tbuckley/cabot-search huggingface dataset:
Phase I and Preliminary Results of a Phase II Study (TERAPLASCoV2) of Convalescent Plasma in Patients with Severe and Life-Threatening Pneumonia Caused By Sars-Cov-2
Authors: Fernando Pérez-Jacobo, Luis Villela Villela, Edgar Velásquez-Vega, Jesús Hernández, Melani Otañez, Mónica Arellano-Mendoza, Rosa Sosa-Camas, Víctor Manríquez-Bonillas, Rubén Bejar-Cornejo, Fausto Pérez, Joanna Chávez-Ochoa, Bernardo Ramos-Vadillo, Mabel Limón-Palafox, Karen Jacobo-López, Alondra Vázquez Hernández, Ofelia Rosales Del Real, Lidia Mondragón-Posadas, Alma Pérez De la O, Pablo Rodríguez-Morales, Ma. Luisa Millán Cureño, Martha Gómez Meza, Cecilia Padilla-Ibarra, Alan Soto-Gaxiola, Edgar Melgoza-Gonzáles, Diana Hinojosa-Trujillo, Emilio Reyes-Jiménez, Marcos Serrato-Félix, Hilario Martínez Arredondo, Rodolfo Lehmann Mendoza
Journal: Blood (2020)
Tandem CD19/CD22 Dual Targets CAR-T Cells Therapy Acquires Superior CR Rate Than CD19 CAR-T Cells: A Case Controlled Study
Authors: Wei Cui, Xinyue Zhang, Haiping Dai, Qingya Cui, Baoquan Song, Depei Wu, Xiaowen Tang, Jia Yin, Zheng Li
Journal: Blood (2020)
MATERIA MEDICA AND THERAPEUTICS.
Journal: JAMA (1884)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Mutational Profile and Copy Number Alterations of Follicular Lymphoma Patients with Different Clinical Behavior
Authors: Pablo Mozas, Cristina López, Marta Grau, Sara Valle, Giancarlo Castellano, Alba Navarro, Ferran Nadeu, Blanca González-Farré, Alfredo Rivas-Delgado, Andrea Rivero, Juan Gonzalo Correa, Carlos Castillo, Balagué Olga, Eva Giné, Julio Delgado, Neus Villamor, Magda Pinyol, Patricia Pérez-Galán, Laura Magnano, Elías Campo, Anna Enjuanes, Sílvia Beà, López-Guillermo Armando
Journal: Blood (2020)
Histone H3K27 methyltransferase EZH2 and demethylase JMJD3 regulate hepatic stellate cells activation and liver fibrosis
Authors: Yan Jiang, Chan Xiang, Fan Zhong, Yang Zhang, Liyan Wang, Yuanyuan Zhao, Jiucun Wang, Chen Ding, Li Jin, Fuchu He, Haijian Wang
Journal: Theranostics (2020)

Rationale: As the central hallmark of liver fibrosis, transdifferentiation of hepatic stellate cells (HSCs), the predominant contributor to fibrogenic hepatic myofibroblast responsible for extracellular matrix (ECM) deposition, is characterized with transcriptional and epigenetic remodeling. We aimed to characterize the roles of H3K27 methyltransferase EZH2 and demethylase JMJD3 and identify their effective pathways and novel target genes in HSCs activation and liver fibrosis. Methods: In primary HSCs, we analyzed effects of pharmacological inhibitions and genetic manipulations of EZH2 and JMJD3 on HSCs activation. In HSCs cell lines, we evaluated effects of EZH2 inhibition by DZNep on proliferation, cell cycling, senescence and apoptosis. In CCl4 and BDL murine models of liver fibrosis, we assessed in vivo effects of DZNep administration and Ezh2 silencing. We profiled rat primary HSCs transcriptomes with RNA-seq, screened the pathways and genes associated with DZNep treatment, analyzed EZH2 and JMJD3 regulation towards target genes by ChIP-qPCR. Results: EZH2 inhibition by DZNep resulted in retarded growth, lowered cell viability, cell cycle arrest in S and G2 phases, strengthened senescence, and enhanced apoptosis of HSCs, decreased hepatic collagen deposition and rescued the elevated serum ALT and AST activities of diseased mice, and downregulated cellular and hepatic expressions of H3K27me3, EZH2, α-SMA and COL1A. Ezh2 silencing by RNA interference in vitro and in vivo showed similar effects. JMJD3 inhibition by GSK-J4 and overexpression of wild-type but not mutant Jmjd3 enhanced or repressed HSCs activation respectively. EZH2 inhibition by DZNep transcriptionally inactivated TGF-β1 pathway, cell cycle pathways and vast ECM components in primary HSCs. EZH2 inhibition decreased H3K27me3 recruitment at target genes encoding TGF-β1 pseudoreceptor BAMBI, anti-inflammatory cytokine IL10 and cell cycle regulators CDKN1A, GADD45A and GADD45B, and increased their expressions, while Jmjd3 overexpression manifested alike effects. Conclusions: EZH2 and JMJD3 antagonistically modulate HSCs activation. The therapeutic effects of DZNep as epigenetic drug in liver fibrosis are associated with the regulation of EZH2 towards direct target genes encoding TGF-β1 pseudoreceptor BAMBI, anti-inflammatory cytokine IL10 and cell cycle regulators CDKN1A, GADD45A and GADD45B, which are also regulated by JMJD3. Our present study provides new mechanistic insight into the epigenetic modulation of EZH2 and JMJD3 in HSCs biology and hepatic fibrogenesis.
YTHDF3 Induces the Translation of m6A-Enriched Gene Transcripts to Promote Breast Cancer Brain Metastasis
Authors: Guoqiang Chang, Lei Shi, Youqiong Ye, Hailing Shi, Lixian Zeng, Shweta Tiwary, Jason T. Huse, Lei Huo, Li Ma, Yongjie Ma, Sicong Zhang, Jianwei Zhu, Victoria Xie, Peng Li, Leng Han, Chuan He, Suyun Huang
Journal: Cancer Cell (2020)
Tackle social factors to reduce stillbirth, say researchers
Authors: Jacqui Wise
Journal: BMJ (2020)

Pregnant women who experience psychological stress, domestic abuse, deprivation, or unemployment are more likely to have a stillborn baby, a new study shows.1

Researchers from Tommy’s Maternal and Fetal Health Research Centre at the University of Manchester also found that attending more antenatal appointments than currently recommended could reduce the odds of stillbirth.

In 2015 the UK was ranked 24th of 49 high income countries, with a stillbirth rate of 2.9 in 1000 births. In response, the UK government aims to reduce stillbirth rates by 50% by 2025 through initiatives such as the Saving Babies’ Lives Care Bundle.2

The case-control study, published in the British Journal of …
Second Relapse of Pediatric Patients with Acute Myeloid Leukemia: A Report on Current Treatment Strategies and Outcome of the AML-BFM Study Group
Authors: Mareike Rasche, Emma Steidel, Martin Zimmermann, Jean-Pierre Bourquin, Heidrun Boztug, Iveta Janotová, Edward A. Kolb, Thomas Lehrnbecher, Nils Von Neuhoff, Naghmeh Niktoreh, Nora Muehlegger, Lucie Sramkova, Jan Stary, Christiane Walter, Ursula Creutzig, Michael Dworzak, Dirk Reinhardt
Journal: Blood (2020)
COVID-19 in Patients with Hematological Malignancies: High False Negative Rate with High Mortality
Authors: Alex Niu, Bo Ning, Francisco Socola, Hana Safah, Tim Reynolds, Moayed Ibrahim, Firas Safa, Tina Alfonso, Alfred Luk, David M Mushatt, Tony Hu, Nakhle S. Saba
Journal: Blood (2020)
Long-Term Survival and Gradual Recovery of B Cells in Patients with Refractory Large B Cell Lymphoma Treated with Axicabtagene Ciloleucel (Axi-Cel)
Authors: Caron Jacobson, Frederick L. Locke, Armin Ghobadi, David B. Miklos, Lazaros J. Lekakis, Olalekan O. Oluwole, Yi Lin, Ira Braunschweig, Brian T. Hill, John M. Timmerman, Abhinav Deol, Patrick M. Reagan, Patrick J. Stiff, Ian W. Flinn, Umar Farooq, Andre H. Goy, Peter A. McSweeney, Javier Munoz, Tanya Siddiqi, John M. Rossi, Adrian Bot, Lianqing Zheng, Remus Vezan, Zahid Bashir, Jenny J. Kim, Rong Chu, Sattva S. Neelapu
Journal: Blood (2020)
Molecular Features and Functional Implications of Germline Variants in Triple-Negative Breast Cancer
Authors: Ding Ma, Si-Yu Chen, Jin-Xiao Ren, Yu-Chen Pei, Cong-Wei Jiang, Shen Zhao, Yi Xiao, Xiao-En Xu, Guang-Yu Liu, Xin Hu, Xiao-Zhen Liang, Ke-Da Yu, Da-Qiang Li, Yi-Zhou Jiang, Zhi-Ming Shao
Journal: JNCI Journal of the National Cancer Institute (2020)

The germline variant spectrum of triple-negative breast cancer (TNBC) is different from that of other subtypes and has demonstrated ethnic differences. However, the germline variants of TNBC among Chinese patients and its clinical significance remain unclear.Using our multi-omics TNBC cohort (n = 325), we determined the spectrum of germline variants in TNBC and aimed to illustrate their biological and clinical implications.Overall, 16.0% (52 of 325) of TNBC patients harbored at least 1 pathogenic or likely pathogenic germline variant. These germline variants were associated with early onset of TNBC, the occurrence of contralateral breast cancer, the basal-like immune-suppressed mRNA subtype, and the homologous recombination deficiency (HRD) mutation subtype. Somatic allele-specific imbalance was observed in 54.1% of these germline variants, which was correlated with early onset of breast cancer and elevated HRD. The genes BRCA1 (7.4%), RAD51D (2.8%), and BRCA2 (2.2%) were those most frequently mutated. The RAD51D germline variants, especially K91fs, were enriched in Chinese patients with TNBC compared with Caucasian and African American patients. The Chinese-specific RAD51D germline variants were functionally associated with the instability of the RAD51D protein, HRD, and sensitivity to PARP inhibitors.Chinese TNBC patients have a distinct spectrum of germline variants, with a remarkable impact on the clinical and molecular characteristics of the tumor. Integrative germline-somatic analysis may help identify TNBC patients who are most likely to be affected by their germline variants and in performing clinical interventions more precisely. The RAD51D variants enriched in our cohort may serve as therapeutic targets and guide precision treatment of TNBC.
Abstract 500: Impact of Oxidative Stress and Fancj on Heart Health
Authors: Kaitlin A Lowran, Mikayla McCarthy, Laura Campbell, Colin Wu
Journal: Circulation Research (2020)

G-quadruplexes (or G4s) are structures formed by guanine-rich nucleic acid sequences. G4s must be promptly unfolded in cells; otherwise, they can interfere with DNA replication, RNA transcription, and other essential processes. Guanines bases are susceptible to oxidative stress forming 8-oxoguanines (8oxoG). Although 8oxoG-modified DNA sequences can still fold into stable G4s, it is not known how 8oxoG4s are repaired in human cells. In our previous study, we have shown that the FANCJ DNA helicase targets G4s using an AKKQ amino acid motif. Here, we have examined the interactions of FANCJ with various 8oxoG4s using biolayer interferometry and fluorescence spectroscopy. We show that a FANCJ AKKQ peptide alone can recognize G4s with an affinity of 3.7uM. Moreover, this motif binds to 8oxoG4s with greater affinities of 1.3 to 2.3uM. A detailed description of the mechanisms by which 8oxoG4s are repaired is essential for understanding how human hearts respond to oxidative stress. To test the importance of FANCJ AKKQ-G4 interactions in cells, we measured the total extent of oxidative DNA damage in human cardiac cells by single-cell electrophoresis. Cells that overexpress FANCJ can readily overcome the chemical stress induced by hydrogen peroxide treatment and the G4-stabilizing compound telomestatin. On the contrary, cells that produce a FANCJ AAAQ mutant, which cannot interact with G4s, resulted in an accumulation of 8oxoG4s. Based on this evidence, FANCJ plays an important role to alleviate the damage caused by oxidative stress. In future experiments, we plan to further examine the cardiovascular risks of DNA damage caused by FANCJ malfunctions.
Comparison of Patient Outcomes with Two Different Formulations of Melphalan As Conditioning Chemotherapy for Autologous Stem Cell Transplantation in Multiple Myeloma
Authors: Filiz Yucebay, Ashleigh Keiter, Qiuhong Zhao, Alison Neal, Nita Williams, Nidhi Sharma, Francesca Cottini, Maria Chaudhry, Ashley Rosko, Don M. Benson, Yvonne A. Efebera, Naresh Bumma, Abdullah Khan, Srinivas Devarakonda
Journal: Blood (2020)
Liver X Receptor (LXR) Is a Novel and Reversible Regulator of Trauma-Induced Coagulopathy
Authors: Peter Einersen, Sanchayita Mitra, Reid Selby, Ernest E. Moore, Marguerite Kelher, Miguel Fragoso, Daran Schiller, Megan Swope, Geoffrey Nunns, Navin Vigneshwar, James Chandler, Arsen Ghasabayan, John Desisto, Bridget Sanford, Monika Dzieciatkowska, Linda Johnson, Mitchell J. Cohen, Angelo D'Alessandro, Erik Peltz, Anirban Banerjee, Kirk Hansen, Christopher C. Silliman, Kenneth Jones
Journal: Blood (2020)
Geographical Distance from Quaternary Treatment Center Does Not Impact Choice of Upfront Therapy, Clinical Trial Participation and Outcomes in Patients with Newly Diagnosed AML
Authors: Samantha A Hershenfeld, Steven M Chan, Vikas Gupta, Dawn Maze, Caroline J McNamara, Mark D. Minden, Tracy Murphy, Andre C. Schuh, Hassan Sibai, Karen W.L. Yee, Aaron D Schimmer
Journal: Blood (2020)
Prognostic Impact of the Latency Time from the Administration of Cytotoxic Therapy to the Development of Therapy-Related Myeloid Neoplasms
Authors: Claudia Nunez-Torron, Adolfo Saez, Berta Mercedes Michael Fernández, Irene Garcia-Garcia, Juan Marquet Palomanes, Miguel Piris-Villaespesa, Jesus Villarrubia, Valentín Garcia-Gutiérrez, Gemma Moreno Jiménez, Javier Lopez Jimenez, Pilar Herrera Puente
Journal: Blood (2020)
The Grndad Registry: Contemporary Natural History Data and an Analysis of Real-World Patterns of Use and Limitations of Disease Modifying Therapy in Adults with SCD
Authors: Alexandra Boye-Doe, Elizabeth Brown, Charu Puri-Sharma, Anjulika Chawla, Joshua J Field, Lynne D. Neumayr, Susan Padrino, Payal Desai, Deepa Manwani, Sophie M. Lanzkron, Jane A. Little
Journal: Blood (2020)
Myeloid Blast Crisis of Philadelphia Positive Chronic Myeloid Leukemia and Philadelphia Positive Acute Myeloid Leukemia Treated at the AP-HP in Paris: A Retrospective Analysis
Authors: Matteo Dragani, Rathana Kim, Clémence Loiseau, Madalina Uzunov, Felipe Suarez, Didier Bouscary, Philippe Rousselot, Etienne Lengline, Raphael Itzykson, Jean Michel Cayuela, Nicolas Boissel, Herve Dombret, Delphine Rea, Emmanuel Raffoux
Journal: Blood (2020)
Assessment of Measurable Residual Disease (MRD) in Chronic Lymphocytic Leukemia (CLL) and Multiple Myeloma (MM) Among U.S. Community Hematologists/ Oncologists (cH/O)
Authors: Ajeet Gajra, Yamini S Rathish, Yolaine Jeune-Smith, Andrew J Klink, Bruce Feinberg
Journal: Blood (2020)
Physicians' Experience in Blood Supply Shortages and the Top Factors That Impact the Clinical, Economic, and Humanistic Outcomes of Myelodysplastic Syndrome (MDS) Patients in 5 European Countries
Authors: Shaloo Gupta, Thomas Schroeder, Austin Kulasekararaj, Halley Constantino, Jay Grisolano, Jackson Tang, Shalon Jones, Derek Tang
Journal: Blood (2020)
Treatment Outcome for Symptomatic Patients with Clonal Cytopenia of Undetermined Significance: A Single-Institution Retrospective Study
Authors: Zhuoer Xie, Ahmad Nanaa, Antoine Saliba, Rong He, Phuong L. Nguyen, Dragan Jevremovic, Patricia Greipp, Mohamed Salama, Naseema Gangat, Hassan B. Alkhateeb, Ayalew Tefferi, Mark Litzow, Mrinal M. Patnaik, Mithun Vinod Shah, Aref Al-Kali
Journal: Blood (2020)
Abstract 519: Talin is Required for Normal Adult Heart Function
Authors: Yoshitake Cho, Ruixia Li, Ana M Manso, Robert S Ross
Journal: Circulation Research (2020)

Talin (Tln) is a component of muscle costameres that links integrins to other components of the cellular cytoskeleton and plays an important role in maintaining the cellular integrity of cardiac myocytes (CM). There are two talin genes, Tln1 and Tln2, expressed in the heart. Tln1 is ubiquitously expressed, and Tln2 is dominantly expressed in CM. In our previous study, we show that the global deletion of Tln2 in mice (T2KO) caused no structural or functional changes in the heart, presumably because CM Tln1 became up-regulated. However, we found that mice lacking both CM Tln1 and Tln2 exhibit cardiac dysfunction by 4 weeks (w) of age with 100% mortality by 6 months (m), showing Tln plays an essential role in cardiac development and in maintaining cardiac function. In this study, we produced a tamoxifen (Tamo)-inducible mouse model in which Tln1 could be explicitly reduced in the adult CM (T1icKO), and then generate T1icKO:T2KO (T1/2dKO), so that the function of Tln could be assessed in the postnatal heart. T2KO and Tln1/2dKO mice were injected with Tamo at 8w. Echocardiograms were performed to evaluate cardiac function up to 8w post-Tamo injection. While T2KO mice showed normal cardiac function, T1/2dKO exhibited a gradual decrease in function post-Tamo injection. At 8w post-Tamo injection, T1/2dKO mice showed cardiac hypertrophy, fibrosis, and heart failure. To understand the mechanism by which deletion CM talin leads to cardiac dysfunction, left ventricular tissue protein lysates from T2KO and T1/2dKO mice at 4w post-Tamo when cardiac function (echo) and structure were preserved in dKO. The protein lysates were subjected to quantitative mass spectrometry analysis. We found there are 1,100 proteins differentially expressed in T2KO and T1/2dKO hearts. Pathway analysis was performed, and the results showed that proteins involved in vesicle transport, protein folding, and innate immunity are most up-regulated in the T1/2dKO heart. Taken together, our results show that Tln is required for maintaining proper cardiac function in the adult heart. The deletion of Tln in CM results in the up-regulation of multiple intracellular pathways, and we are currently studying the role of each pathway in the pathogenesis of heart failure induced by CM Tln deletion.
Outcomes of Patients with <i>CRLF2</i>-Overexpressing Acute Lymphoblastic Leukemia without Down Syndrome: A Report from the Children's Oncology Group
Authors: Sarah K Tasian, Yunfeng Dai, Meenakshi Devidas, Kathryn G Roberts, Richard C Harvey, I-Ming L Chen, Andrew J Carroll, Nyla A Heerema, Shalini C Reshmi, Julie M Gastier-Foster, Michael J Borowitz, Brent L Wood, Charles G Mullighan, Cheryl L Willman, Kelly W Maloney, Eric C Larsen, Anne L Angiolillo, Reuven J Schore, Michael J Burke, Wanda L Salzer, Naomi J Winick, William L. Carroll, Stephen P Hunger, Elizabeth A. Raetz, Karen R Rabin, Mignon L. Loh
Journal: Blood (2020)
Salicylates enhance CRM1 inhibitor antitumor activity by induction of S-phase arrest and impairment of DNA-damage repair
Authors: Jithma P. Abeykoon, Xiaosheng Wu, Kevin E. Nowakowski, Surendra Dasari, Jonas Paludo, S. John Weroha, Chunling Hu, Xiaonan Hou, Jann N. Sarkaria, Ann C. Mladek, Jessica L. Phillips, Andrew L. Feldman, Aishwarya Ravindran, Rebecca L. King, Justin Boysen, Mary J. Stenson, Ryan M. Carr, Michelle K. Manske, Julian R. Molina, Prashant Kapoor, Sameer A. Parikh, Shaji Kumar, Steven I. Robinson, Jia Yu, Judy C. Boughey, Liewei Wang, Matthew P. Goetz, Fergus J. Couch, Mrinal M. Patnaik, Thomas E. Witzig
Journal: Blood (2020)
Improving Evaluation of Disease Burden at Diagnosis in Hodgkin Lymphoma
Authors: Ines Herraez, Leyre Bento, Jaume Daumal, Alessandra Repetto, Raquel Del Campo, Adriana Sas, Rafael Ramos, Javier Ibarra, Francesc Mestre, Joan Bargay, Antonia Sampol, Antonio Gutierrez
Journal: Blood (2020)
Comparison of Emapalumab with Conventional Treatment in Patients with Primary Hemophagocytic Lymphohistiocytosis (HLH): Consistent Results Obtained in an Unadjusted and an Adjusted Analysis
Authors: Sarah Dewilde, Emilia Nivelle, Alison Griffiths, Koo Wilson, Jameel Nazir, Michal Pochopien, Franco Locatelli
Journal: Blood (2020)
DNA Methylation Analysis before and during Treatment with Azacitidine Plus Pevonedistat or Azacitidine Alone in Patients with MDS, CMML, and AML Previously Untreated with Hypomethylating Agents
Authors: Soo Park, Brian M Reilly, Timothy Luger, Dan Zhao, Robert J. Fram, Ajeeta B Dash, Rafael Bejar
Journal: Blood (2020)
<i>Therapy Related Myeloid Neoplasm Post PARP Inhibitors: Potential Clonal Selection.</i>
Authors: Jean-Edouard Martin, Sabine Khalife-Hachem, Thomas Grinda, Maria Kfoury, Sylvain Garciaz, Florence Pasquier, Jacques Vargaftig, Madalina Uzunov, Amine Belhabri, Sarah Bertoli, Nathalie Auger, Veronique Saada, Christel Guillouf, Iléana Antony-Debre, Etienne Rouleau, Flore Salviat, Olivier Caron, Patricia Pautier, Gabriel Etienne, Norbert Vey, Filippo Rosselli, Stephane De Botton, Alexandra Leary, Christophe Marzac, Jean-Baptiste Micol
Journal: Blood (2020)
<i>BCL2A1</i>: A Novel Target in Refractory Acute Myeloid Leukemia with <i>FLT3</i>-ITD/D835 Dual Mutations
Authors: Kotoko Yamatani, Tomohiko Ai, Kaori Saito, Haeun Yang, Vivian Ruvolo, Po Yee Mak, Sonoko Kinjo, Kazuho Ikeo, Hironori Harada, Kazuhiro Katayama, Takashi Miida, Marina Konopleva, Weiguo Zhang, Bing Z Carter, Yoshihide Hayashizaki, Michael Andreeff, Yoko Tabe
Journal: Blood (2020)
Covalent modification of Keap1 at Cys77 and Cys434 by pubescenoside a suppresses oxidative stress-induced NLRP3 inflammasome activation in myocardial ischemia-reperfusion injury
Authors: Yuanyuan Cheng, Liangkai Cheng, Xiang Gao, Sixuan Chen, Peng Wu, Caiyan Wang, Zhongqiu Liu
Journal: Theranostics (2020)

Background and Purpose: Kelch ECH-associating protein 1 (Keap1) is a crucial chaperonin for E3 ubiquitin ligases. Modification of the key reactive cysteine residues in Keap1 affects the interaction between Keap1 and its substrate nuclear factor erythroid 2-related factor 2 (Nrf2), subsequently regulating oxidative stress and NLPR3 inflammasome activation, which are important factors for myocardial ischemia-reperfusion injury (MI/RI). Pubescenoside A (PBA), an active compound from Ilex pubescens, has antithrombotic and anti-inflammatory effects. However, the effect of PBA on MI/RI is still unknown. In the present study, we aimed to determine whether PBA can protect the heart against MI/RI and clarify the direct target and the underlying mechanism of PBA. Methods: The left anterior descending artery (LAD) ligation-induced MI/RI mice model or oxygen and glucose deprivation/reperfusion (OGD/R) were used to evaluate the cardioprotective effect of PBA. Pull-down assays, co-immunoprecipitation (Co-IP) assays, LC/MS/MS, isothermal calorimetry (ITC) experiments and covalent docking were used to identify the target of PBA. Results: PBA protected cardiomyocytes against OGD/R in vitro and LAD-induced MI/RI in vivo. PBA suppressed NLRP3 inflammation activation and induced the Nrf2 signaling pathway. Interestingly, PBA targeted Keap1 by selectively covalently binding to conserved cysteine residues, cysteine 77 (Cys77) in the BTB domain and cysteine 434 (Cys434) in the Kelch domain of Keap1, subsequently inhibiting ubiquitination of Nrf2 and activating antioxidant enzymes. Additionally, the cysteines of Keap1 has different degree of activation by PBA as follows: Cys77 > Cys434 > Cys23 > Cys38 > Cys226 > Cys273, which further elucidates the cysteine sensitivity of Keap1. Conclusions: Our results indicated that PBA might be a new Nrf2 activator that covalently binds to two critical domains of Keap1, and shows cardioprotective activities against ischemia-reperfusion injury.
Efficacy of Selinexor Based Regimens in Relapsed Refractory Multiple Myeloma: A Systematic Review
Authors: Farhan Khalid, Mydah Sajid Hashmi, Muhammad Tayyeb, Ali Jaan, Zahoor Ahmed, Abdul Jabbar Dar, Sobia Aamir, Qasim Khurshid, Richi Kashyap, Israr Khan, Saif Ur Rehman, Hamid Ehsan, Faiz Anwer
Journal: Blood (2020)