tbuckley/cabot-search huggingface dataset:
New Drug for Chronic Myeloid Leukemia Might Stimulate the Market
Authors: Martin C. Müller
Journal: Clinical Cancer Research (2020)

Abstract The evolution of treatment options over the past 20 years has provided for a normal life expectancy for most patients with chronic myeloid leukemia. Currently approved tyrosine kinase inhibitors mainly differ in potency and side effect profile. Flumatinib goes for deep responses and good tolerability. See related article by Zhang et al., p. 70
A Phase I Study of CD19-Targeted 19(T2)28z1xx CAR T Cells in Adult Patients with Relapsed or Refractory B-Cell Malignancies
Authors: Jae H. Park, Isabelle Riviere, Devanjan S. Sikder, Vladimir P. Bermudez, Brigitte Senechal, Xiuyan Wang, Thomas H. Auchincloss, Claudia Diamonte, Elizabeth Halton, M. Lia Palomba, Renier J. Brentjens, Michel Sadelain
Journal: Blood (2020)
Updated Results from the Phase II Study of Orelabrutinib Monotherapy in Chinese Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Cell Leukemia
Authors: Wei Xu, Yongping Song, Tingyu Wang, Shenmiao Yang, Lihong Liu, Yu Hu, Wei Zhang, Jianfeng Zhou, Sujun Gao, Kaiyang Ding, Huilai Zhang, Zunmin Zhu, Shun-Qing Wang, Bing Xu, Jianda Hu, Ting Liu, Chunyan Ji, Zhongjun Xia, Yan Li, Xin Wang, Huaqiang Zhu, Renbin Zhao, Bin Zhang, Zhixin Xu, Jianyong Li
Journal: Blood (2020)
HETEROLOGOUS TRANSPLANTATION OF MAMMALIAN TUMORS
Authors: Harry S. N. Greene
Journal: The Journal of Experimental Medicine (1941)

The successful heterologous transplantation of several human tumors, including a breast carcinoma, a carcinoma of the colon, a melanotic sarcoma, and a fibrosarcoma, has been reported. Histologically, the appearance of the transplants of the carcinomata differed from that of the spontaneous tumors, but the directly observed growth of the transplanted fragments together with the presence of invasion in microscopic sections afforded proof of successful transfer. Transplants of the sarcomata, on the other hand, were morphologically identical with the primary tumors, and in the case of the fibrosarcoma serial passage to a second generation of animals was successfully performed.
Preclinical Anti-Tumor Activity of Hexabody-CD38 in Patient-Derived B Cell Lymphoma and Acute Myeloid Leukemia Xenograft Models
Authors: Ida H Hiemstra, Maarten L Janmaat, Peter Boross, Jeroen van den Brakel, Wessel ten Hagen, Sanne van Dooremalen, Sieto Bosgra, Bart ECG De Goeij, Grietje Andringa, Laurens Kil, A Kate Sasser, Tahamtan Ahmadi, David Satijn, Esther CW Breij
Journal: Blood (2020)
Chronic Myeloid Leukemia (CML) in Adolescents & Young Adults (AYA): Single Institution 10 Years Experience with 1st Line Imatinib Mesylate (IM)
Authors: Hemant Malhotra, Ajay Yadav, Naveen Gupta, Satyajeet Soni, Jitender Kumar Singh, Bharti Malhotra
Journal: Blood (2020)
Pomalidomide Plus Low Dose Dexamethasone in Relapsed/Refractory Multiple Myeloma Patients: Results of the Real-World 'Powerful' Study
Authors: Evangelos Terpos, Panagiotis Repousis, Chrysavgi Lalayanni, Evdoxia Hatjiharissi, Theodora Assimakopoulou, George Vassilopoulos, Anastasia Pouli, Emmanouil Spanoudakis, Evridiki Michali, Gerassimos Pangalis, Christos Poziopoulos, Marie-Christine Kyrtsonis, Vassiliki Pappa, Argiris Symeonidis, Christos Georgopoulos, Panagiotis Zikos, Helen A. Papadaki, Magda Dadakaridou, Kiki Karvounis-Marolachakis, Petros Patos, Eirini Katodritou
Journal: Blood (2020)
Five-Year Analysis of Murano Study Demonstrates Enduring Undetectable Minimal Residual Disease (uMRD) in a Subset of Relapsed/Refractory Chronic Lymphocytic Leukemia (R/R CLL) Patients (Pts) Following Fixed-Duration Venetoclax-Rituximab (VenR) Therapy (Tx)
Authors: Arnon P. Kater, Thomas J. Kipps, Barbara Eichhorst, Peter Hillmen, James D'Rozario, Carolyn Owen, Sarit E Assouline, Nicole Lamanna, Tadeusz J. Robak, Javier de la Serna, Ulrich Jaeger, Guillaume Cartron, Marco Montillo, Clemens Mellink, Brenda J. Chyla, Cameron Wilson, Jenny Wu, Yanwen Jiang, Marcus Lefebure, Michelle Boyer, John F. Seymour
Journal: Blood (2020)
Prognostic Relevance of Genetic Abnormalities in Blastic Transformation of Chronic Myeloid Leukemia
Authors: Yotaro Ochi, Kenichi Yoshida, Ying-Jung Huang, Ming-Chung Kuo, Ko Sasaki, Noriko Hosoya, Nobuhiro Hiramoto, Rabindranath Bera, Yasuhito Nannya, Yusuke Shiozawa, June Takeda, Yosaku Watatani, Hideki Makishima, Yuichi Shiraishi, Kenichi Chiba, Hiroko Tanaka, Masashi Sanada, Takayuki Ishikawa, Akifumi Takaori-Kondo, Satoru Miyano, Kinuko Mitani, Seishi Ogawa, Lee-Yung Shih
Journal: Blood (2020)
Healthcare Utilization and Costs Associated with Different Treatment Protocols for Newly Diagnosed Childhood Acute Lymphoblastic Leukemia: A Population-Based Study
Authors: Sumit Gupta, Nicole Mittman, Petros Pechlivanoglou, Qing Li, Uma Athale, Mylene Bassal, Vicky R. Breakey, Paul J. Gibson, Mariana Silva, Veda Zabih, Jason Pole, Rinku Sutradhar
Journal: Blood (2020)
DREAMM-7: A Phase III Study of the Efficacy and Safety of Belantamab Mafodotin (Belamaf) with Bortezomib, and Dexamethasone (B-Vd) in Patients with Relapsed/Refractory Multiple Myeloma (RRMM)
Authors: Robert M. Rifkin, Kevin Boyd, Sebastian Grosicki, Kihyun Kim, Francesco Di Raimondo, Meletios A Dimopoulos, Katja Weisel, Bertrand Arnulf, Roman Hajek, Vania T. M. Hungria, Andrew Spencer, Randy Davis, Antonio Riccio, Chanbin Kim, Jodie Wilkes, Ruth Rutledge, Mala Talekar, Brandon E. Kremer, Ira Gupta, Maria-Victoria Mateos
Journal: Blood (2020)
Cystic Fibrosis Lung Function Decline after Within-Host Evolution Increases Virulence of Infecting <i>Pseudomonas aeruginosa</i>
Authors: Peter Jorth, Samantha Durfey, Amir Rezayat, Jayanthi Garudathri, Anina Ratjen, Benjamin J. Staudinger, Matthew C. Radey, Alan Genatossio, Sharon McNamara, David A. Cook, Moira L. Aitken, Ronald L. Gibson, Timothy L. Yahr, Pradeep K. Singh
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

"Cystic Fibrosis Lung Function Decline after Within-Host Evolution Increases Virulence of Infecting Pseudomonas aeruginosa." American Journal of Respiratory and Critical Care Medicine, 203(5), pp. 637–640
Risk Factors of Neonatal Immune Thrombocytopenia in Pregnant Women Previously Diagnosed with ITP: Results from a French Nationwide Prospective Study
Authors: Stephanie Guillet, Valentine Loustau, Anissa Zarour, Emmanuelle Boutin, Thibault Comont, Odile Souchaud-Debouverie, Nathalie Costedoat-Chalumeau, Brigitte pan-Petesch, Delphine Gobert, Stephane Cheze, Jean-Francois Viallard, Anne-Sophie Morin, Gaetan Sauvetre, Manuel Cliquennois, Bruno Royer, Corinne Haioun, Agathe Masseau, Louis Terriou, Claire Fieschi, Matthieu Mahevas, Marc Michel, Bertrand Godeau
Journal: Blood (2020)
Subcutaneous Mosunetuzumab in Relapsed or Refractory B-Cell Lymphoma: Promising Safety and Encouraging Efficacy in Dose Escalation Cohorts
Authors: Matthew J Matasar, Chan Yoon Cheah, Dok Hyun Yoon, Sarit E Assouline, Nancy L. Bartlett, Matthew Ku, Pratyush Giri, Anna Johnston, Ian W. Flinn, Andre H. Goy, Dimitrios Tzachanis, Carol O'Hear, Shen Yin, Iris To, Kati Sarouei, Chi-Chung Li, Brendan C. Bender, Elicia M. Penuel, Huang Huang, L. Elizabeth Budde
Journal: Blood (2020)
Predictors of Maternal Morbidity Among Participants Enrolled in the Sickle Cell Disease Implementation Consortium Registry
Authors: Rita V Masese, Dominique Bulgin, Liliana Preiss, Mitchell Knisely, Eleanor Stevenson, Jane S. Hankins, Marsha Treadwell, Allison A. King, Victor R. Gordeuk, Julie Kanter, Robert Gibson, Jeffrey A. Glassberg, Paula Tanabe, Nirmish Shah
Journal: Blood (2020)
Consecutive Hypoalbuminemia Predicts Inferior Outcome in Patients with Diffuse Large B-Cell Lymphoma
Authors: Xiaolei Wei, Jingxia Zheng, Zewen Zhang, Qiongzhi Liu, Minglang Zhan, Weimin Huang, Jianbo Liu, Qi Wei, Yongqiang Wei, Ru Feng
Journal: Blood (2020)
Abstract PO-071: MYC influences metastatic heterogeneity in pancreatic cancer
Authors: Ravikanth Maddipati, Robert J. Norgard, Timour Baslan, Komal S. Rathi, Amy Zhang, Pichai Raman, Max D. Wengyn, Taiji Yamazoe, Jinyang Li, David Balli, Michael LaRiviere, Ian W. Folkert, Ian D. Millstein, Jonathan Bermeo, Erica L. Carpenter, Scott Lowe, Christine Iacobuzio-Donahue, Faiyaz Notta, Ben Z. Stanger
Journal: Cancer Research (2020)

Abstract Tumor heterogeneity - resulting from genetic and epigenetic alterations acquired during tumor progression - is a critical driver of phenotypic diversity in most cancers. A lethal consequence of tumor heterogeneity is the acquisition of metastatic traits by tumor cells, leading to poor clinical outcomes. This remains a major problem in pancreatic ductal adenocarcinoma (PDAC), which continues to have the worst prognosis of any major cancer type. While most cases of PDAC present with metastatic disease at the time of diagnosis, the patterns and burden of metastasis can vary widely, with some patients exhibiting a limited metastatic burden while others have more extensive spread, which impacts clinical outcomes. However, the biological and functional differences that drive metastatic heterogeneity are poorly understood. Citation Format: Ravikanth Maddipati, Robert J. Norgard, Timour Baslan, Komal S. Rathi, Amy Zhang, Pichai Raman, Max D. Wengyn, Taiji Yamazoe, Jinyang Li, David Balli, Michael LaRiviere, Ian W. Folkert, Ian D. Millstein, Jonathan Bermeo, Erica L. Carpenter, Scott Lowe, Christine Iacobuzio-Donahue, Faiyaz Notta, Ben Z. Stanger. MYC influences metastatic heterogeneity in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-071.
Abstract 416: Sarcomere Disassembly After Unloading is Regulated by Ubiquitination and Acetylation of Capz and α-actinin
Authors: Christopher Solís, R John Solaro, Chad M Warren, Brenda Russell
Journal: Circulation Research (2020)

Cardiac function mainly depends on the total myocyte mass in the ventricles. Assembly and disassembly of sarcomeres occurs to adjust this mass to altered mechanical demand. In the heart, hypertrophic cardiomyopathy results from myofibrillar assembly controlled by post-translational modification of proteins directed by signaling pathways. More is known about assembly on loading than disassembly on unloading. Here, the hypothesis tested is that unloading of mechanical forces affects acetylation (Ac) and ubiquitination (Ub) of the actin-binding proteins, α-actinin and CapZ. Omecamtiv mecarbil (0.5 μM) and mavacamten (1 μM) were used to increase (load) and decrease (unload) cardiomyocyte tension, respectively, via their action on myosin ATPase. Mavacamten decreased myocyte contractility in rat ventricular myocytes (NRVMs) and caused significant sarcomere disassembly by 6 h and 70% atrophy by 24 h. Assembly was preserved with omecamtiv mecarbil (0.5 μM) over the 24 h time period. Post-translational modification was determined in loaded and unloaded NRVMs at 6 h of drug treatment. Bottom-up mass spectrometry analysis showed single residues in α-actinin and CapZ that were acetylated or ubiquitinated. Acetylation levels appeared to increase in the mavacamten-treated samples while these levels are preserved in untreated and omecamtiv mecarbil-treated samples. Ac and Ub in the Z-discs were quantified on immunofluorescent images. The Z-discs colocalized oligo-Ub (K-48 oligo-Ub linkage) and Ac in untreated samples; this Z-disc localization of Ub and Ac was diminished with unloading. Fluorescence recovery after photobleaching (FRAP) measurements of the dynamics of α-actinin and CapZ after reduced cell tension with mavacamten (1 μM) and omecamtiv mercabil (0.5 μM) are ongoing. Overall, results suggest sarcomere assembly is regulated by mechanical forces through a mechanism involving Ac and Ub of myofibrillar proteins. These findings could have consequences for cardiac heart disease with abnormal sarcomeric proteostasis.
The Discriminatory Ability of the R-ISS Is Equivalent to the ISS in a Large Cohort of Newly Diagnosed Multiple Myeloma (NDMM) Patients
Authors: Anaïs Schavgoulidze, Valerie Lauwers-Cances, Aurore Perrot, Herve Avet-Loiseau, Jill Corre
Journal: Blood (2020)
The Challenge of Recruiting Convalescent Plasma Donors during the COVID-19 Pandemic: Preliminary Results from a Single Center in Midwest Brazil
Authors: Maria do Rosario Ferraz Roberti, Tiago Paiva Prudente, Renato Gomes Castro, Marcos Antonio Candido, Roberta Luiza Rodrigues, Maria Cunha Ribeiro Morelli, Alexandra Vilela Gonçalves, Jaciane Soares de Sá, Layane Marques de Souza, Marcelo Fouad Rabahi, Adriano de Moraes Arantes
Journal: Blood (2020)
SAT0493 CLINICAL PROFILE OF JIA PATIENTS WITH THE CERVICAL SPINE INVOLVEMENT: A SINGLE CENTER RETROSPECTIVE CONTINUOUS STUDY.
Authors: R. Raupov, L. Sorokina, M. Dubko, L. Snegireva, T. Likhacheva, A. Santimov, E. Gaidar, E. Isupova, I. Chikova, T. Kornishina, V. Masalova, M. Kostik
Journal: Annals of the Rheumatic Diseases (2020)

Background: JIA is the most common chronic condition in pediatric rheumatology. The cervical spine (CS) involvement is associated with severe disease activity and disability and has been recognized as a factor of a poor prognosis. Data about the CS involvement is contradictory due to silent CS involvement in some patients. Objectives: the aim of our study was to provide a clinical profile of the patients with the CS involvement. Methods: 753 patients for last 10 years with JIA were analyzed. Patients were divided depending on the CS involvement, which was confirmed by clinical (pain, LOM) and radiological features (effusion in the CS joints). We evaluated active joints and routine tests, such as CRP, ESR, ANA-positivity and HLA B27 Results: The CS involvement was in 101 patients (13.4%). The data are in the table. The CS involvement was more frequently associated with joints of upper body, such as TMJ (23.7% vs 2.9%, p=0.000001), shoulder (29.7% vs 2.9%, p=0.000001), elbow (34.2% vs 12.2%, p=0.000001), wrist (61.4% vs 21.8%, p=0.0000001), MCP (43.6% vs 18.4%, p=0.0000001), PIP (52.5% vs 21.3%, p=0.0000001), DIP (23.8% vs 7.1%, p=0.0000001) and hip (44.6% vs 16.6%, p=0.0000001), and ankle (60.4% vs 40.2%, p=0.0001) from lower body. Parameters CS, yes (n=101) CS, no (n=652) p Female, n (%) 69 (68.3) 388 (59.5) 0.092 ANA-positivity, n (%) 22/57 (38.6) 190/403 (47.2) 0.226 HLA B27-positivity, n (%) 12/33 (36.4) 88/275 (32.0) 0.613 Onset age, years 5.3 (2.7-10.1) 6.1 (3.0- 10.4) 0.241 ESR, mm/h 12.0 (5.0-31.0) 7.0 (3.0- 18.0) 0.0006 CRP, mg/l 3.9 (0.0- 20.0) 1.1 (0.0-9.2) 0.002 Active joints, n (%) 16.0 (9.0-28.0) 5.0 (3.0-10.0) 0.000000 Time before remission, years 2.9 (1.5-5.1) 2.2 (1.1-4.6) 0.046 Oligoarthritis Polyarthritis Psoriatic arthritis Enthesitis-related arthritis Systemic arthritis 5 (5.0) 48 (48.0) 7 (7.0) 22 (21.8) 19 (18.9) 199 (30.5) 217 (33.3) 33 (5.1) 164 (25.2) 39 (6.0) 0.0000001 Uveitis, n (%) 9/76 (11.9) 107/444 (24.1) 0,018 Oral glucocorticosteroids, n (%) 37 (36.7) 115/651 (17.7) 0.00001 Biologic, n (%) 68 (67.3) 283 (43.4) 0.000007 Remission, n (%) 57 (56.4) 428 (65.6) 0.072 Flare, n (%) 10 (9.9) 128/651 (19.7) 0.018 Conclusion: The main risk factors of CS involvement in JIA were polyarthicular and systemic arthritis, high inflammatory activity and involvement of joints of upper body. Patients with CS involvement required more often biologics. Disclosure of Interests: None declared
Outcomes of Patients with Down Syndrome and <i>CRLF2</i>-Overexpressing Acute Lymphoblastic Leukemia (ALL): A Report from the Children's Oncology Group (COG)
Authors: Karen R Rabin, Meenakshi Devidas, Zhiguo Chen, Yunfeng Dai, Sarah K Tasian, Johann K Hitzler, Kathryn G Roberts, Andrew J Carroll, Nyla A Heerema, Michael J Borowitz, Brent L Wood, Charles G Mullighan, Richard C Harvey, I-Ming L Chen, Cheryl L Willman, Shalini C Reshmi, Julie M Gastier-Foster, Kelly W Maloney, Eric C Larsen, Reuven J Schore, Michael J Burke, Wanda L Salzer, Naomi J Winick, William L. Carroll, Elizabeth A. Raetz, Anne Angiolillo, Mignon L. Loh, Stephen P Hunger
Journal: Blood (2020)
Abstract PO-020: Inferring copy number substructure from single-cell transcriptomics in human tumors with CopyKat
Authors: Ruli Gao, Shanshan Bai, Henderson Ying, Yiyun Lin, Tapsi Seth, Min Hu, Emi Sei, Alexander Davis, Fang Wang, Jennifer Rui Wang, Ken Chen, Stacey Moulder, Stephen Lai, Nicholas Navin
Journal: Cancer Research (2020)

Abstract High-throughput single cell transcriptomics analysis is widely used to study human tumors, however a major challenge is distinguishing the stromal cells from the malignant cancer cells, as well as clonal substructure within tumors. To address this challenge, we developed an integrative Bayesian segmentation approach, COPYKAT to estimate genomic copy numbers at 5MB resolution from high-throughput single cell RNA-seq data. We applied COPYKAT to 39,709 single cells from 16 tumors across 4 cancer types, including premalignant and triple-negative breast cancers, pancreatic ductal adenocarcinomas, and anaplastic thyroid cancer. From these data we could accurately (98%) classify tumor cells from stromal cells. In three TNBC tumors COPYKAT resolved multiple clonal subpopulations of genotypes that differed in expression of breast cancer genes and enrichment of cancer hallmarks including EMT and hypoxia. These data show that COPYKAT can accurately resolve clonal copy number substructure in tumors and classify tumor and normal cells in a variety of human cancers. Citation Format: Ruli Gao, Shanshan Bai, Henderson Ying, Yiyun Lin, Tapsi Seth, Min Hu, Emi Sei, Alexander Davis, Fang Wang, Jennifer Rui Wang, Ken Chen, Stacey Moulder, Stephen Lai, Nicholas Navin. Inferring copy number substructure from single-cell transcriptomics in human tumors with CopyKat [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-020.
Cytokine Release Syndrome in Patients with Relapsed/Refractory Multiple Myeloma Treated with Ciltacabtagene Autoleucel in the Phase 1b/2 CARTITUDE-1 Study
Authors: Yi Lin, Thomas Martin, Adam D. Cohen, Andrzej Jakubowiak, Jagoda Jasielec, Saad Z. Usmani, Deepu Madduri, Mounzer Agha, A. Keith Stewart, Indrajeet Singh, Enrique Zudaire, Tzu-Min Yeh, Alicia J. Allred, Yunsi Olyslager, Arnob Banerjee, Jenna D. Goldberg, Jordan M. Schecter, Carolyn C. Jackson, William Deraedt, Dong Geng, Xiaoling Wu, Marlene J. Carrasco, Muhammad Akram, Farah Hossain, Vickie Wang, Jesus G. Berdeja, Sundar Jagannath
Journal: Blood (2020)
Spatial and molecular mapping of Pfkelch13 gene polymorphism in Africa in the era of emerging Plasmodium falciparum resistance to artemisinin: a systematic review
Authors: Nadine K Kayiba, Doudou M Yobi, Evariste Tshibangu-Kabamba, Vo P Tuan, Yoshio Yamaoka, Brecht Devleesschauwer, Dieudonné M Mvumbi, Emile Okitolonda Wemakoy, Patrick De Mol, Georges L Mvumbi, Marie-Pierre Hayette, Angel Rosas-Aguirre, Niko Speybroeck
Journal: The Lancet Infectious Diseases (2020)
Pandemic preparedness: Government hasn’t released full report of exercise, say campaigners
Authors: Clare Dyer
Journal: BMJ (2020)

The UK government is being accused of failing to disclose the full report of a simulation exercise that showed the country was not ready to cope with a pandemic, as campaigners prepare to take the case back to court.NHS doctor Moosa Qureshi and journalist Tommy Greene have said the document released by Matt Hancock, the health and social care secretary for England, on 20 October represented only part of the report on Exercise Cygnus, which in 2016 war gamed the government's response to a future flu pandemic.
Outcome of Patients with T-Cell Acute Lymphoblastic Leukemia/Lymphoma with Early T-Cell Precursor-like Immunophenotype with Strong CD5 Expression
Authors: Kiyomi Morita, Hagop M. Kantarjian, Hong Fang, Farhad Ravandi, Nitin Jain, Marina Konopleva, El Hussein Siba, Feng Wang, Nicholas J. Short, Koichi Takahashi, Rita Khouri, Koji Sasaki, Courtney D. DiNardo, Tapan M. Kadia, Guillermo Garcia-Manero, Naval Daver, Guillermo Montalban Bravo, Sergej Konoplev, Joseph D. Khoury, Elias Jabbour
Journal: Blood (2020)
A β-Globin Locus-Intrinsic Epigenetic Mechanism Underlies Fetal Globin Production in F-Cells
Authors: Eugene Khandros, Peng Huang, Scott A. Peslak, Malini Sharma, Osheiza Abdulmalik, Belinda Giardine, Zhe Zhang, Cheryl A. Keller, Ross C. Hardison, Gerd A. Blobel
Journal: Blood (2020)
A Novel Therapy-Resistance Transcriptional Signature Based on Single Cell Analysis in Kydar Clinical Trial
Authors: Yael C Cohen, Mor Zada, Shuang-Yin Wang, Chamutal Bornstein, Eyal David, Adi Moshe, Baoguo Li, Shir Shlomi, Moshe Gatt, Noa Lavi, Chezi Ganzel, Efrat Lutwak, Ory Rouvio, Iuliana Vaxman, Oren Pasvolsky, Mouna Ballan, Tamar Tadmor, Anatoly Nemets, Osnat Jarchowcky Dolberg, Yevgeny Chober, Olga Shvetz, Merav Leiba, Ofer Shpilberg, Nagib Deli, Irit Avivi, Assaf Weiner, Ido Amit
Journal: Blood (2020)
Discovery of an orally active VHL-recruiting PROTAC that achieves robust HMGCR degradation and potent hypolipidemic activity in vivo
Authors: Guoshun Luo, Zhenbang Li, Xin Lin, Xinyu Li, Yu Chen, Kun Xi, Maoxu Xiao, Hanlin Wei, Lizhe Zhu, Hua Xiang
Journal: Acta Pharmaceutica Sinica B (2020)

HMG-CoA reductase (HMGCR) protein is usually upregulated after statin (HMGCR inhibitor) treatment, which inevitably diminishes its therapeutic efficacy, provoking the need for higher doses associated with adverse effects. The proteolysis targeting chimera (PROTAC) technology has recently emerged as a powerful approach for inducing protein degradation. Nonetheless, due to their bifunctional nature, developing orally bioavailable PROTACs remains a great challenge. Herein, we identified a powerful HMGCR-targeted PROTAC (21c) comprising a VHL ligand conjugated to lovastatin acid that potently degrades HMGCR in Insig-silenced HepG2 cells (DC50 = 120 nmol/L) and forms a stable ternary complex, as predicated by a holistic modeling protocol. Most importantly, oral administration of the corresponding lactone 21b reveled favorable plasma exposures referring to both the parent 21b and the conversed acid 21c. Further in vivo studies of 21b demonstrated robust HMGCR degradation and potent cholesterol reduction in mice with diet-induced hypercholesterolemia, highlighting a promising strategy for treating hyperlipidemia and associated diseases.
Safety and Efficacy of Mitoxantrone Hydrochloride Liposome in Patients with Relapsed or Refractory Peripheral T-Cell Lymphoma and Extranodal NK/T-Cell Lymphoma: A Prospective, Single-Arm, Open-Label, Multi-Center, Phase Ⅱ Clinical Trial
Authors: Yan Gao, Huiqiang Huang, Xiaoxiao Wang, Bing Bai, Yunhong Huang, Haiyan Yang, QingYuan Zhang, Yufu Li, Yan Li, Min Zhou, Runxiang Yang, Bing Xu, Lihong Liu, Yu Yang, Zhigang Peng, Ding Yu, Hui Zhou, Rong yan Zhang, Huilai Zhang, Junyuan Qi, Yaming Xi, Xiaojing Xing, Zhao Wang, Hongmei Jing, Xiaohong Zhang, Liping Ma, Hongyan Jin, Hongxia Yao, Yuerong Shuang, Xuefang Xia, Jianfei Xue, Chunlei Li
Journal: Blood (2020)