Carcinoma, Hepatocellular genetics, Carcinoma, Hepatocellular mortality, Liver Neoplasms immunology, Liver Neoplasms genetics, Liver Neoplasms mortality, Liver Neoplasms pathology, GATA4 Transcription Factor genetics, Chemokine CCL20 genetics, Down-Regulation, Tumor Microenvironment immunology
Abstract

Background: Hepatocellular carcinoma (HCC) is a deadly cancer with a high global mortality rate, and the downregulation of GATA binding protein 4 (GATA4) has been implicated in HCC progression. In this study, we investigated the role of GATA4 in shaping the immune landscape of HCC., Methods: HCC tumor samples were classified into "low" or "normal/high" based on GATA4 RNA expression relative to adjacent non-tumor liver tissues. The immune landscapes of GATA4-low and GATA4-normal/high tumors were analyzed using cytometry by time-of-flight, bulk/spatial transcriptomic analyses and validated by multiplex immunofluorescence., Results: GATA4-low tumors displayed enrichment in exhausted programmed cell death protein 1+ T cells, immunosuppressive regulatory T cells, myeloid-derived suppressor cells, and macrophages, highlighting the impact of GATA4 downregulation on immunosuppression. Spatial and bulk transcriptomic analyses revealed a negative correlation between GATA4 and C-C Motif Chemokine Ligand 20 (CCL20) expression in HCC. Overexpressing GATA4 confirmed CCL20 as a downstream target, contributing to an immunosuppressive tumor microenvironment, as evidenced by increased regulatory T cells and myeloid-derived suppressor cells in CCL20-high tumors. Lastly, the reduced expression of GATA4 and higher expression of CCL20 were associated with poorer overall survival in patients with HCC, implicating their roles in tumor progression., Conclusions: Our study reveals that GATA4 downregulation contributes to an immunosuppressive microenvironment, driven by CCL20-mediated enrichment of regulatory T cells and myeloid-derived suppressor cells in HCC. These findings underscore the critical role of GATA4 reduction in promoting immunosuppression and HCC progression., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Published
2024
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47. IFNγ - IL-17 + CD8 T cells contribute to immunosuppression and tumor progression in human hepatocellular carcinoma.

Author

Lee YH, Chuah S, Nguyen PHD, Lim CJ, Lai HLH, Wasser M, Chua C, Lim TKH, Leow WQ, Loh TJ, Wan WK, Pang YH, Soon G, Cheow PC, Kam JH, Iyer S, Kow A, Bonney GK, Chan CY, Chung A, Goh BKP, Zhai W, Chow PKH, Albani S, Liu H, and Chew V

Subjects
Humans, CD8-Positive T-Lymphocytes, Interferon-gamma, Interleukin-17 genetics, Proteomics, Carcinoma, Hepatocellular immunology, Carcinoma, Hepatocellular pathology, Immune Tolerance, Liver Neoplasms immunology, Liver Neoplasms pathology
Abstract

IL-17-producing CD8 (Tc17) T cells have been shown to play an important role in infection and chronic inflammation, however their implications in hepatocellular carcinoma (HCC) remain elusive. In this study, we performed cytometry by time-of-flight (CyTOF) and revealed the distinctive immunological phenotypes of two IFNγ + and IFNγ - Tc17 subsets that were preferentially enriched in human HCC. Single-cell RNA-sequencing analysis further revealed regulatory circuits governing the different phenotypes of these Tc17 subsets. In particular, we discovered that IFNγ - Tc17 subset demonstrated pro-tumoral characteristics and expressed higher levels of CCL20. This corresponded to increased tumor infiltration of T regulatory cells (Treg) validated by immunohistochemistry in another independent HCC cohort, demonstrating the immunosuppressive functions of IFNγ - Tc17 subset. Most importantly, higher intra-tumoral proportions of IFNγ - Tc17 were associated with poorer prognosis in patients with HCC and this was further validated in The Cancer Genome Atlas (TCGA) HCC cohort. Taken together, this compendium of transcriptomic and proteomic data of Tc17 subsets sheds light on the immunosuppressive phenotypes of IFNγ - Tc17 and its implications in HCC progression., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Published
2023
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48. New High-Throughput Screening Identifies Compounds That Reduce Viability Specifically in Liver Cancer Cells That Express High Levels of SALL4 by Inhibiting Oxidative Phosphorylation.

Author

Tan JL, Li F, Yeo JZ, Yong KJ, Bassal MA, Ng GH, Lee MY, Leong CY, Tan HK, Wu CS, Liu BH, Chan TH, Tan ZH, Chan YS, Wang S, Lim ZH, Toh TB, Hooi L, Low KN, Ma S, Kong NR, Stein AJ, Wu Y, Thangavelu MT, Suzuki A, Periyasamy G, Asara JM, Dan YY, Bonney GK, Chow EK, Lu GD, Ng HH, Kanagasundaram Y, Ng SB, Tam WL, Tenen DG, and Chai L

Subjects
Animals, Antineoplastic Agents therapeutic use, Cell Line, Tumor, Cell Survival drug effects, Cell Survival genetics, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic drug effects, Gene Knockdown Techniques, Humans, Liver Neoplasms genetics, Liver Neoplasms pathology, Male, Mice, Oxidative Phosphorylation drug effects, Transcription Factors genetics, Transcription Factors metabolism, Up-Regulation drug effects, Up-Regulation genetics, Xenograft Model Antitumor Assays, Antineoplastic Agents pharmacology, High-Throughput Screening Assays methods, Liver Neoplasms drug therapy, Transcription Factors antagonists & inhibitors
Abstract

Background & Aims: Some oncogenes encode transcription factors, but few drugs have been successfully developed to block their activity specifically in cancer cells. The transcription factor SALL4 is aberrantly expressed in solid tumor and leukemia cells. We developed a screen to identify compounds that reduce the viability of liver cancer cells that express high levels of SALL4, and we investigated their mechanisms., Methods: We developed a stringent high-throughput screening platform comprising unmodified SNU-387 and SNU-398 liver cancer cell lines and SNU-387 cell lines engineered to express low and high levels of SALL4. We screened 1597 pharmacologically active small molecules and 21,575 natural product extracts from plant, bacteria, and fungal sources for those that selectively reduce the viability of cells with high levels of SALL4 (SALL4 hi cells). We compared gene expression patterns of SALL4 hi cells vs SALL4-knockdown cells using RNA sequencing and real-time polymerase chain reaction analyses. Xenograft tumors were grown in NOD/SCID gamma mice from SALL4 hi SNU-398 or HCC26.1 cells or from SALL4 lo patient-derived xenograft (PDX) cells; mice were given injections of identified compounds or sorafenib, and the effects on tumor growth were measured., Results: Our screening identified 1 small molecule (PI-103) and 4 natural compound analogues (oligomycin, efrapeptin, antimycin, and leucinostatin) that selectively reduced viability of SALL4 hi cells. We performed validation studies, and 4 of these compounds were found to inhibit oxidative phosphorylation. The adenosine triphosphate (ATP) synthase inhibitor oligomycin reduced the viability of SALL4 hi hepatocellular carcinoma and non-small-cell lung cancer cell lines with minimal effects on SALL4 lo cells. Oligomycin also reduced the growth of xenograft tumors grown from SALL4 hi SNU-398 or HCC26.1 cells to a greater extent than sorafenib, but oligomycin had little effect on tumors grown from SALL4 lo PDX cells. Oligomycin was not toxic to mice. Analyses of chromatin immunoprecipitation sequencing data showed that SALL4 binds approximately 50% of mitochondrial genes, including many oxidative phosphorylation genes, to activate their transcription. In comparing SALL4 hi and SALL4-knockdown cells, we found SALL4 to increase oxidative phosphorylation, oxygen consumption rate, mitochondrial membrane potential, and use of oxidative phosphorylation-related metabolites to generate ATP., Conclusions: In a screening for compounds that reduce the viability of cells that express high levels of the transcription factor SALL4, we identified inhibitors of oxidative phosphorylation, which slowed the growth of xenograft tumors from SALL4 hi cells in mice. SALL4 activates the transcription of genes that regulate oxidative phosphorylation to increase oxygen consumption, mitochondrial membrane potential, and ATP generation in cancer cells. Inhibitors of oxidative phosphorylation might be used for the treatment of liver tumors with high levels of SALL4., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Published
2019
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