Citations
Mayo Clinic
47 citation(s) found for "Xu, Xiaoqing".
MYC-Alarmin Axis As a Novel Oncogenic Driver in a Subgroup of Triple Negative Myeloproliferative Neoplasms
Yu, Xiaoqing , Moon, Jungwon , Su, Siyuan , Cheng, Chia‐Ho, Sammut, Rinzine , Ali, Najla H. Al, Patel, Parth , Nakanishi, Shima , Lee, Daesung , Su, Siyuan , Patel, Parth C , Vincelette, Nicole D. , Kuykendall, Andrew , Nguyen, Hai V. , Eksioglu, Erika A. , Chan, Onyee , Lee, Dae Hyun , Ferreira, Renan B , Mo, Qianxing , Cory, Suzanne , Lawrence, Harshani R , Zhang, Ling , Murphy, Daniel J. , Komrokji, Rami S. , Kaufmann, Scott H. , Cleveland, John L. , Yun, Seongseok
Blood | December 1, 2023 | Volume: 142 | Issue: Supplement 1 | Pages: 994-994
Primary Myelofibrosis (PMF) is an aggressive myeloproliferative neoplasm (MPN) characterized by constitutional symptoms, cytopenias, splenomegaly, extramedullary hematopoiesis, bone marrow (BM) fibrosis, and a propensity to transform to acute myeloid leukemia (AML). Despite advances in understanding the underlying genetic abnormalities in MPN and the development of JAK2 inhibitors to treat MF, there is an urgent need to devise new treatment strategies, particularly for triple negative myelofibrosis (TN-MF) cases that lack mutations in the JAK2 kinase pathway and who have inferior outcomes. To identify potential oncogenic drivers in TN-MF, we performed cytogenetic analyses and targeted exome sequencing of 98 genes commonly mutated in myeloid malignancies in 584 MF patients identified from the Total Cancer Care database at Moffitt Cancer Center. Notably, there were no significant differences in the somatic mutation profiles (other than JAK2 activating mutations) between TN vs. JAK2/CALR/MPL mutant MF patients. However, trisomy of chromosome 8 occurs more frequently in TN-MF vs. other subtypes (26.7% vs. 6.2%, p=0.0001). To identify oncogenic drivers in trisomy 8+ TN-MF, we performed scRNA-seq analysis from 18,651 cells ( n=15,850 from 3 normal donors and n=2,801 from a trisomy 8+ TN-MF patient) and identified a total of 1,260 genes that are differentially regulated in hematopoietic stem cells (HSCs) of trisomy 8+ TN-MF compared to normal donors. Among these, 131 genes were located on chromosome 8 and MYC was one of the top 5 genes that are significantly upregulated in trisomy 8+ HSCs. Additional immunohistochemistry staining demonstrated that MYC protein levels in BM cells were significantly higher in trisomy 8+ TN-MF patients vs. trisomy 8- patients. To assess whether MYC might be a driver of MPN, we established an Mx1-Cre +/-;Rosa26 LSL-MYC/LSL-MYC transgenic mouse model that inducibly overexpresses MYC in HSCs following treatment of polyinosinic-polycytidylic acid (pIpC). Forced MYC expression induced profound anemia, monocytosis, megakaryocytic atypia, splenomegaly, increased BM collagen deposition/fibrosis, extramedullary hematopoiesis in spleen and liver, and significantly reduced OS vs. Mx1-Cre +/- wild type controls (median OS 258 days vs. not reached (NR), p<0.0001). MYC also promoted expansion of HSCs, myeloid progenitors, and Gr-1 +/CD11b + mature myeloid cells in BM and spleen; thus, MYC was sufficient to provoke MF-like disease independent of JAK2 pathway mutations. Subsequent scRNA-seq analysis of 25,232 cells ( n=13,552 from control and n=11,680 from a MYC transgenic mouse) revealed that S100a9 mRNA levels were increased by MYC in most major hematopoietic cell types. Supporting oncogenic roles of S100A9 in MYC-driven MF, deletion of S100a9 in Mx1-Cre +/-;Rosa26 LSL-MYC/LSL-MYC;S100a9 -/- mice abolished MYC-induced MF phenotypes and significantly improved OS (median OS NR vs. 225 days, p=0.0345). To test whether inhibition of MYC can suppress MF disease progression in vivo, lethally irradiated CD45.1 +/CD45.2 + WT mice were transplanted with BM cells harvested from CD45.2 + Mx1-Cre +/-;Rosa26 LSL-MYC/LSL-MYC mice that were treated with pIpC 20 weeks prior to transplant. MYCi975, a small molecule that inhibits MYC, reduced MYC and S100a9 protein levels in BM and spleen cells. Further, MYCi975 effectively suppressed MYC-driven MF phenotypes and disease progression, and significantly improved OS (median OS NR vs. 252 days, p=0.0109). In summary, our studies are the first to describe an oncogenic role of MYC in MF pathogenesis, where MYC provokes an alarmin-driven inflammatory circuit, and where the MYC-S100A9 axis represents a therapeutic vulnerability for TN-MF patients. Accordingly, our results provide a strong rationale for testing agents targeting MYC or S100A9 in early phase clinical trials in MPNs having increased MYC levels or activity.
Abstract 6065: Patterns of dysregulated coding and noncoding gene expression in high-grade serous ovarian carcinomas
Reid, Brett M. , Chen, Ann , Chen, Zhihua , Saglam, Ozlen , Teer, Jamie K. , Yu, Xiaoqing , Gayther, Simon A. , Goode, Ellen L. , Sellers, Thomas A. , Lawrenson, Kate , Lawrenson, Kate , Karreth, Florian A. , Kanetsky, Peter A. , Permuth, Jennifer B. , Pharoah, Paul D.P.
Cancer Research | April 4, 2023 | Volume: 83 | Issue: 7_Supplement | Pages: 6065-6065
Abstract Purpose: Identifying dysregulated gene expression in ovarian cancers has been limited by a deficit of available normal tissues. Here, we generated the largest set of high-grade serous ovarian cancer (HGSOC) tumors with normal precursor tissues for transcriptome analyses. Methods: We performed RNA sequencing on 220 primary HGSOCs and 116 benign epithelia (micro-dissected fallopian tube, ovarian surface, and inclusion cysts), and combined samples with 428 HGSOCs from TCGA, 60 HGSOCs from a prior study, and 180 bulk ovary tissues from GTEx. Raw reads were processed with a uniform bioinformatic and quality control pipeline; combined data were batch corrected. We tested for differences in median normalized CPM expression values using the Wilcoxon rank sum test with >2-fold change and a false discovery rate <1% considered statistically significant. We also conducted weighted gene co-expression network analysis in each tissue type. The hypergeometric test was used for enrichment of differentially expressed genes (DEGs) and gene ontologies within modules. Results: Transcriptomes comprised 27,700 expressed genes (8,202 lncRNAs) across 706 HGSOCs, 180 bulk ovary, and 88 ovarian epithelia tissues. Most (~90%) genes were expressed in all tissues; 5% each showed HGSOC- or normal tissue-specific expression and ≥50% were lncRNA. Comparing HGSOCs to ovarian epithelia and to bulk ovary identified 11,804 DEGs with 4,522 lncRNAs (DElncRNA) of which ~50% were tissue-specific. DEGs included MUC16 and multiple GWAS/TWAS implicated susceptibility genes including RAD51, BRIP1, BNC2, TIPARP-AS1, PRC1, KANSL1, ANKLE1, CHMP4C, ESRP2, and CCNE1. The most highly expressed DElncRNA in HGSOC were upregulated RMRP (P=1.4x10-39), SNHG1 (P=3.0x10-27), and HAGLR (P=2.0x10-24) at the HOXD risk locus. The highest expressed DElncRNA in precursor tissues was the HGSOC-downregulated MEG3 (P=1.7x10-67). DEGs were enriched in HGSOC co-expression modules associated with immune response, cell motility/localization, cell cycle regulation, angiogenesis, reproductive development, transcriptional regulation, and metabolic processes. Tissue-specific DElncRNA tended toward upregulation compared to ovarian epithelia with enriched modules associated with cell cycle regulation (hub=BUB1B; top DElncRNA TRPM2-AS, P=1.5x10-38); and toward downregulation compared to bulk ovary with enriched modules associated with chemokine signaling/response (hub= GADD45B, top DElncRNA RP11-87P3.1, P=1.7x10-113). Conclusion: HGSOC-dysregulated lncRNA expression revealed tissue-specific differences that highlight unique biological pathways in precursor epithelia and the ovarian microenvironment that contribute to HGSOC pathogenesis. Our results provide additional evidence to support previously nominated risk genes. Integration with eQTL and GWAS are underway to further elucidate novel HGSOC susceptibility genes. Citation Format: Brett M. Reid, Ann Chen, Zhihua Chen, Florian A. Karreth, Peter Kanetsky, Jennifer B. Permuth, Ozlen Saglam, Jamie Teer, Xiaoqing Yu, Simon Gayther, Ellen Goode, Paul Pharoah, Thomas A. Sellers, Kate Lawrenson. Patterns of dysregulated coding and noncoding gene expression in high-grade serous ovarian carcinomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6065.
Urticaria and/or angioedema secondary to mRNA COVID ‐19 vaccines: Updates from a United States case registry
Anvari, Sara , Jaggers, Jordan, Gonzalez‐Estrada, Alexei , Chong, Hey , Meerbeke, Sara W. Van, Petrov, Andrej A. , Khan, David A. , Freeman, Esther E. , Banerji, Aleena , Blumenthal, Kimberly G. , Gonzalez-Estrada, Alexei , Blumenthal, Kimberly G , Samarakoon, Upeka , Fu, Xiaoqing
Allergy | July 17, 2022 | Volume: 78 | Issue: 1 | Pages: 283-286
Abstract P281: Urinary Metabolites Associated With Blood Pressure on a Low- or High-sodium Diet
Xue, Hong , Song, Haiying , Wan, Yifei, Wang, Tao , Liu, Pengyuan , Liu, Yong , Laud, Purushottam W. , Usa, Kristie , He, Yongcheng , Xue, Hong, Cheng, Yuan , Pan, Xiaoqing, Tian, Zhongmin , Hou, Entai , Lanza, Ian R. , Liang, Mingyu
Hypertension | March 20, 2022 | Volume: 70 | Issue: suppl_1 | Pages: No page available
Dietary salt intake has significant effects on arterial blood pressure and the development of hypertension. Mechanisms underlying salt-dependent changes in blood pressure remain poorly understood. The goal of the present study was to utilize urine samples from the Dietary Approaches to Stop Hypertension (DASH)-Sodium trial and a targeted metabolomic approach to identify associations of urinary metabolites with blood pressure phenotypes on low- or high-sodium intake. We examined urinary levels of metabolites in 103 participants of the DASH-Sodium trial after 30 days on a defined diet containing high sodium (targeting 150 mmol sodium intake per day) or low sodium (50 mmol sodium per day). Systolic or diastolic pressure was 10 or more mmHg higher on the high-sodium intake in 51 of the 103 participants. Targeted chromatography/mass spectrometry analysis was performed in 24-h urine samples for 10 metabolites related to the tricarboxylic acid cycle and 47 amino metabolites. Urinary metabolite levels improved the prediction of classification of blood pressure salt-sensitivity based on race, age and sex. Random forest and generalized linear mixed model analyses identified significant (false discovery rate <0.05) associations between 24 h excretions of β-aminoisobutyric acid, cystine, citrulline, homocysteine and lysine and systolic blood pressure and between cystine and diastolic blood pressure. The differences of 24 h excretion of homocysteine between low- and high-sodium intakes were significantly associated with the differences in diastolic blood pressure. These associations were significant with or without considering demographic factors. Treatment with β-aminoisobutyric acid significantly attenuated high-salt-induced hypertension in Dahl salt-sensitive rats. These findings support the presence of new mechanisms of blood pressure regulation involving metabolic intermediaries.
Phase 2 study of venetoclax plus carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma
Costa, Luciano J. , Monohan, Gregory, Kovacsovics, Tibor , Burwick, Nicholas , Kaufman, Jonathan L. , Hong, Wan‐Jen , Dail, Monique , Masud, Abdullah Al , Munasinghe, Wijith, Ross, Jeremy A. , Bueno, Orlando F. , Kumar, Shaji , Stadtmauer, Edward A. , Kaufman, Jonathan L , Dail, Monique , Kumar, Shaji K , Costa, Luciano J , Davies, Faith E. , Jakubowiak, Andrzej , Salem, Ahmed Hamed , Yang, Xiaoqing
Blood Advances | September 1, 2021 | Volume: 5 | Issue: 19 | Pages: 3748-3759
10.1182/bloodadvances.2020004146
| PMID 34470049
Abstract Proteins in the antiapoptotic B-cell lymphoma 2 (BCL-2) family play a role in the pathophysiology of multiple myeloma (MM). Venetoclax is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis of MM cells, and its efficacy may be potentiated through combination with agents that increase BCL-2 dependency or have complementary mechanisms of action. The safety, tolerability, pharmacokinetics, and antitumor activity of venetoclax in combination with carfilzomib and dexamethasone (VenKd) in adults with relapsed/refractory MM (RRMM) were investigated in this phase 2 dose-escalation study. Oral venetoclax (400 or 800 mg) was administered daily in combination with intravenous carfilzomib (27, 56, or 70 mg/m2) and oral dexamethasone (20 or 40 mg) in 4 dose-finding cohorts. The expansion cohort received venetoclax 800 mg, carfilzomib 70 mg/m2, and dexamethasone 40 mg. Forty-nine patients received treatment. Median prior lines of therapy was 1 (range, 1-3), and median time in the study was 27 months. The most common treatment-emergent adverse events were diarrhea (65%), fatigue (47%), nausea (47%), and lymphopenia (35%). Serious adverse events occurred in 26 (53%) patients. Of 3 treatment-emergent deaths, 1 was considered treatment related. The overall response rate was 80% in all patients, 92% in patients with t(11;14) (n = 13), and 75% in patients without (n = 36). The rate of complete response or better was 41%. Median progression-free survival was 22.8 months. Treatment with VenKd was well tolerated and showed promising response rates in this RRMM patient population, with greater responses observed in patients with t(11;14). This trial is registered at www.clinicaltrials.gov as #NCT02899052.
Mortality in acute pancreatitis with persistent organ failure is determined by the number, type, and sequence of organ systems affected
Machicado, Jorge D. , Gougol, Amir , Tan, Xiaoqing , Gao, Xiaotian , Pothoulakis, Ioannis , Talukdar, Rupjyoti , Gulla, Aistė , Stevens, Tyler , Barbu, Sorin T. , Nawaz, Haq , Gutierrez, Silvia C., Zarnescu, Narcis , Capurso, Gabriele , Easler, Jeffrey J. , Τriantafyllou, Κonstantinos , Thakkar, Shyam , Ocampo, Carlos , de‐Madaria, Enrique , Coté, Gregory A. , Conwell, Darwin L. , Hart, Phil A. , Tang, Gong , Pothoulakis, Ioannis , de-Madaria, Enrique , Paragomi, Pedram , Kochhar, Rakesh K. , Goenka, Mahesh Kumar , González, José Alberto , Singh, Vikesh K. , Ferreira, Miguel Godinho , Peláez‐Luna, Mario , Wu, Bechien U. , Papachristou, Georgios I.
United European Gastroenterology Journal | April 19, 2021 | Volume: 9 | Issue: 2 | Pages: 139-149
10.1002/ueg2.12057
| PMID 33871926
Abstract Background Persistent organ failure (POF) is the strongest determinant of mortality in acute pancreatitis (AP). There is a paucity of data regarding the impact of different POF attributes on mortality and the role of different characteristics of systemic inflammatory response syndrome (SIRS) in the risk of developing POF. Objective We aimed to assess the association of POF dynamic features with mortality and SIRS characteristics with POF. Methods We studied 1544 AP subjects prospectively enrolled at 22 international centers (APPRENTICE consortium). First, we estimated the association of onset, duration, and maximal score of SIRS with POF. Then, we evaluated the risk of mortality based on POF onset, duration, number, type, and sequence of organs affected. Analyses were adjusted for potential confounders. Results 58% had SIRS, 11% developed POF, and 2.5% died. Early SIRS, persistent SIRS, and maximal SIRS score ≥ 3 were independently associated with higher risk of POF ( p < 0.05). Mortality risk in POF was higher with two (33%, odds ratio [OR] = 10.8, 3.3–34.9) and three (48%, OR = 20.2, 5.9–68.6) organs failing, in comparison to single POF (4%). In subjects with multiple POF, mortality was higher when the cardiovascular and respiratory systems failed first or concurrently as compared to when the renal system failed first or concurrently with other organ ( p < 0.05). In multivariate regression model, the number and sequence of organs affected in POF were associated with mortality ( p < 0.05). Onset and duration of POF had no impact mortality. Conclusion In AP patients with POF, the risk of mortality is influenced by the number, type, and sequence of organs affected. These results are useful for future revisions of AP severity classification systems.
Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition) 1
Klionsky, Daniel J., Abdel‐Aziz, Amal Kamal , Abdellatif, Mahmoud , Abdoli, Asghar , Abel, Steffen , Abeliovich, Hagai , Abildgaard, Marie H. , Abudu, Yakubu Princely , Acevedo‐Arozena, Abraham , Adamopoulos, Iannis E. , Adeli, Khosrow , Adolph, Timon E. , Adornetto, Annagrazia , Aflaki, Elma, Agam, Galila , Aggarwal, Bharat B. , Agnello, Maria, Agostinis, Patrizia , Agrewala, Javed N. , Agrotis, Alexander , Aguilar, Patricia V., Ahmad, S. Tariq, Ahumada-Castro, Ulises , Aits, Sonja , Aizawa, Shu, Akkoç, Yunus , Akoumianaki, Tonia, Akpinar, Hafize Aysin , Al‐Abd, Ahmed M. , Al-Akra, Lina, Gharaibeh, Abeer , Alaoui‐Jamali, Moulay A. , Alberti, Simon , Alessandri, Cristiano , Alonso, Alicia , Altan‐Bonnet, Nihal , Álvarez, Élida, Alves, Sara , Costa, Cristine Alvès da , Alzaharna, Mazen M. , Amadio, Marialaura , Amantini, Consuelo , Amaral, Cristina , Ambrosio, Susanna , Amer, Amal O. , Ammanathan, Veena , An, Zhenyi, Andrabi, Shaida A. , Andres, Allen M. , Ann, David K. , Anozie, Uche C. , Ansari, Mohammad Y. , Antas, Pedro , Antebi, Adam , Antón, Zuriñe , Anwar, Tahira , Apétoh, Lionel , Araki, Toshiyuki , Araki, Yasuhiro , Araya, Jun , Arévalo, María‐Ángeles , Argüelles, Sandro , Arias, Esperanza , Arikkath, Jyothi , Ariosa, Aileen, Aroca, Ángeles , Arroyo, Daniela S., Arsov, Ivica, Artero, Rubén , Asaro, Dalia Maria Lucia, Ashur‐Fabian, Osnat , Atanasov, Atanas G. , Au, Alicia K. , Auberger, Patrick , Auner, Holger W. , Aurelian, Laure , Avagliano, Laura , Ávalos, Yenniffer , Aveleira, Célia A. , Aydın, Yücel , Ayyadevara, Srinivas , Azzopardi, Maria , Baba, Misuzu, Backer, Jonathan , Bae, Soo Han , Baehrecke, Eric H. , Bagetta, Giacinto , Bagniewska‐Zadworna, Agnieszka , Bai, Hua , Bai, Xiyuan , Bairagi, Nandadulal , Baksi, Shounak , Balbi, Teresa , Ballester, María , Balazadeh, Salma , Balzan, Rena , Bandopadhyay, Rina , Banerjee, Sulagna , Bánréti, Ágnes , Baracca, Alessandra , Barbati, Cristiana , Bargiela, Ariadna , Barilà, Daniela , Barlow, Peter G. , Barmada, Sami J. , Barreiro, Esther , Bártek, Jiří , Bartel, Bonnie , Bartolomé, Alberto , Barve, Gaurav , Bassham, Diane C. , Baulieu, E.E. , Baumgarner, Bradley L. , Bayry, Jagadeesh , Beale, Rupert , Beau, Isabelle , Beaumatin, Florian , Bechara, Luiz Roberto Grassmann , Beck, George R. , Beers, Michael F. , Begun, Jakob , Behrends, Christian , Bejarano, Eloy , Bel, Shai , Belaïd, Amine , Belgareh‐Touzé, Naïma, Bellarosa, Cristina , Belleudi, Francesca , Belló-Pérez, Melissa , Beltran, Jackeline Soares de Oliveira , Beltran, Sebastián, Benbrook, Doris M. , Bendorius, Mykolas , Benítez, Bruno A. , Benito‐Cuesta, Irene , Bensalem, Julien , Berchtold, Martin W. , Berezowska, Sabina , Bergamaschi, Daniele , Berliocchi, Laura , Berlioz‐Torrent, Clarisse , Bernard, Amélie , Besirli, Cagri G. , Besteiro, Sébastien , Betin, Virginie M.S., Beyaert, Rudi , Bezbradica, Jelena S. , Bhaskar, Kiran , Bhatia‐Kiššová, Ingrid, Bhattacharya, Sujoy , Bhuiyan, Md. Shenuarin , Bi, Xiaolin , Biden, Trevor J. , Bijian, Krikor , Billes, Viktor , Binart, Nadine , Bincoletto, Cláudia , Blanco, Gonzalo , Blas‐García, Ana , Błasiak, Janusz , Blomgran, Robert , Blum, Janice S. , Boada-Romero, Emilio, Boban, Mirta , Boeuf, Philippe , Boland, Barry , Bomont, Pascale , Bonaldo, Paolo , Bonam, Srinivasa Reddy , Bonfili, Laura , Bootman, Martin D. , Bordi, Matteo , Borner, Christoph , Bornhäuser, Beat , Bose, Santanu , Botas, Juan , Boulanger, Chantal M. , Bourgeois, Benjamin , Bourke, Nollaig M. , Bousquet, Guilhem , Boya, Patricia , Bozhkov, Peter V. , Bozi, Luiz H. M. , Bozkurt, Tolga O. , Pedro, José Manuel Bravo‐San , Brest, Patrick , Bringer, Marie-Agnès , Briones‐Herrera, Alfredo , Broaddus, V. Courtney, Brodersen, Peter , Brodsky, Jeffrey L. , Bronson, Paola G. , Bronstein, Jeff M. , Brown, Rhoderick E. , Brum, Patrı́cia C. , Bruno, Daniele , Bryson‐Richardson, Robert J. , Bucci, Cecilia , Buchrieser, Carmen , Bueno, Marta , Buchan, J. Ross , Buckingham, Erin M., Budak, Hikmet , Budini, Mauricio , Bultynck, Geert , Burada, Florin , Burgoyne, Joseph R. , Burón, María I. , Bustos, Victor , Büttner, Sabrina , Byrd, Aaron , Cabas, Isabel , Cabrera, Sandra , Cadwell, Ken , Cai, Jingjing , Cai, Lu , Cai, Qian , Calbet, José A. L. , Caldwell, Guy A. , Call, Jarrod A. , Calvani, Riccardo , Calvo, Ana Cristina , Calvo‐Rubio, Miguel , Câmara, Niels Olsen Saraiva , Camonis, Jacques , Camougrand, Nadine , Campanella, Michelangelo , Campbell, Edward M. , Campos, Juliane C. , Camuzard, Olivier , Cancino, Jorge , Caniggia, Isabella , Canonico, Barbara , Cantı́, Carles , Cao, Bin , Caramés, B. , Cardenal‐Muñoz, Elena , Cárdenas, César , Cárdenas, Luis , Cardoso, Sandra M. , Carew, Jennifer S. , Carle, Georges F. , Carleton, Gillian , Carloni, Silvia , Carneiro, Letícia A. M. , Carosi, Julian M. , Carra, Serena , Carrier, Alice , Carter, A. Brent, Carvalho, Andreia Neves , Casanova, Magali , Casas, Josefina , Cassioli, Chiara , Castillo, Karen , Castillo‐Lluva, Sonia , Castoldi, Francesca , Castori, Marco , Castro, Ariel F. , Castro‐Hernández, Javier , Cavadas, Cláudia , Cavaliere, Federica, Cavallini, Gabriella , Cavinato, Maria , Rica, Paula Cebollada , Cechowska‐Pasko, Marzanna , Cerqueira, João , Cerutti, Janete M. , Çetintaş, Vildan Bozok , Cetrullo, Silvia , Chagin, Andrei S. , Chai, Chee‐Yin , Chakrabarti, Gopal , Chakraborty, Tapas , Chakraborty, Trinad , Chami, Mounia , Chamilos, Georgios , Chan, David W. , Chan, Edmond Y. W., Chan, Ho Yin Edwin , Chan, Helen H., Chan, Hung , Chan, Matthew T.V. , Chan, Yau Sang , Chang, Hao‐Chun , Chang, Kai , Chao, Jie , Charlet‐Berguerand, Nicolas , Chatterjee, Samrat , Chaube, Shail K. , Chaudhary, Anu , Chauhan, Santosh , Chaum, Edward , Checler, Frédéric , Cheetham, Michael E. , Chen, Chang‐Shi , Chen, Jian‐Fu , Chen, Liam L., Chen, Mingliang , Chen, Mu‐Kuan , Chen, Ning , Chen, Wei , Chen, Xinming , Chen, Xiongwen , Chen, Yan , Chen, Ye‐Guang , Chen, Yingyu , Chen, Yongqiang , Chen, Zhefan Stephen , Chen, Zhihua , Cheng, Xiu‐Tang , Cheng, Yiyun , Cheng, Zhiyong , Cheong, Jit Kong , Cherry, Sara , Cheung, Chi F., Cheung, Chun Hei Antonio , Cheung, King‐Ho , Chevet, Éric , Chi, Richard J., Chiaradonna, Ferdinando , Chiariello, M , Chica, Nathalia , Chiocca, Susanna , Chiong, Mario , Chiou, Shih‐Hwa , Chiramel, Abhilash I., Chiurchiù, Valerio , Cho, Dong-Hyung, Choe, Seong‐Kyu , Choi, Augustine M.K. , Choi, Mary E. , Choudhury, Kamalika Roy , Chow, Norman , Chua, Jason P. , Chua, John Jia En , Chung, Hyewon , Chung, Kin Pan , Chung, So‐Hyang , Chung, Yuen-Li, Ciechomska, Iwona A. , Cinque, Laura , Çırak, Sebahattin , Clarke, Robert , Clementi, Emilio , Coccia, Eliana M. , Codogno, Patrice , Colasanti, Tania , Colasuonno, Fiorella , Colbert, Robert A. , Colell, Anna , Coll, Núria S. , Collins, Mark O. , Colombo, Marı́a I. , Colón‐Ramos, Daniel A. , Cominetti, Márcia R. , Consiglio, Antonella , Conte, A. , Contu, Viorica Raluca , Cookson, Mark , Coombs, Kevin M. , Costa, Maria do Carmo , Costantino, Sarah , Costelli, Paola , Criollo, Alfredo , Crippa, V. , Cristofani, Riccardo , Csizmadia, Tamás , Cui, Bing , Cui, Yixian , Culetto, Emmanuel , Cumino, Andrea C. , Cybulsky, Andrey V. , Czaja, Mark J. , Czuczwar, Stanisław J. , D’Adamo, Stefania , D’Amelio, Marcello , D’Orazi, Gabriella , Silva, James Almada da , Dafsari, Hormos Salimi , Daglia, Maria , Dai, Xiaoxia , Dai, Yun , Dai, Yuyuan , Col, Jessica Dal , Dalhaimer, Paul , Valle, Luisa Dalla , Dallenga, Tobias , Dalmasso, Guillaume , Dando, Ilaria , Das, Hiranmoy , Dasari, Santosh K. , Dash, Srikanta, Dauphinee, Adrian N. , Davies, Jeffrey S. , Dávila, Valeria A. , Davis, Roger J. , Naidu, Sharadha Dayalan , Bosscher, Karolien De , Leonibus, Chiara De , Barbosa, Mayara Garcia de Mattos , Meyer, Guido R.Y. De , Palma, Clara De , Virgilio, Claudio De , Zio, Daniela De , Decuypere, Jean-Paul , Deehan, Mark , Deflorian, Gianluca , Dehay, Benjamin , Delaney, Joe R. , Delorme‐Axford, Elizabeth , Demers, Nicholas D. , Deng, Hongbin , Dengjel, Jörn , Dent, Paul, DePamphilis, Melvin L., Descoteaux, Albert , Devis, Laura , Devkota, Sushil , Devuyst, Olivier , Dewson, Grant , Dharmasivam, Mahendiran , Domenico, Fabio Di , Fazio, Pietro Di , Fonzo, Alessio Di , Guardo, Giovanni Di , Guglielmo, Gianni M. Di , Leo, Luca Di , Malta, Chiara Di , Nardo, Alessia Di, Rienzo, Martina Di , Diao, Jiajie , Diaz-Araya, Guillermo, Díaz‐Laviada, Inés , Dickinson, Jared M. , Diederich, Marc , Dieudé, Mélanie , Ding, Shiping , Ding, Wen-Xing, Dinić, Jelena , Dinić, Miroslav , Dinkova‐Kostova, Albena T. , Distler, Jörg H. W. , Đokić, Jelena , Emre, Serap , Dong, Xiaonan , Dong, Zhiwu , Dorn, Gerald W. , Dou, Juan, Dowaidar, Moataz , Drucker, Liat , Du, Ailian , Du, Guangwei , Du, Hai‐Ning , Toit, André du , Duan, Shao-Bin , Duan, Xiaoqiong , Duarte, Sónia , Dupont, Nicolas , Durán, Raúl V. , Dyshlovoy, Sergey A. , Ebrahimi‐Fakhari, Darius , Eckhart, Leopold , Edelstein, Charles L. , Efferth, Thomas , Eid, Nabil , Eisenberg, Tobias , Eissa, N. Tony, Ejarque, Miriam , Andaloussi, Abdeljabar El, El‐Hage, Nazira , Eleuteri, Anna Maria , El‐Shafey, Eman S. , Elgendy, Mohamed , Elizalde, María Mercedes , Elsässer, Hans‐Peter , Elsherbiny, Eslam S. , Emre, N. C. Tolga , Eng, Christina H. , Engedal, Nikolai , Engelsen, Agnete S. T. , Enserink, Jorrit M. , Escalante, Ricardo , Esclatine, Audrey , Eskelinen, Eeva‐Liisa , Espert, Lucile , Eusebio, Makandjou-Ola , Facchiano, Antonio , Facchiano, Francesco , Fadeel, Bengt , Fader, Claudio M., Faesen, Alex C. , Fairlie, W. Douglas , Falcó, Alberto , Fan, Daping , Fan, Jie , Fang, Evandro Fei , Fang, Yanshan , Fang, Yognqi, Farfel‐Becker, Tamar, Faure, Mathias , Fazeli, Gholamreza , Fedele, Anthony O., Feldman, Arthur M. , Feng, Jiachun , Feng, Lifeng , Feng, Wei , Araujo, Thaís Fenz , Ferguson, Thomas A., Fernández, Álvaro F. , Fernández‐Veledo, Sonia , Fernie, Alisdair R. , Ferrante, Anthony W. , Ferraresi, Alessandra , Ferrari, M , Ferreira, Julio Cesar Batista , Ferro‐Novick, Susan , Figueras, António , Filadi, Riccardo , Filigheddu, Nicoletta , Fimia, Gian María , Finetti, Francesca , Finkbeiner, Steven , Fisher, Edward A. , Fisher, Paul B. , Fliesler, Steven J. , Flo, Trude Helen , Florance, Ida , Florey, Oliver , Florio, Tullio , Fodor, Erika , Forlino, Antonella , Fortini, Paola , Fracassi, Anna , Franconi, Flavia , Frankel, Lisa B. , Fröhlich, Leopold F. , Fuentes, José M. , Fujiki, Yukio , Fulda, Simone , Furuya, Norihiko , Gack, Michaela U. , Gaffke, Lidia , Galadari, Sehamuddin , Galasso, Alessia , Galindo, Marı́a F. , Kankanamalage, Sachith Gallolu , Galluzzi, Lorenzo, Galy, Vincent , Gammoh, Noor , Ganley, Ian G. , Gao, Feng , Gao, Minghui , Gao, Ping , Gao, Wentao , Gao, Xiaobo , Garcerá, Ana , Garcia, María Noé , García, Verónica , Portillo, Francisco Garcı́a-del , García‐Escudero, Vega , García‐García, Aracely , García‐Macía, Marina , García‐Moreno, Diana , García‐Ruiz, Carmen , García‐Sanz, Patricia , Garg, Abhishek D. , Garofalo, Tina , Gassen, Nils C. , Gatica, Damián , Geiss‐Friedlander, Ruth , Genschik, Pascal , Gerbino, Valeria , Gerhardt, Christoph , Germain, Kyla , Germain, Marc , Afshar, Elham Ghasemipour, Ghavami, Saeid , Ghosh, Manosij , Giamas, Georgios , Giatromanolaki, Alexandra , Gibson, Gary E. , Ginet, Vanessa, Girardin, Stephen E. , Giridharan, Mridhula, Giuliano, Sandy , Giulivi, Cecilia , Giuriato, Sylvie , Giustiniani, Julien , Gluschko, Alexander , Goder, Veit , Goginashvili, Alexander , Gołąb, Jakub , Golebiewska, Anna , Gomes, Luciana Rodrigues, Gomez, Rodrigo Enrique, Gómez‐Sánchez, Rubén , Gómez‐Sintes, Raquel , Gong, Qingqiu , González‐Gallego, Javier , González‐Polo, Rosa A. , González‐Reyes, José A. , González-Rodríguez, Patricia , Goping, Ing Swie , Gorbunov, Nikolai V., Görgülü, Kıvanç , Gorojod, Roxana Mayra , Gorski, Sharon M. , Gotor, Cecilia , Gözüaçık, Devrim , Graef, Martin , Gräler, Markus H. , Granatiero, Veronica, Grasso, Daniel , Gray, Joshua P. , Greenhough, Alexander , Gregory, Stephen L. , Griffin, Edward F., Gros, Frédéric , Grose, Charles , Gross, Angelina S. , Грубер, Флориан , Grumati, Paolo , Gu, Xueyan , Guan, Jun‐Lin , Guardia, Carlos M. , Guda, Kishore , Guerra, Flora , Guerri, Consuelo , Guha, Prasun , Guillén, Carlos , Gujar, Shashi , Gukovskaya, Anna S. , Gukovsky, Ilya , Gunst, Jan , Günther, Andreas , Guo, Chuanyong , Guo, Chun , Guo, Hongqing , Guo, Ming , Gupta, Pawan , Gupta, Swapnil , Gupta, Veer Bala , Gupta, Vivek , Gutterman, David D. , H.B., Ranjitha, Haber, James E. , Hać, Aleksandra , Haidar, Mansour , Halldén, Gunnel , Hamacher‐Brady, Anne , Hamasaki, Maho , Hansen, Malene , Hao, Zijian, Harada, Masaru , Harhaji‐Trajkovic, Ljubica , Hariharan, Nirmala , Haspel, Jeffrey A. , Haucke, Volker , Hawkins, Wayne D. , Haynes, Cole M. , Hays, Thomas S. , He, Congcong , He, Qin , He, Rong‐Rong , He, You‐Wen , Heakal, Yasser, Heberle, Alexander Martin , Hejtmancik, J. Fielding , Henkel, Vanessa, Herb, Marc , Herman-Antosiewicz, Anna , Hernández, Agustín , Hernández, Carlos , Hernández-Díaz, Sergio , Hernández–Gea, Virginia , Herpin, Amaury , Herreros, Judit , Hervás, Javier H. , Hesselson, Daniel , Hetz, Claudio , Higuchi, Yujiro , Hilfiker, Sabine , Hill, Joseph A., Ho, Emmanuel A. , Ho, Idy H. T. , Ho, Philip Wing‐Lok , Ho, Shu‐Leong , Ho, Wan Yun, Hoet, Peter , Hofius, Daniel , Höhn, Annika , Hong, Yi-Ren Hong Chang-Won, Hooper, Lora V. , Hsin, I‐Lun , Hu, Bing , Hu, Dong , Hu, Wei , Hu, Zhuowei , Hua, Jinlian, Huan, Chongmin , Huang, Chuanshu , Huang, Chunling , Huang, Haishan , Huang, Michael , Huang, Shan , Huang, Tianzhi , Huang, Xing , Huang, Yuxiang , Hubert, Virginie , Hübner, Christian A. , Hughes, Stephanie M. , Hughes, William E. , Hummer, Gerhard , Hurley, James H. , Hussain, Sabah N. A. , Hussain, Salik , Hutabarat, Martina , Hwang, Hui-Yun, Ieni, Antonio , Ikeda, Fumiyo , Imagawa, Yusuke , Imbriano, Carol , Imoto, Masaya , Inman, Denise M. , Inoki, Ken , Iozzo, Renato V. , Iribarren, Pablo , Ishaq, Mohd , Ishimwe, Nestor , Ismail, Nahed , Issazadeh‐Navikas, Shohreh , Itakura, Eisuke , Ito, Daisuke , Ivankovic, Davor , Ivanova, Saška , Iyer, Anand Krishnan V. , Izquierdo, José M. , Jacobo‐Herrera, Nadia , Jacquin, Élise , Jadiya, Pooja , Jaeschke, Hartmut , Jagannath, Chinnaswamy, Jakobsson, Johan , Janji, Bassam , Jansen‐Dürr, Pidder , Jansson, Patric J. , Januszewski, Sławomir, Jeltsch‐David, Hélène , Jenny, Andreas , Jensen, Thomas E. , Jessen, Niels , Jia, Lijun , Jia, Rui , Jiang, Qing , Jiang, Richeng , Jiang, Teng , Jiang, Xuejun , Jiang, Yu , Jiménez-Sánchez, María , Jin, Fengyan , Jin, Li , Jin, Luqi, Jin, Si , Joffre, Carine , Johnston, Simon A. , Jokitalo, Eija , Juárez, Esmeralda , Juhász, Gábor , Jun, Youngsoo , Jung, Chang Hwa , Jung, Sung‐Chul , Jungbluth, Heinz , Jungverdorben, Johannes , Just, Steffen , Kaasik, Allen , Kaganovich, Daniel , Kain, Renate , Kajimura, Shingo , Kalamvoki, Maria , Kalia, Manjula , Kalinowski, Danuta S. , Kaludercic, Nina , Kalvari, Ioanna , Kamińska, Joanna , Kanamori, Hiromitsu , Kang, Chanhee , Kang, Rui , Kang, Sang Sun , Kaniyappan, Senthilvelrajan , Kanki, Tomotake , Kanneganti, Thirumala‐Devi , Kanthasamy, Arthi , Kantorow, Marc , Kapuy, Orsolya , Karim, Md. Razaul , Kato, Masaru , Kauppinen, Anu , Kaushal, Gur P. , Kawasaki, Kiyoshi, Kazan, Kemal , Keber, Ursula , Keller, Kate E. , Kenific, Candia M. , Kepp, Oliver , Kern, Andreas , Keulers, Tom G. , Khalfin, Boris , Khalil, Hany , Khan, Shahid Y. , Khandelwal, Vinoth Kumar Megraj, Khandia, Rekha , Kho, Widuri , Khobrekar, Noopur V. , Khuansuwan, Sataree , Khundadze, Mukhran , Killackey, Samuel A. , Kim, Dasol , Kim, Deok Ryong, Kim, Do‐Hyung , Kim, Dong‐Eun , Kim, Eun‐Kyoung , Kim, Hak-Rim, Kim, Hee-Sik , Kim, Hyung-Ryong, Kim, Jeong Hun , Kim, Joungmok , Kim, Seong‐Jun , Kimball, Scot R., Kimchi, Adi , Kimmelman, Alec , Kimura, Tomonori , King, Matthew, Kinsey, Conan G. , Kirshenbaum, Lorrie A. , Kishi, Shuji , Kitamoto, Katsuhiko , Kitaoka, Yasushi , Kitazato, Kaio, Kitsis, Richard N. , Kjærulff, Ole , Klein, Peter S. , Klopstock, Thomas , Klucken, Jochen , Knævelsrud, Helene , Ko, Fred , Kobayashi, Satoru, Koch, Ina , Koch, Jan Christoph , Kögel, Donat , Koh, Young Ho , Kocatürk, Nur Mehpare , Komatsu, Masaaki, König, Jeannette , Kono, Toru, Korkmaz, Gözde , Korsnes, Mónica Suárez , Koskela, Ali , Kota, Janaiah , Kotake, Yaichiro , Kotler, Monica L., Kou, Yanjun , Koukourakis, Michael I., Koustas, Evangelos , Kovács, Tibor , Kovács, Tibor, Kraft, Claudine , Krainc, Dimitri, Krämer, Helmut, Krasnodembskaya, Anna , Kretz‐Remy, Carole , Kroemer, Guido, Kuenen, Sabine , Kuerschner, Lars , Kukar, Thomas , Kumar, Ajay , Kumar, Deepak, Kumar, Dhiraj, Kumar, Sharad , Kume, Shinji , Kumsta, Caroline , Kundu, Chanakya Nath , Kundu, Mondira, Kunnumakkara, Ajaikumar B. , Kutlu, Özlem , Kwak, SeongAe , Kwon, Yong Tae , Spada, Albert La, Labonté, Patrick , Ladoire, Sylvain , Laface, Ilaria, Lafont, Frank , Lagace, Diane C. , Lahiri, Vikramjit , Lai, Zhibing, Laird, Angela S. , Lakkaraju, Aparna , Lan, Sheng‐Hui , Landajuela, Ane , Lane, Darius J.R. , Lange, Carsten , Langer, Rupert , Lapaquette, Pierre, Laporte, Jocelyn , Lastres-Becker, Isabel, Lau, Wilson Chun Yu , Laurie, Gordon W. , Le, Weidong, Stunff, Hervé Le , Leary, Alexandre Y , Lebrun, Jean-Jacques, Leck, Lionel , Lee, Changwook , Lee, Chung‐Pei , Lee, Da-Hye , Lee, Edward B., Lee, Erinna F. , Lee, Gyun Min, Lee, He-Jin, Lee, Heung Kyu , Lee, Jason S. , Lee, Jin-A, Lee, Joo‐Yong , Lee, Michael , Lee, Min Goo , Lee, Min Jae, Lee, Myung‐Shik , Lee, Sangyoon , Lee, Stella Y. , Lee, Sung, Lee, Won Hee , Lee, Yong‐ho , Lee, Youngil , Lei, Yu L., Lei, Yuchen , Leikin, Sergey , Lemus, Leticia , Leng, Shuilong, Lenoir, Olivia , Lenz, Guido , Lenz, Heinz Josef, Lenzi, Paola, León, Yolanda , Leschczyk, Christoph, Leskelä, Stina, Letellier, Elisabeth , Leung, Chi-Ting, Leung, Po Sing , Leventhal, Jeremy S. , Levine, Beth, Lewis, Patrick A. , Ley, Klaus , Li, Bin , Li, Da‐Qiang , Li, Jian‐Ming , Li, Jiong , Li, Liwu , Li, Mei , Li, Ming , Li, Mingchuan , Li, Pin‐Lan, Li, Ming‐Qing , Li, Qing , Li, Sheng , Li, Wei , Li, Wenming , Li, Xue , Li, Yi-Ping, Li, Yuan , Li, Zhiqiang, Li, Zhiyong , Li, Zhiyuan , Lian, Jiqin, Liang, Chengyu, Liang, Qiangrong, Liang, Weicheng , Liang, Yongheng, Liang, YongTian , Liao, Guanghong , Liao, Lujian , Liao, Yung-Feng, Librizzi, Mariangela, Lie, Pearl P.Y. , Lim, Hyunjung J., Lima, Thania Rios Rossi , Limana, Federica , Lin, Chao , Lin, Chih-Wen, Lin, Dar‐Shong , Lin, Fu‐Cheng , Lin, Jiandie D. , Lin, Kurt M., Lin, Kwang‐Huei , Lin, Qiong, Lin, Shaofeng , Lin, Su-Ju, Lin, Wenyu , Lin, Yao‐Xin , Lin, Yee‐Shin, Linden, Rafael, Lindner, Paula , Lipinski, Marta M. , Lipovšek, Saška, Lisiak, Natalia , Liton, Paloma B. , Liu, Chao , Liu, Ching‐Hsuan , Liu, Fang , Liu, Hua-feng , Liu, Huifang , Liu, Jia , Liu, Jing , Liu, Leyuan, Liu, Wei , Liu, Wende , Liu, Xiao-Hong, Liu, Xu , Liu, Yanfen , Liu, Yang, Liu, Yang, Liu, Yueyang , Liu, Yule , Livingston, J. Andrew, Lizcano, José M. , Ljubojević-Holzer, Senka , Lleonart, Matilde E. , Llobet‐Navàs, David , Llorente, Alicia, Lo, Chih Hung , Lobato‐Márquez, Damián , Long, Yun , Loos, Ben , Loos, Julia A. , López-Doménech, Guillermo, López‐Guerrero, José Antonio , López-Jiménez, Ana T. , López-Pérez, Óscar , López-Valero, Israel, Lorenowicz, Magdalena J. , Lorente, Mar , Lossi, Laura , Lotersztajn, Sophie , Lovell, Jonathan F., Lovy, Alenka , Lőw, Péter, Lu, Guang , Lu, Haocheng , Lu, Jiahong , Lu, Mengji, Lu, Shuyan, Luciani, Alessandro , Lucocq, John M., Ludovico, Paula , Luftig, Micah A. , Luhr, Morten, Luis-Ravelo, Diego , Lum, Julian J., Luna-Dulcey, Liany, Lund, Anders H. , Lund, Viktor K. , Lüningschrör, Patrick , Luo, Honglin, Luo, Rongcan , Luo, Zhi , Luparello, Claudio , Lüscher, Bernhard , Luu, Luan , Lyakhovich, Alex , Lyamzaev, Konstantin G. , Lystad, Alf Håkon , Lytvynchuk, Lyubomyr , Alvin, C. H. , Ma, Ning-Fang, Ma, Quanhong , Ma, Xinliang , Ma, Yueyun , Ma, Zhenyi , MacDougald, Ormond A. , MacIntosh, Gustavo C. , Macleod, Kay F. , Maday, Sandra , Madeo, Frank , Madesh, Muniswamy , Madl, Tobias , Madrigal‐Matute, Julio , Maeda, Akiko, Maejima, Yasuhiro , Magariños, Marta , Mahavadi, Poornima , Maiani, Emiliano , Maiese, Kenneth , Maiti, Panchanan , Maiuri, Maria Chiara , Major, Michael Ben, Makareeva, Elena , Malik, Fayaz , Mallilankaraman, Karthik , Maloyan, Alina , Mammadova, Najiba, Man, Gene Chi Wai , Manai, Federico , Mancias, Joseph D. , Mandelkow, Eva‐Maria , Manfredi, Angelo A. , Manshian, Bella B. , Manzano, Raquel , Marchese, Chiara , Marchetti, Sandrine , Marcucci, F, Mardente, Stefania , Mareninova, Olga A. , Mari, Muriel , Marinelli, Sara , Mariño, Guillermo , Mariotto, Sofia , Martin, Alexandre , Martin, Katie R. , Martin, Sara L. , Martín‐Segura, Adrián , Martin-Burriel, Inmaculada, Martín-Rincón, Marcos , Martín‐Sanz, Paloma , Martinez, Aitor , Martı́nez, Ana , Martinez-Lopez, Nuria, Martínez‐Vicente, Marta , Martins, Daniel Oliveira , Martins, Joilson O. , Martins, Waleska K. , Martins-Marques, Tania, Marzetti, Emanuele , Masaldan, Shashank , Masclaux-Daubresse, Celine, Mashek, Douglas G. , Massa, Valentina , Massieu, Lourdes , Masyuk, Anatoliy I. , Masyuk, Tetyana V., Matheu, Ander , Matoba, Satoaki , Matsuzaki, Sachiko , Mattar, Pamela , Mattè, Alessandro , Mauriz, José L., Mauthe, Mario , Maycotte, Paola , Mayer, Johanna , Mazzoni, Cristina , Mazzulli, Joseph R. , McCarty, Nami , McGill, Mitchell R. , McKenna, Sharon L. , McLoughlin, Fionn , McNiven, Mark A., McWilliams, Thomas G. , Medeiros, Tania , Medina, Diego L., Megeney, Lynn A. , Megyeri, Klára , Mehrpour, Maryam , Mehta, Jawahar L. , Meijer, Alfred J., Mejlvang, Jakob , Meléndez, Alicia , Melk, Annette, Memişoğlu, Gönen , Mendes, A.F. , Meng, Delong , Meng, Fei, Mercier, A., Mergny, Jean‐Louis , Merkley, Seth D. , Meske, Volker, Mestre, Ana Cecilia, Metur, Shree Padma, Meyer, C., Meyer, Hemmo , Mi, Wenyi , Mialet‐Perez, Jeanne , Miao, Jun‐Ying, Micale, Lucia , Miki, Yasuo, Milan, Enrico , Milczarek, Małgorzata , Miller, Samuel I. , Millward, Steven W. , Mirzaei, Hamed, Mirzaei, Hamid Reza , Mirzaei, Mehdi , Mishra, Amit , Mishra, Nandita , Mishra, Paras Kumar, Misirkić, Maja , Misasi, Roberta, Misra, Amit , Misso, Gabriella , Mitchell, Claire H. , Mitou, Géraldine, Miura, Tetsuji , Miyazaki, Makoto, Miyazaki, Mitsunori , Miyazaki, Taiga , Miyazawa, Keisuke, Mizushima, Noboru , Mogensen, Trine H. , Mohammadinejad, Reza , Mohamud, Yasir , Mohanty, Abhishek , Möhlmann, Torsten , Moley, Kelle H. , Möller, Andreas, Mollereau, Bertrand , Mollinedo, Faustino, Montagna, Costanza , Monteiro, Mervyn J. , Montella, Andrea , Montes, L. Ruth , Montico, Barbara , Mony, Vinod K., Compagnoni, Giacomo Monzio , Moore, Michael N. , Moosavi, Mohammad Amin , Morales‐Álamo, David , Moratalla, Rosario , Moreira, Paula I. , Morelli, Elena , Moreno-Blas, Daniel , Morgan, Alwena H. , Morin, Fabrice , Morishita, Hideaki , Moriyama, Mariko , Moriyasu, Yuji, Morleo, Manuela , Morselli, Eugenia , Moruno-Manchon, Jose F. , Moscat, Jorge , Motori, Elisa , Moura, Andréa Felinto , Mrakovcic, Maria, Muciño-Hernández, Gabriel, Mukherjee, Anupam , Mukhopadhyay, Subhadip , Levy, Jean M. Mulcahy , Mulero, Victoriano, Muller, Sylviane, Münch, Christian , Muñoz-Cánoves, Pura, Muñoz‐Galdeano, Teresa , Murakawa, Tomokazu , Murphy, Brona M. , Murthy, Aditya, Myöhänen, Timo T. , Mysorekar, Indira U. , Mytych, Jennifer , Nabavi, Seyed Mohammad , Nagy, Péter , Nahimana, Aimable , Nakagawa, Ichiro, Nakamura, Ken , Nandi, Shyam Sundar , Nanjundan, Meera, Nanni, Monica , Napolitano, Gennaro , Narita, Masashi, Nassif, Melissa , Nathan, Ilana , Natsumeda, Manabu , Naudé, Ryno J., Naumann, Christin , Naveiras, Olaia , Navid, Fatemeh , Nawrocki, Steffan T., Nazarko, Taras Y. , Nazio, Francesca , Negoita, Florentina , Neill, Thomas , Neisch, Amanda L. , Netea, Mihai G. , Neubert, Patrick , Neumann, Dietbert , Neutzner, Albert , Newton, Phillip T. , Ney, Paul A., Ng, Charlene Cheuk Wing, Ng, T.B., Nguyen, Hang Thi Thu , Nguyen, Long T. , Ni, Hong-Min, Cheallaigh, Clíona Ní , Ni, Zhenhong , Nicolao, M. Celeste, Nicoli, Francesco , Nieto‐Díaz, Manuel , Niranjan, Rituraj , Nishimune, Hiroshi , Niso-Santano, Mireia, Nixon, Ralph A. , Nobili, Annalisa , Noda, Takeshi , Nogueira-Recalde, Uxía , Nombela, Iván , Novak, Ivana, Novoa, Beatriz , Nukina, Nobuyuki , Nussbaum-Krammer, Carmen, Nylandsted, Jesper , O’Donovan, Tracey R. , O’Leary, Seónadh M. , O’Rourke, Eyleen J. , O’Sullivan, Mary P. , O’Sullivan, Timothy E., Oddo, Salvatore , Oehme, Ina, Ogawa, Michinaga , Ogier‐Denis, Éric , Ögmundsdóttir, Margrét H. , Öğretmen, Besim , Oh, Goo Taeg , Oh, Seon‐Hee , Oh, Young J. , Ohama, Takashi, Ohashi, Yohei , Ohmuraya, Masaki, Oikonomou, Vasileios , Ojha, Rani , Okazawa, Hitoshi , Oku, M., Oliván, Sara , Oliveira, Jorge M.A. , Ollmann, Michael, Olzmann, James A. , Omari, Shakib , Önal, Gizem, Ondrej, Martin , Ong, Sang‐Bing , Onnis, Anna , Orellana, Juan , Orellana‐Muñoz, Sara , Ortega-Villaizán, María del Mar , Ortiz‐González, Xilma R. , Osiewacz, Heinz D. , Osman, Abdel‐Hamid K. , Otsu, Kinya, Ott, Christiane , Ou, Jing-hsiung James, Outeiro, Tiago F., Öztürk, Melek , Pagès, Gilles, Pahari, Susanta , Pajares, Marta, Pal, Rituraj, Paladino, Simona , Palmieri, Michela , Palmisano, Giuseppe , Pan, Qingjun , Pan, Xin , Panasyuk, Ganna , Pandey, Rahul , Pandey, Udai B., Pandya, Vrajesh , Paneni, Francesco , Pang, Shirley Yin-Yu, Papademetrio, Daniela L. , Papinski, Daniel, Papp, Diana , Park, Hwan Tae , Park, Ji-Man, Park, Jong‐In , Park, Junsoo, Park, Sang-Youel, Pasquier, Adrien , Pasquier, Benoit , Passos, João F. , Pastore, Nunzia , Patschan, Daniel , Pattingre, Sophie , Pedraza‐Alva, Gustavo , Pedraza-Chaverri, Jose, Pedrozo, Zully , Pei, Gang , Pei, Jianming , Peled-Zehavi, Hadas, Pellegrini, Joaquín Miguel , Pelletier, Joffrey , Peñalva, Miguel A., Peng, Di , Peng, Ying , Pennuto, Maria , Pentimalli, Francesca , Pereira, Cláudia MF, Pereira, Gustavo J.S. , Pereira, Lílian Cristina , Almeida, Luís Pereira de , Perera, Nirma D. , Pérez-Lara, Ángel, Pérez‐Oliva, Ana B. , Perl, András , Pestell, Richard G. , Petrache, I., Petrovski, Goran , Pfirrmann, Thorsten , Pfister, Astrid S., Pi, Huifeng , Pickrell, Alicia M. , Picot, Sandy, Pierantoni, Giovanna Maria , Pierre, Philippe , Pierrefite‐Carle, Valérie , Pierzynowska, Karolina , Pietruczuk, Mirosława , Pimentel-Muiños, Felipe X., Pinar, Mario , Pinheiro, Roberta Olmo , Pinkas‐Kramarski, Ronit , Pircs, Karolina , Piya, Sujan , Pizzo, Paola , Platta, Harald W. , Plomann, Markus , Pocock, Roger , Pöggeler, Stefanie , Pohl, Christian, Poirot, Marc , Poletti, Angelo , Ponpuak, Marisa , Popelka, Hana , Popova, Bilyana , Porta, Helena, Alcón, Soledad Porte , Portilla-Fernández, Eliana , Potts, Malia B. , Powers, Ted, Prahlad, Veena , Prajsnar, Tomasz K. , Praticò, Domenico , Prencipe, Rosaria, Priault, Muriel , Proikas‐Cezanne, Tassula , Puertollano, Rosa , Puglielli, Luigi, Pulinilkunnil, Thomas , Puri, Deepika , Puri, Rajat, Puyal, Julien , Qi, Yongmei , Quadrilatero, Joe , Quarleri, Jorge, Raben, Nina, Rabinowich, Hannah, Ragona, Debora, Rahmati, Marveh , Raia, Valeria, Raimundo, Nuno , Rajasekaran, Namakkal-Soorappan, Rao, Sriganesh Ramachandra , Rami, Abdelhaq, Ramírez‐Pardo, Ignacio , Ramsden, D. , Randow, Felix , Ranieri, Danilo , Rao, Hai , Rao, Rekha , Rathore, Sumit , Ratnayaka, J. Arjuna , Ratovitski, Edward A., Ravanan, Palaniyandi, Ravegnini, Gloria , Ray, Swapan K. , Rebecca, Vito, Reggiori, Fulvio , Reigada, David , Reiling, Jan H., Rein, Theo , Reipert, Siegfried , Rekha, Rokeya Sultana , Ren, Hongmei, Ren, Jun , Ren, Weichao , Renault, Tristan, Renga, Giorgia , Reue, Karen, Rewitz, Kim , Ramos, Bruna Ribeiro de Andrade , Riazuddin, S. Amer, Ribeiro‐Rodrigues, Teresa , Riccio, Victoria , Richardson, Des R. , Risbud, Makarand V. , Risueño, Ruth M. , Ritis, Konstantinos, Rizza, Salvatore , Rizzuto, Rosario , Roberts, Scott J. , Roberts, Luke D., Robinson, Katherine J. , Rocchi, Stéphane , Rodrigues, Tiago , Silva, Vagner Ramon Rodrigues , Rodriguez-Barrueco, Ruth, Rodríguez‐Henche, Nieves , Rogers, Robert S. , Rogov, Vladimir V., Rojo, Ana I. , Romanello, Vanina, Romani, Luigina , Romano, Alessandra , Romano, Patricia Silvia , Romeo-Guitart, David, Romero, Luís C. , Romero, Montserrat , Roney, Joseph C. , Rongo, Christopher , Rosenfeldt, Mathias T. , Rosenstiel, Philip , Rosenwald, Anne , Roth, Steven, Rouschop, Kasper M.A. , Roussel, Benoit D. , Roux, Sophie , Rovere–Querini, Patrizia, Roy, Ajit , Rozières, Aurore , Ruano, Diego , Rubtsova, Maria P. , Ruckdeschel, Klaus, Ruckenstuhl, Christoph , Rudolf, Emil, Rudolf, Rüdiger, Ruggieri, Alessandra , Ruparelia, Avnika A. , Rusmini, P. , Russell, Ryan R., Russo, Gian Luigi , Russo, Maria , Russo, Rossella , Ryabaya, O. O. , Sabater-Arcis, María , Sacher, M, Sachse, Carsten , Sadhu, Abhishek , Säftig, Paul , Sahebkar, Amirhossein, Şahin, Mustafa , Şahin, Özgür , Saito, Nayuta , Saito, Tsunenori , Sakai, Yasuyoshi , Sakamaki, Jun-Ichi , Saksela, Kalle , Salazar, Gloria , Salazar-Degracia, Anna, Salekdeh, Ghasem Hosseini , Saluja, Ashok K. , Sampaio‐Marques, Belém , Sánchez, Marı́a C. , Sánchez-Alcázar, José A., Sanchez‐Vera, Victoria , Sancho‐Shimizu, Vanessa , Santambrogio, Laura , Santana, Magda M., Santoni, G, Sanz, Alberto , Saran, Shweta , Sardiello, Marco, Sargeant, Timothy J. , Sarin, Apurva , Sarkar, Chinmoy, Sarkar, Sovan , Sarrias, Maria-Rosa, Sarkar, Surajit , Sarmah, Dipanka Tanu, Sarparanta, J. , Sathyanarayan, Aishwarya , Ranganayaki, S. , Scaglione, K. Matthew , Scatozza, Francesca , Schafer, Zachary T. , Schaible, Ulrich E., Schapira, Anthony H.V. , Scharl, Michael , Schein, Catherine H. , Schiaffino, Maria Vittoria , Schiappacassi, Mónica , Schindl, Rainer , Schlattner, Uwe , Schmidt, Oliver, Schmitt, Roland , Schmidt, Stephen D., Schmitz, Ingo , Schmukler, Eran, Schneider, Anja , Schneider, Bianca E. , Schober, Romana , Schoijet, Alejandra C. , Schramm, M., Schröder, Bernd , Schuh, Kai , Schüller, Christoph , Schulze, Ryan J. , Schürmanns, Lea , Schwamborn, Jens C. , Schwarten, Melanie , Scott, Melanie J. , Scotto, Kathleen W., Scrima, Andrea , Scrivo, Aurora , Sebastián, David , Sebti, Salwa , Sedej, Simon , Segev, Nava , Seglen, Per O., Selleck, Scott B. , Selsby, Joshua, Sendtner, Michael , Şentürk, Şerif , Seranova, Elena, Sergi, Consolato M., Serra-Moreno, Ruth , Sesaki, Hiromi , Settembre, Carmine, Setty, Subba Rao Gangi , Sgarbi, Gianluca , Sha, Ou , Shacka, John J., Shah, Javeed A. , Shang, Dantong, Shao, Feng, Sharbati, Soroush , Sharkey, Lisa M. , Sharma, Dipali , Sharma, Gaurav, Sharma, Kulbhushan , Sharma, Pawan , Sharma, Surendra, Shen, Han‐Ming , Shen, Hongtao , Shen, Jiangang , Shen, Ming , Shen, Weili , Shen, Zheni, Sheng, Rui , Sheng, Zu-Hang, Shi, Jianjian , Shi, Ying–Hong , Shiba‐Fukushima, Kahori, Shieh, Jeng‐Jer , Shimada, Yohta , Shimizu, Shigeomi, Shimozawa, Makoto , Shintani, Takahiro , Shoemaker, Christopher J. , Shojaei, Shahla, Shoji, Ikuo , Shravage, Bhupendra V. , Shridhar, Viji, Shu, Chih‐Wen , Shu, Hong-Bing, Shui, Ke, Shukla, Arvind Kumar , Shutt, Timothy E. , Sica, Valentina , Siddiqui, Aleem , Sierra-Torre, Virginia, Signorelli, Santiago , Silva, Bruno Jorge de Andrade , Silva, Johnatas D. , Silva-Pavez, Eduardo , Silvente‐Poirot, Sandrine , Simmonds, Rachel E. , Singh, Anurag K. , Singh, Rajat Kumar , Singh, Shivendra V. , Singh, Shrawan Kumar , Singh, Sudha , Singh, Sunaina , Singh, Surinder Pal , Sinha, Debasish, Sinha, Rohit A. , Sinha, Sangita, Sirko, Agnieszka , Sivridis, Efthimios L., Skendros, Panagiotis , Sohn, Eun Jung , Sok, Sophia P. M. , Soldati, Thierry , Soler, Rosa M. , Somarelli, Jason A. , Sonawane, Avinash , Song, Fuyong, Song, Hyun Kyu , Song, Kunhua , Sorice, Maurizio , Soukas, Alexander A. , Soukup, Sandra‐Fausia , Sousa, Diana , Sousa, Nadia, Bharath, M. M. Srinivas , Clair, Daret St., Stagni, Venturina, Staiano, Leopoldo , Stankov, Metodi V. , Stathopulos, Peter B. , Stefan, Katja, Stefan, Sven Marcel , Stefanis, Leonidas, Steffan, Joan S. , Steinkasserer, Alexander , Stenmark, Harald, Sterneckert, Jared , Stevens, Craig , Storch, Stephan , Strappazzon, Flavie , Strohecker, Anne M. , Stupack, Dwayne G., Su, Huanxing , Su, Ling‐Yan , Suarez-Fontes, Ana Márcia , Subirada, Paula V., Sudhandiran, Ganapasam, Sue, Carolyn M. , Sui, Xinbing , Summers, Corey M., Sun, Guangchao , Sun, Zhongjie , Sunahara, Karen K. S. , Susztak, Katalin, Šutovský, Peter , Suzuki, Hidekazu , Sweeney, Gary , Symons, J. David , Sze, Stephen Cho Wing , Szewczyk, Nathaniel J. , Tabęcka-Łonczynska, Anna, Tabolacci, Claudio , Taegtmeyer, Heinrich, Tagaya, Mitsuo , Tai, Haoran , Tait, Stephen W. G., Takahashi, Yoshinori , Tam, Chit , Tam, Shing Yau , Tampellini, Davide , Tamura, Atsushi , Tan, Eng-King, Tan, Ya‐Qin , Tanaka, Masaki , Tang, Daolin , Tang, Jingfeng , Tang, Tie-Shan , Tao, Zhipeng , Taouis, Mohammed , Tavernarakis, Nektarios, Taylor, Allen, Teixeira, Natércia , Tekirdağ, Kumsal Ayşe, Tencomnao, Tewin , Tenreiro, Sandra , Tharaux, Pierre‐Louis , Thedieck, Kathrin , Thekkinghat, Arvind A. , Thinwa, Josephine , Thirumalaikumar, Venkatesh P. , Thomes, Paul G. , Thorburn, Andrew , Thum, Thomas, Thumm, Michael , Tian, Ling, Tichý, Aleš , Timmerman, Vincent , Titorenko, Vladimir I. , Toivonen, Janne M. , Tomaipitinca, Luana , Tomar, Dhanendra , Tomás‐Zapico, Cristina , Tomić, Sergej , Tong, Chao, Tong, Xin , Torgersen, Maria L., Torii, Satoru , Torres-López, Liliana , Torriglia, Alicia , Towers, Christina G. , Towns, Roberto, Tran, Quynh‐Giao , Travassos, Leonardo H. , Tremel, Shirley , Trougakos, Ioannis P., Tsao, Betty P. , Tse, Tak Fu, Tsvetkov, Andrey S. , Tumbarello, David A. , Tyler, Jessica K., Tyutereva, Elena V. , Uchiyama, Yasuo , Ugun‐Klusek, Aslihan , Uhlig, Holm H. , Ułamek-Kozioł, Marzena, Ulasov, Ilya V. , Umekawa, Midori, Ungermann, Christian , Urbe, Sylvie, Uribe-Carretero, Elisabet , Uversky, Vladimir N. , Vaccaro, María I. , Vahsen, Björn F. , Vakifahmetoglu-Norberg, Helin, Valdor, Rut , Valente, Maria João , Valko, Ayelén , Vallée, Richard, Valverde, Ángela M. , Berghe, Greet Van den, Veen, Stijn van der , Kaer, Luc Van , Loosdregt, Jorg van , Wijk, Sjoerd J. L. van , Vandenberghe, Wim , Vanhorebeek, Ilse , Vannier-Santos, Marcos A., Vannini, Nicola , Vanrell, M. Cristina, Vantaggiato, Chiara , Varela‐Nieto, Isabel , Varga, Máté , Vasconcelos, M. Helena , Vats, Somya , Vega-Rubín-de-Celis, Silvia , Velasco, Guillermo , Velázquez, Ariadna P., Vellai, Tibor , Vellenga, Edo , Verdier, Mireille , Verginis, Panayotis , Vergne, Isabelle , Verkade, Paul , Verma, Manish , Verstreken, Patrik , Vervliet, Tim , Vervoorts, Jörg , Víctor, Víctor M., Vidoni, Chiara , Vieira, Otília V. , Vierstra, Richard D., Viganò, Sonia , Vihinen, Helena , Vijayan, Vinoy, Vila, Miquel , Villalba, José M., Villalobo, Antonio , Villarejo‐Zori, Beatriz , Vincent, Olivier , Vindis, Cécile , Viret, Christophe , Vocadlo, David J. , Voitsekhovskaja, Olga V. , Volonté, Cinzia , Volta, Mattia , Vomero, Marta , Haefen, Clarissa von, Vooijs, Marc , Voos, Wolfgang , Vučićević, Ljubica , Waguri, Satoshi , Waite, Kenrick A., Wakatsuki, Shuji , Walker, David W., Walker, Mark J. , Walter, Jochen, Wandosell, Francisco , Wang, Bo , Wang, Chao-Yung, Wang, Chen , Wang, Chenran, Wang, Chenwei , Wang, Cun-Yu, Wang, Fengming, Wang, Han, Wang, Hexiang , Wang, Hong‐Gang , Wang, Jianrong, Wang, Jigang , Wang, Jun-Dong , Wang, Kui , Wang, Lianrong, Wang, Liming , Wang, Maggie Haitian, Wang, Meiqing , Wang, Nanbu , Wang, Pengwei , Wang, Ping , Wang, Ping, Wang, Q., Wang, Qiong , Wang, Wentao , Wang, Xinnan, Wang, Xuejun , Wang, Yan, Wang, Yanchang , Wang, Yanzhuang , Wang, Yihua , Wang, Yu , Wang, Yuqi , Wang, Zhe, Wang, Zhenyu , Wang, Zhouguang , Watanabe, Eizo, Watchon, Maxinne , Wawrzyńska, Anna , Weaver, Timothy E., Węgrzyn, Grzegorz, Wehman, Ann M. , Wei, Huafeng , Wei, Taotao , Wei, Yongjie, Weiergräber, Oliver H. , Weihl, Conrad C., Weindl, Günther , Weiskirchen, Ralf , Wen, Runxia H. , Werner, Antonia, Weykopf, Beatrice , Whitton, J. Lindsay , Wiktorska, Katarzyna , Wildenberg, Manon E. , Wileman, Tom, Wilkinson, Simon , Williams, Brett, Williams, Robin S. B. , Williamson, Peter R. , Wilson, Richard A. , Winsor, Nathaniel J. , Wodrich, Harald , Woehlbier, Ute , Wollert, Thomas , Wong, Richard W., Wong, Vincent Kam Wai , Wong, W. Wei-Lynn, Wu, Anguo , Wu, Kenneth K., Wu, Shan‐Ying , Wu, William Ka Kei , Wu, Shufang, Wu, Xiaoqing , Wu, Yao‐Wen , Wu, Yihua , Xavier, Ramnik J. , Xia, Hongguang , Xia, Lixin , Xia, Zhengyuan , Ge, Xiang , Xiang, Jin , Xiang, Mingliang , Xiang, Wei , Xiao, Guozhi , Xiao, Hengyi , Xiao, Hongtao , Xiao, Jian, Xiao, Lan , Xiao, Shi , Xiao, Yin , Xie, Baoming, Xie, Zhiping , Xie, Min , Xie, Yuxiang , Xie, Zhonglin, Xilouri, Maria , Xu, En , Xu, Jin‐Rong , Xu, Liang , Xu, Xiulong , Xue, Yu , Yakhine-Diop, Sokhna M. S. , Yamaguchi, Masamitsu , Yamamoto, Ai , Yamashina, Shunhei, Yan, Shengmin , Yan, Shian-Jang, Yan, Zhen , Yang, Chuanbin , Yang, Dun-Sheng, Yang, Huan , Yang, Huang-Tian, Yang, Hui , Yang, Jing , Yang, Jingyu , Yang, Ling , Liu, Yang , Yang, Ming , Yang, Seungwon, Yang, Shu , Yang, Shun-Fa , Yang, Wannian, Yang, Wei , Yang, Xiaoyong , Yang, Yi , Yao, Xiaoqiang , Yao, Yong-Gang , Yao, Yong-ming, Yasui, Takahiro , Yazdankhah, Meysam, Yi, Cong , Yin, Xiao-Ming , Yin, Yanhai , Yin, Zhangyuan , Yin, Ziyi , Ying, Meidan , Ying, Zheng, Yip, Calvin K. , Yiu, Stephanie Pei Tung , Yoo, Young Hyun , Yoshimori, Tamotsu, Yousefi, Bahman, Yu, Boxuan , Yu, Haiyang , Yu, Jun, Li, Yu , Yu, Ming‐Lung , Yu, Seong-Woon, Yu, Victor C. , Yu, Zhengping, Yuan, Junying , Yuan, Ling‐Qing , Yuan, Shilin , Yuan, Yanggang , Yuan, Zengqiang , Yue, Jianbo , Yue, Zhenyu , Yung, Raymond , Zacks, David, Zaffagnini, Gabriele , Zambelli, Vanessa O. , Zanella, Isabella , Zang, Qun S. , Zanivan, Sara , Zappavigna, Silvia , Zaragoza, P. , Zarbalis, Konstantinos S., Zarebkohan, Amir , Zarrouk, Amira , Zeitlin, Scott, Zeng, Jialiu , Zeng, Judeng , Žerovnik, Eva , Zhan, Lixuan , Zhang, Donna D., Zhang, Hong , Zhang, Honghe , Zhang, Huafeng , Zhang, Huaye, Zhang, Huiling , Zhang, Jianbin , Zhang, Jingpu , Zhang, Kalin Yanbo , Zhang, Leshuai W. , Zhang, Lu , Zhang, Luoying , Zhang, Menghuan, Zhang, Peng , Zhang, Sheng , Zhang, Xiangnan, Zhang, Xiao-Wei, Zhang, Xiaolei , Zhang, Xiaoyan , Zhang, Xin , Zhang, Xinxin , Zhang, Yang, Zhang, Yi , Zhang, Yingdong , Zhang, Yuanyuan , Zhang, Yuchen , Zhang, Zhe , Zhang, Zhibing , Zhang, Zili , Zhao, Haobin, Zhao, Lei , Zhao, Shuang , Zhao, Tongbiao , Zhao, Ying, Zhao, Yongchao , Zhao, Yongliang , Zhao, Yuting , Zheng, Guoping , Zheng, Kai, Zheng, Ling , Zheng, Shizhong , Zheng, Xi‐Long , Zheng, Zu‐Guo , Zhivotovsky, Boris, Zhong, Qing , Zhou, Ao, Zhou, Ben , Zhou, Cefan , Zhou, Gang , Zhou, Hongbo , Zhou, Kailiang, Zhou, Rongjia , Zhou, Yanshuang, Zhou, Yinghong , Zhou, Yubin , Zhou, Zhengyu, Zhou, Zhou , Zhu, Binglin , Zhu, Changlian , Zhu, Guo‐Qing , Zhu, Haining , Zhu, Hongxin, Zhu, Yanping , Zhu, Yushan , Zhuang, Haixia , Zhuang, Xiaohong , Zimmermann, Christine , Żołądek, Teresa , Zong, Wei‐Xing, Zorov, Dmitry B. , Zorzano, Antonio, Zou, Weiping, Zou, Zhen , Zou, Zhengzhi, Zuryn, Steven , Kenchappa, Chandra Shekar, Li, Zuguo , Lin, Yong , Sluimer, Judith C. , Stallings, Christina L. , Tong, Chun-Kit, Wang, Ping , Hu, Bo , Lee, Edward B. , Tse, Hung‐Fat , Suszták, Katalin , Lei, Yu Leo , Yu, M-L , Dai, Yun , Bartolome, Alberto , Brown, Rhoderick E , Passos, João F , Paneni, Francesco , Sahin, Özgür , Pereira de Almeida, Luis , Ren, Jun , Bornhauser, Beat , Kumar, Sharad , Sampaio-Marques, Belém , Ludovico, Paula , Luftig, Micah , Begun, Jakob , Krasnodembskaya, Anna D , Dafsari, Hormos Salimi , Chevet, Eric , Tse, Hung-Fat , Barmada, Sami , Ebrahimi-Fakhari, Darius , Cavadas, Claudia , Sue, Carolyn M , Cardenal-Muñoz, Elena , Lee, Edward B , Golebiewska, Anna , Calbet, Jose A L , Boya, Patricia , Maday, Sandra , Klionsky, Daniel J. , Abdelfatah, Sara , Abdoli, Asghar , Agarwal, Anupam , Ahmed, Zubair M. , Alcocer‐Gómez, Elísabet , Ali, Muhammad , Al‐Bari, Md. Abdul Alim , Aliwaini, Saeb H. , Alizadeh, Javad , Almacellas, Eugènia , Almasan, Alexandru , Alonso, G. , Altieri, Dario C. , Andersen, Stig Uggerhøj , Andrade-Silva, Magaiver , Angelini, Sabrina , Apostolova, Nadezda , Arasaki, Kohei , Araújo, Wagner L. , Arden, Catherine , Arimoto, Hirokazu , Armstrong-James, Darius P. H. , Pelloquin, Laetitia , Aschner, Michael , Ashrafizadeh, Milad , Autelli, Riccardo , Aveic, Sanja , Avin‐Wittenberg, Tamar , Ayton, Scott , Backues, Steven K. , Bae, Dong-Hun , Bae, Ok‐Nam , Baek, Ahruem , Baek, Seung‐Hoon , Baek, Sung Hee , Bai, Jie , Bai, Yidong , Baldari, Cosima T. , Balduini, Walter , Ballabio, Andrea , Banerjee, Sreeparna , Bao, Yan , Baptista, Maurı́cio S. , Barreto, George Emilio , Basagoudanavar, Suresh H. , Bast, Robert C. , Basu, Alakananda , Batoko, Henri , Batten, Isabella , Behrens, Georg M. N. , Bei, Roberto , Behl, Christian , Bello‐Morales, Raquel , Beltrán, Sebastián , Bergami, Matteo , Bergmann, Andreas , Berthoux, Lionel , Bhattacharya, Resham , Bhattacharyya, Shalmoli , Bhutia, Sujit Kumar , Bi, Lanrong , Birgisdottir, Åsa Birna , Bjørkøy, Geir , Blomgren, Klas , Boada-Romero, Emilio , Boesze‐Battaglia, Kathleen , Bonifacino, Juan S. , Boone, Brian A. , Borthakur, Gautam , Bosch, Jürgen , Bose, Santanu , Botana, Luis Miguel , Boulton, Michael E. , Bourdenx, Mathieu , Brackney, Doug E. , Brandts, Christian , Braun, Ralf J. , Braus, Gerhard H. , Bravo, Roberto , Brody, Steven L. , Brown, Carolyn Nicole , Brumell, John Hunter , Brunetti‐Pierri, Nicola , Buitrago‐Molina, Laura Elisa , Buraschi, Simone , Buch, Shilpa J. , Butturini, Elena , Cairó, Montserrat , Caldwell, Kim A. , Campbell‐Valois, François‐Xavier , Campello, Silvia , Campesi, Ilaria , Almeida, Danilo Cândido de , Canesi, Laura , Caraglia, Michele , Carchman, Evie H. , Carmona‐Gutiérrez, Didac , Carnevali, Oliana , Carrier, Lucie , Carroll, Bernadette , Carter, A. Brent , Casas, Caty , Castillo, Eliseo F. , Castro‐Caldas, Margarida , Castro‐Obregón, Susana , Catz, Sergio , Cayuela, María Luisa , Cecarini, Valentina , Cecconi, Francesco , Cenci, Simone , Ceperuelo‐Mallafré, Victòria , Cervia, Davide , Chae, Han–Jung , Chakrabarti, Oishee , Chan, Edmond Y. W., Chan, Edward D. , Chandra, Partha Kumar , Chang, Chih‐Peng , Chang, Chunmei , Chapman, Tracey , Chen, Guang‐Chao , Chen, Leilei , Chen, Lin , Chen, Quan , Chen, Ruey‐Hwa , Chen, Shi , Chen, Wei‐Qiang , Chen, Xu , Chen, Yu-Jen , Chen, Yujie , Chen, Zhi , Chen, Zhijian J. , Chen, Zhixiang , Cheng, Hanhua , Cheng, Jun , Cheng, Shi‐Yuan , Cheng, Wei Nee , Cheng, Xiaodong , Chen, Zhong , Cheong, Heesun , Chernyak, Boris V. , Chi, Richard J., Chiang, Aks , Chiarelli, Roberto , Chu, Charleen T. , Chung, Seockhoon , Cianfanelli, Valentina , Cifuentes, Mariana , Cirone, Mara , Clague, Michael J. , Cohen, Ehud , Cohen, Mickaël M. , Čolić, Miodrag J , Combaret, Lydie , Comincini, Sergio , Conte, Andrea, Conti, Fabrizio , Coppens, Isabelle , Corasaniti, Maria Tiziana , Corkery, Dale , Cordes, Nils , Cortese, Katia , Coto‐Montes, Ana M. , Crack, Peter John , Crespo, José L. , Cuadrado, Antonio , Cui, Jun , Cui, Yong , D’Arcangelo, Daniela , D’Lugos, Andrew C. , Dagda, Ruben Karim , Dagdas, Yasin , Daμμe, Markus , Dantuma, Nico P. , Darling, April L. , Dasarathy, Srinivasan , Daumke, Oliver , Davis, Tanja , Amicis, Francesca De , Felice, Francesca De , Franceschi, Lucia De , Milito, Angelo De , Nunzio, Cosimo De , Santi, Mauro De , Debnath, Jayanta , DeBosch, Brian J. , DeGregori, James V. , Rio, Gabriel del , Delbridge, Lea M.D. , Delpino, M. Victoria , Demarchi, Francesca , Dembitz, Vilma , Deng, Zhiqiang , Denton, Donna , Der, Channing J , Deretić, Vojo , Dhiman, Rohan , Bernardo, Diego di , Cristina, Manlio Di , Nardo, Alessia Di, Sano, Federica Di , Diallinas, George , Diaz-Araya, Guillermo, Đikić, Ivan , Ding, Wen‐Xing , Dini, Luciana , Dionne, Marc , Diwan, Abhinav , Dixon, Ian , Djavaheri‐Mergny, Mojgan , Dobrinski, Ina , Dobrovinskaya, Oxana R. , Dobrowolski, Radek , Dobson, Renwick C. J. , Donadelli, Massimo , Dong, Bo, Dötsch, Volker , Dou, Huan , Dridi, Sami , Du, Caigan , Du, Li‐Lin , Dubrovska, Anna , Dunlop, Elaine A. , Dwarakanath, Bilikere Srinivasa Rao , Eftekharpour, Eftekhar , Eichinger, Ludwig , Eissa, N. 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Autophagy | March 24, 2021 | Volume: 17 | Issue: 1 | Pages: 1-382
Integrative Analysis of the Genomic and Transcriptomic Landscape of Relapsed/Refractory Multiple Myeloma Patients Treated With Venetoclax in Combination With Bortezomib and Dexamethasone: Biomarker Analyses From the Phase 3 BELLINI Study
Spencer, Andrew , Kumar, Shaji , Popat, Rakesh , Jalaluddin, Muhammad, Lü, Xin , Zha, Zheng , Dunbar, Fengjiao, Vishwamitra, Deeksha , Mantis, Christine, Melhem‐Bertrandt, Amal , O’Dwyer, Michael , Popat, Rakesh , Moreau, Philippe , Dail, Monique , Jalaluddin, Muhammad, Yang, Xiaoqing , Ross, Jeremy A. , Harrison, Simon J
Blood | February 8, 2021 | Volume: 136 | Issue: Supplement 1 | Pages: 40-41
Background: Multiple myeloma (MM) is a clonal plasma cell malignancy characterized by a complex genomic landscape with molecular and clinical heterogeneity. Venetoclax (Ven) is a selective, potent, oral BCL-2 inhibitor currently under investigation as a potential targeted therapy for the treatment of relapsed/refractory (RR) MM. Using a next-generation sequencing (NGS)-based approach, the mutational landscape and gene expression profile (GEP) of patients (pts) with RRMM in BELLINI was evaluated for potential impact on observed clinical outcomes in key biomarker subgroups. Methods: BELLINI (NCT02755597) is a randomized, double-blind, multicenter Phase 3 study of bortezomib + dexamethasone (Bd) + either Ven or placebo (Pbo) in pts with RRMM who received 1-3 prior therapies and were sensitive or naïve to proteasome inhibitors. Pts were randomized 2:1 to receive Ven 800 mg/d or Pbo + Bd. The following biomarker analyses were performed by central laboratory assessments of CD138-enriched bone marrow mononuclear cells collected at baseline: BCL2 gene expression by quantitative PCR (qPCR), cytogenetic abnormalities by interphase fluorescence in situ hybridization (FISH), identification of somatic mutations by whole-exome sequencing (WES), and transcriptomic analysis by RNA sequencing (RNAseq). Correlation between mutational status, BCL2high status (Harrison et al. Blood. 2019:134 suppl:142), cytogenetics, GEP, and survival outcomes were examined by pairwise t-test and by hazard ratio (HR) from Cox proportional hazard model. Results: As of the data cutoff (13 Sep 2019), 291 pts were randomized (194 to Ven and 97 to Pbo); 262 pts (90.0%) were evaluable by FISH, 257 pts (88.3%) by qPCR, 197 pts (67.7%) by WES, and 184 pts (63.2%) by RNAseq. The mutational landscape of evaluable pts was highly heterogeneous (Figure 1A). MAPK pathway mutations were the most prevalent (62/197 pts; 31.5%); however, recurrent mutations in the NF-kB pathway (TRAF3 or CYLD) were also observed (12/197 pts; 6.1%). Within the MAPK pathway, the most frequently mutated genes were KRAS (39/197 pts; 19.8%), NRAS (8/197 pts; 4.1%), BRAF (8/197 pts; 4.1%), and NF1 (12/197 pts; 6.1%). Although a higher rate of pts with a MAPK mutation was observed in the t(11;14) and BCL2high subgroup compared to pts without these biomarkers (39/101 pts [38.6%] vs 23/95 pts [24.2%]; P=.04), improvement in progression-free survival (PFS) with Ven+Bd was observed in pts with (HR=0.08; 95% CI, 0.02-0.31; P<.001) or without (HR, 0.31 [95% CI, 0.16-0.63]; P=.001) a MAPK pathway mutation. High somatic mutation loads are associated with increased genomic instability, resistance to therapy, and decreased overall survival (OS) in MM. High tumor mutation burden (TMB), defined as ≥20 mutations/megabase of sequenced DNA, was observed in 12/197 pts (6.1%). Although there were a limited number of high TMB pts, reduced PFS (HR, 4.55 [95% CI, 2.33-8.88]; P<.001) and OS (HR, 3.89 [95% CI, 1.76-8.56]; P<.001) compared to low TMB pts was observed regardless of treatment arm. WES detected a recurrent BCL2 mutation (Ala43Thr) in 15/197 pts (7.6%). This BCL2 mutation has not previously been identified in MM and did not appear to affect survival outcomes among pts in either arm. Supervised clustering of RNAseq data grouped pts into respective MM GEP (Zhan et al. Blood. 2006;108:2020) at the following frequencies: CD-1 (2.7%), CD-2 (8.2%), HY (40.2%), MF (1.6%), MS (10.9%), LB (5.4%), and PR (31.0%). As shown in Figure 1B, 16/20 pts (80%) allocated to the CD-1/CD-2 cluster had a t(11;14) mutation, but 17/20 pts (85%) and 2/3 pts (67%) in MS and MF GEP groups had t(4;14) or t(14;16) mutations, respectively. The HY GEP group was primarily (56/74 pts; 76%) hyperdiploid by FISH. Though a higher rate of pts with a HY GEP (50/98 pts [51.0%] vs 24/86 pts [27.9%]; P<.001) and a lower rate of PR GEP (11/98 pts [11.2%] vs 46/86 pts [53.5%]; P<.001) were observed in the t(11;14) and BCL2high subgroups compared with non-t(11;14) and BCL2low subgroups, respectively, improvement in PFS with Ven+Bd was independent of GEP classification. Conclusion: Using an integrative approach of genomic and transcriptomic profiling, response to Ven+Bd in key biomarker subgroups was shown to be independent of concurrent mutations in key oncogenic signaling pathways and GEPs known to be prognostic in MM; however, high mutation load appears to be a clinically relevant risk factor that negatively affects survival in MM. Disclosures O'Dwyer: Celgene: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); BMS: Research Funding; Carrick Therapeutics: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Janssen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AbbVie: Consultancy; ONK Therapeutics: Consultancy, Current Employment, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Spencer:Roche: Honoraria; Sanofi: Consultancy, Honoraria; Pharmamar: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Secura Bio: Consultancy, Honoraria; Servier: Consultancy, Honoraria, Research Funding; HaemaLogiX: Consultancy, Honoraria, Research Funding. Kumar:Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Tenebio: Other, Research Funding; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Kite Pharma: Consultancy, Research Funding; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Genecentrix: Consultancy; Cellectar: Other; MedImmune: Research Funding; Karyopharm: Consultancy; Sanofi: Research Funding; Merck: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Carsgen: Other, Research Funding; Dr. Reddy's Laboratories: Honoraria; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Novartis: Research Funding. Popat:AbbVie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other: Travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Bristol Myers Squibb: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Celgene: Consultancy, Honoraria. Moreau:Abbvie: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Honoraria; Novartis: Honoraria. Dail:Genentech: Current Employment, Current equity holder in publicly-traded company. Jalaluddin:AbbVie: Current Employment, Other: may hold stock or stock options. Yang:Abbvie: Current Employment, Current equity holder in publicly-traded company. Lu:AbbVie: Current Employment, Current equity holder in publicly-traded company. Zha:Abbvie: Current Employment, Current equity holder in publicly-traded company. Dunbar:Abbvie: Current Employment, Current equity holder in publicly-traded company. Vishwamitra:AbbVie, Inc.: Current Employment, Other: may hold stock or other options. Mantis:Abbvie: Current Employment, Current equity holder in publicly-traded company. Melhem-Bertrandt:AbbVie: Current Employment; Astellas: Ended employment in the past 24 months. Ross:AbbVie: Current Employment, Current equity holder in publicly-traded company. Harrison:F. Hoffmann-La Roche: Consultancy, Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Patents & Royalties: wrt panobinostat; Janssen: Honoraria; Haemalogix: Consultancy; BMS: Consultancy, Honoraria.
Tfeb Links MYC Signaling to Epigenetic Control of Acute Myeloid Leukemia Cell Death and Differentiation
Yu, Xiaoqing , Yang, Chunying , Hitosugi, Taro , Cheng, Chia‐Ho, Freischel, Audrey R. , Watson, G., Schaub, Franz X. , Vedder, Alexis , Cen, Ling , McGraw, Kathy L. , Yun, Seongseok , Vincelette, Nicole D. , Fernandez, Mario R. , Zhang, Ling , Li, Weimin , Hou, Hsin‐An , Murphy, Daniel J. , Ballabio, Andrea , Kaufmann, Scott H. , Berglund, Anders , Cleveland, John L.
Blood | February 8, 2021 | Volume: 136 | Issue: Supplement 1 | Pages: 12-13
MYC gene amplification and somatic mutations are frequent in both adult and pediatric AML although how MYC drives and contributes to the development and maintenance of AML has not been resolved. Transcription factor EB (TFEB) is a master regulator of genes that control autophagy and lysosome biogenesis, a central catabolic recycling pathway that regulates cell survival. Given the oncogenic effects of MYC in AML and that the induction of autophagy compromises AML cell growth and survival, we tested if the oncogenic effect of MYC depends on its suppression of TFEB transcription programs in AML. In support of this hypothesis, inducible MYC expression in K562 and THP-1 leukemia cells was sufficient to suppress expression of TFEB and its target genes. Further and conversely, MYC knockdown in NB4 AML cells provoked increased expression of TFEB mRNA and protein, as well as increased expression of TFEB target genes. Notably, dose response studies demonstrated that expression of TFEBS211A, constitutively nuclear form of TFEB that is refractory to control by mTORC1 signaling, dramatically impairs proliferation of HL60, OCI-AML2 and OCI-AML3 AML cells. In addition, induction of TFEBS211A provoked rampant apoptosis. Of important, overexpression of TFEBS211A in HL-60 and OCI-AML3 cells was also sufficient to promote monocytic and granulocytic differentiation, as judged by morphological changes and the acquisition of mature monocytic and granulocytic markers including CD11b, Gr1, and CD15. To identify TFEB targets that might contribute to myeloid/granulocytic differentiation, we performed RNA-seq analysis of HL60 leukemia cells engineered to inducibly express the TFEBS211A transgene. Using a cut-off of fold change>4 with q<0.01, a total of 1152 genes were differentially regulated following the induction of TFEBS211A in HL60 cells. As expected, this included the robust induction of nearly all TFEB target genes associated with the autophagy-lysosome pathway, but also of STAT1, KLF4, KLF6, CEBPB, CSF1 and GATA2 genes that are necessary and/or sufficient to provoke terminal monocytic and granulocytic differentiation of AML cells. Surprisingly, among genes induced by TFEB in HL60 cells is IDH1, which catalyzes the production of α-ketoglutarate (α-KG), a required substrate of the TET family of dioxygenases that convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). In particular, TFEBS211A expression provoked increases in levels of α-KG and significant increases in global levels of 5hmC in genomic DNA of HL60 leukemia cells both ex vivo and in vivo. Furthermore, TFEB-mediated induction of IDH1/2 mRNA and protein, and of IDH1 promoter activity, was antagonized by inducible expression of MYC. To assess the global effects of TFEB on 5mC/5hmC landscapes, we performed paired reduced representation bisulfite (BS)- and oxidation bisulfite (oxBS)-sequencing. As predicted, TFEBS211A induced both loss and gains of 5mC, but there were more losses (n = 722) than gains (n = 459) across all 22 chromosomes. Quite remarkably, and consistent with TFEB-provoked increases of 5hmC signals, TFEBS211A exclusively induced 5hmC gains (in a total of 863 genes), and 37% and 36% of these 5hmC gains occurred in promoter regions and CpG islands, and across all 22 chromosomes. Comparison of BS- and oxBS-seq versus RNA-seq analyses of HL60 cells expressing TFEB revealed significant changes in mRNA levels and concomitant differential changes in 5mC and 5hmC marks in KLF4, KLF6, STAT3, TP73, andFOXO1 that have pivotal roles in controlling myeloid cell differentiation and death. Collectively, these findings demonstrate that MYC suppresses TFEB expression and function in AML cells, and that TFEB functions as a tumor suppressor that provokes AML cell differentiation and death. Strikingly, these responses rely on epigenetic control, where TFEB directly induces the transcription of IDH1 and IDH2 to provoke global hydroxylation of 5-methylcytosine and the expression of genes that drive terminal differentiation and apoptosis. Thus, a MYC-TFEB-IDH1/2-TET2 circuit controls AML cell fate. Disclosures Murphy: Merck: Research Funding; Puma Biotech: Research Funding. Ballabio:CASMA Therapeutics: Other: Co-Founder. Kaufmann:Takeda Pharmaceuticals: Research Funding.
Targeting BCL‐2 with venetoclax and dexamethasone in patients with relapsed/refractory t(11;14) multiple myeloma
Kaufman, Jonathan L. , Gasparetto, Cristina , Schjesvold, Fredrik , Moreau, Philippe , Dunbar, Fengjiao, Vishwamitra, Deeksha , Unger, Stefanie, Macartney, Tammy, Yu, Yao , Ross, Jeremy A. , Hong, Wan‐Jen , Maciag, Paulo , Pauff, James M., Kumar, Shaji , Schjesvold, Fredrik H , Moreau, Philippe , Kaufman, Jonathan L , Touzeau, Cyrille , Facon, Thierry T.F. , Boise, Lawrence , Jiang, Yanwen , Yang, Xiaoqing , Unger, Stefanie, Pesko, John Carl , Salem, Ahmed Hamed
American Journal of Hematology | December 28, 2020 | Volume: 96 | Issue: 4 | Pages: 418-427
10.1002/ajh.26083
| PMID 33368455
AbstractVenetoclax (Ven) is a selective small‐molecule inhibitor of BCL‐2 that exhibits antitumoral activity against MM cells with t(11;14) translocation. We evaluated the safety and efficacy of Ven and dexamethasone (VenDex) combination in patients with t(11;14) positive relapsed/refractory (R/R) multiple myeloma (MM). This open‐label, multicenter study had two distinct phases (phase one [P1], phase two [P2]). Patients in both phases received VenDex (oral Ven 800 mg/day + oral Dex 40 mg [20 mg for patients ≥75 years] on days 1, 8, and 15, per 21–day cycle). The primary objective of the P1 VenDex cohort was to assess safety and pharmacokinetics. Phase two further evaluated efficacy with objective response rate (ORR) and very good partial response or better. Correlative studies explored baseline BCL2 (BCL‐2) and BCL2L1 (BCL‐XL) gene expression, cytogenetics, and recurrent somatic mutations in MM. Twenty and 31 patients in P1 and P2 with t(11;14) positive translocation received VenDex. P1/P2 patients had received a median of 3/5 lines of prior therapy, and 20%/87% were refractory to daratumumab. Predominant grade 3/4 hematological adverse events (AEs) with ≥10% occurrence included lymphopenia (20%/19%), neutropenia (15%/7%), thrombocytopenia (10%/10%), and anemia (5%/16%). At a median follow‐up of 12.3/9.2 months, ORR was 60%/48%. The duration of response estimate at 12 months was 50%/61%, and the median time to progression was 12.4/10.8 months. In biomarker evaluable patients, response to VenDex was independent of concurrent del(17p) or gain(1q) and mutations in key oncogenic signaling pathways, including MAPK and NF‐kB. VenDex demonstrated efficacy and manageable safety in heavily‐pre‐treated patients with t(11;14) R/R MM.