tbuckley/cabot-search huggingface dataset:
KAT6A and ENL Form an Epigenetic Transcriptional Control Module to Drive Critical Leukemogenic Gene-Expression Programs
Authors: Fangxue Yan, Jinyang Li, Jelena Milosevic, Ricardo Petroni, Suying Liu, Zhennan Shi, Salina Yuan, Janice M. Reynaga, Yuwei Qi, Joshua Rico, Sixiang Yu, Yiman Liu, Susumu Rokudai, Neil Palmisiano, Sara E. Meyer, Pamela J. Sung, Liling Wan, Fei Lan, Benjamin A. Garcia, Ben Z. Stanger, David B. Sykes, M. Andrés Blanco
Journal: Cancer Discovery (2021)

Abstract Epigenetic programs are dysregulated in acute myeloid leukemia (AML) and help enforce an oncogenic state of differentiation arrest. To identify key epigenetic regulators of AML cell fate, we performed a differentiation-focused CRISPR screen in AML cells. This screen identified the histone acetyltransferase KAT6A as a novel regulator of myeloid differentiation that drives critical leukemogenic gene-expression programs. We show that KAT6A is the initiator of a newly described transcriptional control module in which KAT6A-catalyzed promoter H3K9ac is bound by the acetyl-lysine reader ENL, which in turn cooperates with a network of chromatin factors to induce transcriptional elongation. Inhibition of KAT6A has strong anti-AML phenotypes in vitro and in vivo, suggesting that KAT6A small-molecule inhibitors could be of high therapeutic interest for mono-therapy or combinatorial differentiation-based treatment of AML. Significance: AML is a poor-prognosis disease characterized by differentiation blockade. Through a cell-fate CRISPR screen, we identified KAT6A as a novel regulator of AML cell differentiation. Mechanistically, KAT6A cooperates with ENL in a “writer–reader” epigenetic transcriptional control module. These results uncover a new epigenetic dependency and therapeutic opportunity in AML. This article is highlighted in the In This Issue feature, p. 587
CHARACTERISTICS AND OUTCOMES OF BACTEREMIA IN PATIENTS WITH CARDIOGENIC SHOCK ON TEMPORARY MECHANICAL CIRCULATORY SUPPORT
Authors: Raunak M. Nair, Sachin Kumar, Talha Saleem, Adil Vural, Hassan Mehmood Lak, Andrew Higgins, Ran Lee, Paul Cremer, Penelope Rampersad, Venu Menon
Journal: Journal of the American College of Cardiology (2022)
VALIDATION OF 2021 ESC GUIDELINE RECOMMENDATIONS FOR CARDIAC PACING IN PREEXISTING RBBB PATIENTS UNDERGOING TAVI WITH A BALLOON-EXPANDABLE VALVE
Authors: Toshiaki Isogai, Iryna Dykun, Ankit Agrawal, Shashank Shekhar, Khaldoun G. Tarakji, Oussama M. Wazni, Ankur Kalra, Amar Krishnaswamy, Grant W. Reed, Samir R. Kapadia, Rishi Puri
Journal: Journal of the American College of Cardiology (2022)
INCREASED MORTALITY AND WORSE CARDIAC OUTCOME OF ACUTE MYOCARDIAL INFARCTION IN THE COVID-19 PATIENTS
Authors: Oktafin Srywati Pamuna, Muhamad Rizki Fadlan, Indra Prasetya, Setyasih Anjarwani, M. Saifur Rohman
Journal: Journal of the American College of Cardiology (2022)
Association of Patient-Reported Outcomes With Subsequent Nonfatal Self-injury After a New Cancer Diagnosis
Authors: Julie Hallet, Rinku Sutradhar, Elie Isenberg-Grzeda, Christopher W. Noel, Alyson L. Mahar, Simone N. Vigod, James Bolton, Julie Deleemans, Wing C. Chan, Natalie G. Coburn, Antoine Eskander, Barbara Haas, Stephanie Mason, Nicole Look-Hong, Janet Ellis, Lesley Goltib Conn, Karen Fergus, Craig Earle, Kiersty Hong
Journal: JAMA Oncology (2022)

Nonfatal self-injury (NFSI) is a patient-centered manifestation of severe distress occurring in 3 out of 1000 patients after cancer diagnosis. How to identify patients at risk for NFSI remains unknown.To examine the associations between patient-reported outcome measures and subsequent NFSI in patients with cancer.This population-based matched case-control study included adults with a new cancer diagnosis reporting an Edmonton Symptom Assessment System (ESAS) score within 36 months of diagnosis in Ontario, Canada, 2007 to 2019. Data analysis was performed January 2007 to December 2019.Cases included patients with NFSI, and controls were patients without NFSI. Cases and controls were matched 1:4. Multivariable conditional logistic regression assessed the association between moderate to severe ESAS symptom scores and total ESAS (t-ESAS, range 0-90) score with NFSI in the subsequent 180 days.Of 408 858 patients reporting 1 or more ESAS assessments, 425 patients experienced NFSI and reported an ESAS score in the preceding 180 days. Of those, 406 cases were matched to 1624 control patients without an NFSI. Cases reported a higher proportion of moderate to severe symptoms and higher t-ESAS score than controls prior to the event. After adjustment, moderate to severe anxiety (odds ratio [OR], 1.61; 95% CI, 1.14-2.27), depression (OR, 1.66; 95% CI, 1.20-2.31), and shortness of breath (OR, 1.65; 95% CI, 1.18-2.31) and each 10-point increase in t-ESAS score (OR, 1.51; 95% CI, 1.40-1.63) were independently associated with higher odds of subsequent NFSI.In this case-control study, reporting moderate to severe anxiety, depression, and shortness of breath and an increasing t-ESAS score after cancer diagnosis were associated with higher odds of NFSI in the following 180 days. These data support the prospective use of routine ESAS screening as a means of identifying patients at higher risk for NFSI to improve supportive care.
Effectiveness and safety of pulse oximetry in remote patient monitoring of patients with COVID-19: a systematic review
Authors: Ahmed Alboksmaty, Thomas Beaney, Sarah Elkin, Jonathan M Clarke, Ara Darzi, Paul Aylin, Ana-Luísa Neves
Journal: The Lancet Digital Health (2022)

The COVID-19 pandemic has led health systems to increase the use of tools for monitoring and triaging patients remotely. In this systematic review, we aim to assess the effectiveness and safety of pulse oximetry in remote patient monitoring (RPM) of patients at home with COVID-19. We searched five databases (MEDLINE, Embase, Global Health, medRxiv, and bioRxiv) from database inception to April 15, 2021, and included feasibility studies, clinical trials, and observational studies, including preprints. We found 561 studies, of which 13 were included in our narrative synthesis. These 13 studies were all observational cohorts and involved a total of 2908 participants. A meta-analysis was not feasible owing to the heterogeneity of the outcomes reported in the included studies. Our systematic review substantiates the safety and potential of pulse oximetry for monitoring patients at home with COVID-19, identifying the risk of deterioration and the need for advanced care. The use of pulse oximetry can potentially save hospital resources for patients who might benefit the most from care escalation; however, we could not identify explicit evidence for the effect of RPM with pulse oximetry on health outcomes compared with other monitoring models such as virtual wards, regular monitoring consultations, and online or paper diaries to monitor changes in symptoms and vital signs. Based on our findings, we make 11 recommendations across the three Donabedian model domains and highlight three specific measurements for setting up an RPM system with pulse oximetry.
CORONARY MICROVASCULAR DYSFUNCTION IS AN INDEPENDENT PREDICTOR OF DEVELOPING CANCER IN PATIENTS WITH NON-OBSTRUCTIVE CORONARY ARTERY DISEASE (NOCAD)
Authors: Nazanin Rajai, Ali Ahmad, Takumi Toya, Lilach O. Lerman, Joerg Herrmann, Amir Lerman
Journal: Journal of the American College of Cardiology (2022)
CARDIAC MASS AND INTERMITTENT COMPLETE HEART BLOCK DUE TO GRANULOMATOSIS WITH POLYANGIITIS
Authors: Amrita Balgobind, Peter Vlismas, Eric P. Stahl, Leah Traube, Jeffrey M. Levsky, Perry Cohen, Azeem Latib, Ulrich P. Jorde, Shivank Madan
Journal: Journal of the American College of Cardiology (2022)
RESCUE THERAPY OF LATE ANTIBODY-MEDIATED REJECTION WITH SEVERE GRAFT DYSFUNCTION
Authors: Piyachat Pipatpongsopon, Bundit Naratreekoon, Pimpin Incharoen, Duangtawan Thammanichanond, Teerapat Yingchoncharoen, Narongrit Kanthatat, Mann Chandavimol, Piya Samankatiwat
Journal: Journal of the American College of Cardiology (2022)
Addressing dyslipidemic risk beyond LDL-cholesterol
Authors: Alan R. Tall, David G. Thomas, Ainara G. Gonzalez-Cabodevilla, Ira J. Goldberg
Journal: Journal of Clinical Investigation (2022)

Despite the success of LDL-lowering drugs in reducing cardiovascular disease (CVD), there remains a large burden of residual disease due in part to persistent dyslipidemia characterized by elevated levels of triglyceride-rich lipoproteins (TRLs) and reduced levels of HDL. This form of dyslipidemia is increasing globally as a result of the rising prevalence of obesity and metabolic syndrome. Accumulating evidence suggests that impaired hepatic clearance of cholesterol-rich TRL remnants leads to their accumulation in arteries, promoting foam cell formation and inflammation. Low levels of HDL may associate with reduced cholesterol efflux from foam cells, aggravating atherosclerosis. While fibrates and fish oils reduce TRL, they have not been uniformly successful in reducing CVD, and there is a large unmet need for new approaches to reduce remnants and CVD. Rare genetic variants that lower triglyceride levels via activation of lipolysis and associate with reduced CVD suggest new approaches to treating dyslipidemia. Apolipoprotein C3 (APOC3) and angiopoietin-like 3 (ANGPTL3) have emerged as targets for inhibition by antibody, antisense, or RNAi approaches. Inhibition of either molecule lowers TRL but respectively raises or lowers HDL levels. Large clinical trials of such agents in patients with high CVD risk and elevated levels of TRL will be required to demonstrate efficacy of these approaches.
HSR22-177: Real-World Utilization of Lenvatinib+Pembrolizumab Combination Therapy for the Treatment of Advanced Endometrial Cancer in the United States: ENdometrial cancer DOsing in the real-World (ENDOW) Study
Authors: Keiko Wada, Vimalanand Prabhu, Yi Wang, Jingchuan Zhang
Journal: Journal of the National Comprehensive Cancer Network (2022)

"HSR22-177: Real-World Utilization of Lenvatinib+Pembrolizumab Combination Therapy for the Treatment of Advanced Endometrial Cancer in the United States: ENdometrial cancer DOsing in the real-World (ENDOW) Study" published on 31 Mar 2022 by National Comprehensive Cancer Network.
FIBRIN TARGETED PHASE SHIFT MICROBUBBLES FOR THE TREATMENT OF MICROVASCULAR OBSTRUCTION
Authors: Soheb Anwar Mohammed, Muhammad Wahab Amjad, Xucai Chen, Maria F. Acosta, Dillon Hanrahan, Evan C. Unger, Emmanuelle J. Meuillet, John J. Pacella
Journal: Journal of the American College of Cardiology (2022)
A Pragmatic, Stepped-Wedge, Cluster-controlled Clinical Trial of Real-Time Pneumonia Clinical Decision Support
Authors: Nathan C. Dean, Caroline G. Vines, Jason R. Carr, Jenna G. Rubin, Brandon J. Webb, Jason R. Jacobs, Allison M. Butler, Jaehoon Lee, Al R. Jephson, Nathan Jenson, Missy Walker, Samuel M. Brown, Jeremy A. Irvin, Matthew P. Lungren, Todd L. Allen
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Care of emergency department (ED) patients with pneumonia can be challenging. Clinical decision support may decrease unnecessary variation and improve care. Objectives: To report patient outcomes and processes of care after deployment of electronic pneumonia clinical decision support (ePNa): a comprehensive, open loop, real-time clinical decision support embedded within the electronic health record. Methods: We conducted a pragmatic, stepped-wedge, cluster-controlled trial with deployment at 2-month intervals in 16 community hospitals. ePNa extracts real-time and historical data to guide diagnosis, risk stratification, microbiological studies, site of care, and antibiotic therapy. We included all adult ED patients with pneumonia over the course of 3 years identified by International Classification of Diseases, 10th Revision discharge coding confirmed by chest imaging. Measurements and Main Results: The median age of the 6,848 patients was 67 years (interquartile range, 50–79), and 48% were female; 64.8% were hospital admitted. Unadjusted mortality was 8.6% before and 4.8% after deployment. A mixed effects logistic regression model adjusting for severity of illness with hospital cluster as the random effect showed an adjusted odds ratio of 0.62 (0.49–0.79; P < 0.001) for 30-day all-cause mortality after deployment. Lower mortality was consistent across hospital clusters. ePNa-concordant antibiotic prescribing increased from 83.5% to 90.2% (P < 0.001). The mean time from ED admission to first antibiotic was 159.4 (156.9–161.9) minutes at baseline and 150.9 (144.1–157.8) minutes after deployment (P < 0.001). Outpatient disposition from the ED increased from 29.2% to 46.9%, whereas 7-day secondary hospital admission was unchanged (5.2% vs. 6.1%). ePNa was used by ED clinicians in 67% of eligible patients. Conclusions: ePNa deployment was associated with improved processes of care and lower mortality. Clinical trial registered with www.clinicaltrials.gov (NCT03358342).
PREDICTORS OF OUTCOMES OF TRANSCATHETER AORTIC VALVE IMPLANTATION IN PATIENTS WITH AORTIC INSUFFICIENCY
Authors: Abdul-Rahman M. Suleiman, Heba Osman, Adam Chalek, Chaitu Dandu, Mohamed Zghouzi, Waqas Ullah, Parveen Razvi, Yasar Sattar, Carlos Oveido, Nada Elmakshbr, Rashid Alhusain, Nasser M. Lakkis, M. Chadi Alraies
Journal: Journal of the American College of Cardiology (2022)
NOV-INVASIVE AND AUTOMATED MEASUREMENT OF EJECTION FRACTION USING MACHINE LEARNING ALGORITHMS ON CARDIAC ACOUSTIC SIGNALS: A COMPARISON WITH ECHOCARDIOGRAPHY
Authors: Kimberly Howard-Quijano, Kanav Saraf, Per H. Borgstrom, Christopher I. Baek, Michael Wasko, Xu Zhang, Yi Zheng, Samir F. Saba, William Kaiser, Aman Mahajan
Journal: Journal of the American College of Cardiology (2022)
Abstract P3-09-17: Systems-scale characterization of the human immunome in breast cancer for precision medicine
Authors: Stephen Yi
Journal: Cancer Research (2022)

Abstract It becomes more clear that many deleterious cancer mutations could exhibit a 'gain-of-function' (GOF) behavior. Systematic investigation of such mutations has been lacking and largely overlooked. Advances in next-generation sequencing have identified thousands of genomic variants that perturb the normal functions of proteins, further contributing to diverse phenotypic consequences in breast cancer. Alterations in immune-related pathways are common hallmarks of cancer. A comprehensive understanding of how cancer mutations rewire immune signaling networks and functional output in breast cancer is instrumental to realize the full potential of immunotherapy. Here, we systematically interrogated somatic mutations involved in immune signaling that alter immune responses in cancer patients. To do so, we developed a network-based integrative model to prioritize potential immune responder genes. Identified mutations were enriched in essential protein domains and genes identified were associated with responsiveness to multiple immunotherapy modalities. These genes were used to devise an interactome network propagation framework integrated with drug-associated gene signatures to identify potential immunomodulatory drug candidates in breast cancer. Together, our systems-level analysis results help interpret the heterogeneous immune responses among patients and serve as a resource for future functional studies and targeted breast cancer therapeutics. This study is significant and innovative, as it demonstrates that integration of multi-omics data can help identify critical molecular determinants for effective targeted therapeutics. Citation Format: Stephen Yi. Systems-scale characterization of the human immunome in breast cancer for precision medicine [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-09-17.
Inferring transmission fitness advantage of SARS-CoV-2 variants of concern from wastewater samples using digital PCR, Switzerland, December 2020 through March 2021
Authors: Lea Caduff, David Dreifuss, Tobias Schindler, Alexander J Devaux, Pravin Ganesanandamoorthy, Anina Kull, Elyse Stachler, Xavier Fernandez-Cassi, Niko Beerenwinkel, Tamar Kohn, Christoph Ort, Timothy R Julian
Journal: Eurosurveillance (2022)

BackgroundThroughout the COVID-19 pandemic, SARS-CoV-2 genetic variants of concern (VOCs) have repeatedly and independently arisen. VOCs are characterised by increased transmissibility, increased virulence or reduced neutralisation by antibodies obtained from prior infection or vaccination. Tracking the introduction and transmission of VOCs relies on sequencing, typically whole genome sequencing of clinical samples. Wastewater surveillance is increasingly used to track the introduction and spread of SARS-CoV-2 variants through sequencing approaches.AimHere, we adapt and apply a rapid, high-throughput method for detection and quantification of the relative frequency of two deletions characteristic of the Alpha, Beta, and Gamma VOCs in wastewater.MethodsWe developed drop-off RT-dPCR assays and an associated statistical approach implemented in the R package WWdPCR to analyse temporal dynamics of SARS-CoV-2 signature mutations (spike Δ69-70 and ORF1a Δ3675-3677) in wastewater and quantify transmission fitness advantage of the Alpha VOC.ResultsBased on analysis of Zurich wastewater samples, the estimated transmission fitness advantage of SARS-CoV-2 Alpha based on the spike Δ69-70 was 0.34 (95% confidence interval (CI): 0.30-0.39) and based on ORF1a Δ3675-3677 was 0.53 (95% CI: 0.49-0.57), aligning with the transmission fitness advantage of Alpha estimated by clinical sample sequencing in the surrounding canton of 0.49 (95% CI: 0.38-0.61).ConclusionDigital PCR assays targeting signature mutations in wastewater offer near real-time monitoring of SARS-CoV-2 VOCs and potentially earlier detection and inference on transmission fitness advantage than clinical sequencing.
IL-1 and IL-1ra are key regulators of the inflammatory response to RNA vaccines
Authors: Siri Tahtinen, Ann-Jay Tong, Patricia Himmels, Jaehak Oh, Andres Paler-Martinez, Leesun Kim, Sara Wichner, Yoko Oei, Mark J. McCarron, Emily C. Freund, Zhainib Adel Amir, Cecile C. de la Cruz, Benjamin Haley, Craig Blanchette, Jill M. Schartner, Weilan Ye, Mahesh Yadav, Ugur Sahin, Lélia Delamarre, Ira Mellman
Journal: Nature Immunology (2022)
DEEP PHENOTYPING BY MACHINE LEARNING OF PARTICIPANTS IN THE SYSTOLIC BLOOD PRESSURE INTERVENTION TRIAL (SPRINT)
Authors: Nuha Gani, Gauri Dandi, Zyannah Mallick, Chirag Nagpal, Areeb Gani, Anwar Husain, Yves Rosenberg, Ahmed A.K. Hasan
Journal: Journal of the American College of Cardiology (2022)
Necroptosis-driving genes<i>RIPK1, RIPK3</i>and<i>MLKL-p</i>are associated with intratumoral CD3<sup>+</sup>and CD8<sup>+</sup>T cell density and predict prognosis in hepatocellular carcinoma
Authors: Lorenzo Nicolè, Tiziana Sanavia, Rocco Cappellesso, Valeria Maffeis, Jun Akiba, Akihiko Kawahara, Yoshiki Naito, Claudia Maria Radu, Paolo Simioni, Davide Serafin, Giuliana Cortese, Maria Guido, Giacomo Zanus, Hirohisa Yano, Ambrogio Fassina
Journal: Journal for ImmunoTherapy of Cancer (2022)

Hepatocellular carcinoma (HCC) is a highly lethal cancer and the second leading cause of cancer-related deaths worldwide. As demonstrated in other solid neoplasms and HCC, infiltrating CD8
ASSOCIATION BETWEEN SYSTEMIC VASCULITIS AND CORONARY MICROVASCULAR DYSFUNCTION IN THE ABSENCE OF OBSTRUCTIVE CORONARY ARTERY DISEASE
Authors: Brittany Weber, Zachary Wallace, Sean Parks, Claire Cook, Dan Huck, Jenifer Brown, Sanjay Divakaran, Jon Mark Hainer, Courtney Foster Bibbo, Viviany R. Taqueti, Sharmila Dorbala, Ron Blankstein, Katherine P. Liao, Ayaz Aghayev, Hyon K. Choi, Marcelo F. Di Carli
Journal: Journal of the American College of Cardiology (2022)
A CASE OF MAY-THURNER SYNDROME WITH DEEP VENOUS THROMBOSIS MANAGED WITH CATHETER-DIRECTED THROMBOLYSIS
Authors: Muhammad Faraz Anwaar, Veena Gujju, Jehanzeb Khan, Heyyan Bin Khalil, Satyam Krishan, Beau Michael Hawkins
Journal: Journal of the American College of Cardiology (2022)
Impact of the Omicron variant on SARS-CoV-2 reinfections in France, March 2021 to February 2022
Authors: Jonathan Bastard, Benjamin Taisne, Julie Figoni, Alexandra Mailles, Julien Durand, Myriam Fayad, Laurence Josset, Anna Maisa, Sylvie van der Werf, Isabelle Parent du Châtelet, Sibylle Bernard-Stoecklin
Journal: Eurosurveillance (2022)

Since the first reports in summer 2020, SARS-CoV-2 reinfections have raised concerns about the immunogenicity of the virus, which will affect SARS-CoV-2 epidemiology and possibly the burden of COVID-19 on our societies in the future. This study provides data on the frequency and characteristics of possible reinfections, using the French national COVID-19 testing database. The Omicron variant had a large impact on the frequency of possible reinfections in France, which represented 3.8% of all confirmed COVID-19 cases since December 2021.
COVID-19 Cases and Disease Severity in Pregnancy and Neonatal Positivity Associated With Delta (B.1.617.2) and Omicron (B.1.1.529) Variant Predominance
Authors: Emily H. Adhikari, Lorre MacDonald, Jeffrey A. SoRelle, Jessica Morse, Jessica Pruszynski, Catherine Y. Spong
Journal: JAMA (2022)

Deshayne B. Fell, PhD; Tavleen Dhinsa, MSc; Gillian D. Alton, PhD; Eszter Török, PhD; Sheryll Dimanlig-Cruz, MSc; Annette K. Regan, PhD; Ann E. Sprague, PhD; Sarah A. Buchan, PhD; Jeffrey C. Kwong, MD; Sarah E. Wilson, MD; Siri E. Håberg, MD, PhD; Christopher A. Gravel, PhD; Kumanan Wilson, MD; Darine El-Chaâr, MD; Mark C. Walker, MD; Jon Barrett, MD; Shannon E. MacDonald, PhD; Nannette Okun, MD; Prakesh S. Shah, MD; Shelley D. Dougan, MSc; Sandra Dunn, PhD; Lise Bisnaire, PhD
COMPLETENESS OF HEMODYNAMIC PROFILING IN THE CATHETERIZATION LABORATORY AMONG POST-MYOCARDIAL INFARCTION CARDIOGENIC SHOCK PATIENTS IS ASSOCIATED WITH IMPROVED IN-HOSPITAL MORTALITY
Authors: Hamza Ouazani Chahdi, Juliette Beaulieu, Chloé Moazzami, Laurie-Anne Boivin-Proulx, Alexis Matteau, Samer Mansour, E. Marc Jolicoeur, François Gobeil, Brian J. Potter
Journal: Journal of the American College of Cardiology (2022)
LC3-associated phagocytosis in bone marrow macrophages suppresses acute myeloid leukemia progression through STING activation
Authors: Jamie A. Moore, Jayna J. Mistry, Charlotte Hellmich, Rebecca H. Horton, Edyta E. Wojtowicz, Aisha Jibril, Matthew Jefferson, Thomas Wileman, Naiara Beraza, Kristian M. Bowles, Stuart A. Rushworth
Journal: Journal of Clinical Investigation (2022)

The bone marrow (BM) microenvironment regulates acute myeloid leukemia (AML) initiation, proliferation, and chemotherapy resistance. Following cancer cell death, a growing body of evidence suggests an important role for remaining apoptotic debris in regulating the immunologic response to and growth of solid tumors. Here, we investigated the role of macrophage LC3-associated phagocytosis (LAP) within the BM microenvironment of AML. Depletion of BM macrophages (BMMs) increased AML growth in vivo. We show that LAP is the predominate method of BMM phagocytosis of dead and dying cells in the AML microenvironment. Targeted inhibition of LAP led to the accumulation of apoptotic cells (ACs) and apoptotic bodies (ABs), resulting in accelerated leukemia growth. Mechanistically, LAP of AML-derived ABs by BMMs resulted in stimulator of IFN genes (STING) pathway activation. We found that AML-derived mitochondrial damage-associated molecular patterns were processed by BMMs via LAP. Moreover, depletion of mitochondrial DNA (mtDNA) in AML-derived ABs showed that it was this mtDNA that was responsible for the induction of STING signaling in BMMs. Phenotypically, we found that STING activation suppressed AML growth through a mechanism related to increased phagocytosis. In summary, we report that macrophage LAP of apoptotic debris in the AML BM microenvironment suppressed tumor growth.
HYPERTROPHIC CARDIOMYOPATHY COMPLICATED BY REFRACTORY ELECTRICAL STORM
Authors: Hiroki Nakayama, Junya Komatsu, Yuki Nishimura, Hiroki Sugane, Hayato Hosoda, Ryuichiro Imai, Yoko Nakaoka, Koji Nishida, Shuichi Seki, Shoichi Kubokawa, Masahiko Fukatani, Kazuya Kawai, Naohisa Hamashige, Yoshinori L. Doi
Journal: Journal of the American College of Cardiology (2022)