tbuckley/cabot-search huggingface dataset:
SAFETY AND EFFICACY OF DPP4 INHIBITORS IN ACUTE MYOCARDIAL INFARCTION: A BIOMARKER DRIVEN DOUBLE-BLINDED RANDOMIZED CONTROLLED TRIAL
Authors: Paulo Rizzo Genestreti, Remo Furtado, Rocío Salsoso, Talia Dalcoquio, Carlos Nakashima, Viviane Lima, Raiza Colodetti, Aline Ferrari, Andre Franci, Fernando Menezes, Luciano Baracioli, Jose Nicolau
Journal: Journal of the American College of Cardiology (2021)
Immunoglobulin A–specific deficiency induces spontaneous inflammation specifically in the ileum
Authors: Takashi Nagaishi, Taro Watabe, Kunihiko Kotake, Toshihiko Kumazawa, Tomomi Aida, Kohichi Tanaka, Ryuichi Ono, Fumitoshi Ishino, Takako Usami, Takamasa Miura, Satomi Hirakata, Hiroko Kawasaki, Naoya Tsugawa, Daiki Yamada, Kazuhiro Hirayama, Soichiro Yoshikawa, Hajime Karasuyama, Ryuichi Okamoto, Mamoru Watanabe, Richard S Blumberg, Takahiro Adachi
Journal: Gut (2021)

Objective Although immunoglobulin A (IgA) is abundantly expressed in the gut and known to be an important component of mucosal barriers against luminal pathogens, its precise function remains unclear. Therefore, we tried to elucidate the effect of IgA on gut homeostasis maintenance and its mechanism. Design We generated various IgA mutant mouse lines using the CRISPR/Cas9 genome editing system. Then, we evaluated the effect on the small intestinal homeostasis, pathology, intestinal microbiota, cytokine production, and immune cell activation using intravital imaging. Results We obtained two lines, with one that contained a &lt;50 base pair deletion in the cytoplasmic region of the IgA allele (IgA tail-mutant; IgA tm/tm ) and the other that lacked the most constant region of the IgH α chain, which resulted in the deficiency of IgA production (IgA −/− ). IgA −/− exhibited spontaneous inflammation in the ileum but not the other parts of the gastrointestinal tract. Associated with this, there were significantly increased lamina propria CD4 + T cells, elevated productions of IFN-γ and IL-17, increased ileal segmented filamentous bacteria and skewed intestinal microflora composition. Intravital imaging using Ca 2+ biosensor showed that IgA −/− had elevated Ca 2+ signalling in Peyer’s patch B cells. On the other hand, IgA tm/tm seemed to be normal, suggesting that the IgA cytoplasmic tail is dispensable for the prevention of the intestinal disorder. Conclusion IgA plays an important role in the mucosal homeostasis associated with the regulation of intestinal microbiota and protection against mucosal inflammation especially in the ileum.
LACK OF ASSOCIATION BETWEEN 99MTC-PYP HEART TO CONTRALATERAL RATIO AND SHORT-TERM SURVIVAL IN PATIENTS REFERRED FOR TRANSTHYRETIN CARDIAC AMYLOIDOSIS EVALUATION
Authors: Trejeeve Martyn, Joshua Saef, Muzna Hussain, Ossama Abou Hassan, Eoin Donnellan, Jerry Estep, WH Wilson Tang, Patrick Collier, Mazen Hanna, Wael Jaber
Journal: Journal of the American College of Cardiology (2021)
CHARACTERIZATION OF MYOCARDIAL INJURY WITH HIGH-SENSITIVITY TROPONIN
Authors: Nayrana Griffith, Dylan Walter, Sant Kumar, Heather Fahey, Sriram Padmanabhan, Bridgit Rweikiza, Raman Venkatesh, Jose Vargas, Monvadi Srichai-Parsia
Journal: Journal of the American College of Cardiology (2021)
Prognostic significance of genome-wide DNA methylation profiles within the randomized, phase 3, EORTC CATNON trial on non-1p/19q deleted anaplastic glioma
Authors: C Mircea S Tesileanu, Martin J van den Bent, Marc Sanson, Wolfgang Wick, Alba A Brandes, Paul M Clement, Sara C Erridge, Michael A Vogelbaum, Anna K Nowak, Jean F Baurain, Warren P Mason, Helen Wheeler, Olivier L Chinot, Sanjeev Gill, Matthew Griffin, Leland Rogers, Walter Taal, Roberta Rudà, Michael Weller, Catherine McBain, Myra E van Linde, Thais S Sabedot, Youri Hoogstrate, Andreas von Deimling, Iris de Heer, Wilfred F J van IJcken, Rutger W W Brouwer, Kenneth Aldape, Robert B Jenkins, Hendrikus J Dubbink, Johan M Kros, Pieter Wesseling, Kin Jip Cheung, Vassilis Golfinopoulos, Brigitta G Baumert, Thierry Gorlia, Houtan Noushmehr, Pim J French
Journal: Neuro-Oncology (2021)

Survival in patients with IDH1/2-mutant (mt) anaplastic astrocytomas is highly variable. We have used the prospective phase 3 CATNON trial to identify molecular factors related to outcome in IDH1/2mt anaplastic astrocytoma patients.The CATNON trial randomized 751 adult patients with newly diagnosed 1p/19q non-codeleted anaplastic glioma to 59.4 Gy radiotherapy +/- concurrent and/or adjuvant temozolomide. The presence of necrosis and/or microvascular proliferation was scored at central pathology review. Infinium MethylationEPIC BeadChip arrays were used for genome-wide DNA methylation analysis and the determination of copy number variations (CNV). Two DNA methylation-based tumor classifiers were used for risk stratification. Next-generation sequencing (NGS) was performed using 1 of the 2 glioma-tailored NGS panels. The primary endpoint was overall survival measured from the date of randomization.Full analysis (genome-wide DNA methylation and NGS) was successfully performed on 654 tumors. Of these, 432 tumors were IDH1/2mt anaplastic astrocytomas. Both epigenetic classifiers identified poor prognosis patients that partially overlapped. A predictive prognostic Cox proportional hazard model identified that independent prognostic factors for IDH1/2mt anaplastic astrocytoma patients included; age, mini-mental state examination score, treatment with concurrent and/or adjuvant temozolomide, the epigenetic classifiers, PDGFRA amplification, CDKN2A/B homozygous deletion, PI3K mutations, and total CNV load. Independent recursive partitioning analysis highlights the importance of these factors for patient prognostication.Both clinical and molecular factors identify IDH1/2mt anaplastic astrocytoma patients with worse outcome. These results will further refine the current WHO criteria for glioma classification.
COMPARISON OF ACHIEVING 2019 ESC/EAS VERSUS 2018 ACC/AHA LDL-C GOALS FOR PATIENTS WITH ATHEROSCLEROTIC CARDIOVASCULAR DISEASE: A CARDIOVASCULAR RISK SIMULATION FROM THE DA VINCI STUDY
Authors: Kosh R. Ray, Sarah Bray, Alberico L. Catapano, Neil Poulter, Antonio J. Vallejo-Vaz, Julia Brandts, Guillermo Villa
Journal: Journal of the American College of Cardiology (2021)
National routine adult immunisation programmes among World Health Organization Member States: an assessment of health systems to deploy COVID-19 vaccines
Authors: Sarah R Williams, Amanda J Driscoll, Hanna M LeBuhn, Wilbur H Chen, Kathleen M Neuzil, Justin R Ortiz
Journal: Eurosurveillance (2021)

IntroductionAs SARS-CoV-2 disproportionately affects adults, the COVID-19 pandemic vaccine response will rely on adult immunisation infrastructures.AimTo assess adult immunisation programmes in World Health Organization (WHO) Member States.MethodsWe evaluated country reports from 2018 on adult immunisation programmes sent to WHO and UNICEF. We described existing programmes and used multivariable regression to identify independent factors associated with having them.ResultsOf 194 WHO Member States, 120 (62%) reported having at least one adult immunisation programme. The Americas and Europe had the highest proportions of adult immunisation programmes, most commonly for hepatitis B and influenza vaccines (> 47% and > 91% of countries, respectively), while Africa and South-East Asia had the lowest proportions, with < 11% of countries reporting adult immunisation programmes for hepatitis B or influenza vaccines, and none for pneumococcal vaccines. In bivariate analyses, high or upper-middle country income, introduction of new or underused vaccines, having achieved paediatric immunisation coverage goals and meeting National Immunisation Technical Advisory Groups basic functional indicators were significantly associated (p < 0.001) with having an adult immunisation programme. In multivariable analyses, the most strongly associated factor was country income, with high- or upper-middle-income countries significantly more likely to report having an adult immunisation programme (adjusted odds ratio: 19.3; 95% confidence interval: 6.5-57.7).DiscussionWorldwide, 38% of countries lack adult immunisation programmes. COVID-19 vaccine deployment will require national systems for vaccine storage and handling, delivery and waste management to target adult risk groups. There is a need to strengthen immunisation systems to reach adults with COVID-19 vaccines.
CORONARY THROMBOSIS AND MYOCARDIAL INJURY IN A COVID 19 PATIENT
Authors: Mercedes Quiroga, Patricio Pachelo, Susana Taboada, Carola Zambrano, Enrique Domine, Alfredo Hirschson, Eduardo Fernandez Rostello, Demis Picone, Hyon Ju Choe, Irene Zeballos
Journal: Journal of the American College of Cardiology (2021)
ARTIFICIAL-INTELLIGENCE ENHANCED SCREENING FOR CARDIAC AMYLOIDOSIS BY ELECTROCARDIOGRAPHY
Authors: Martha Grogan, Dennis H. Murphree, Michal Shelly, Angela Dispenzieri, Zachi Itzhak Attia, Omar Abou-Ezzeddine, Grace Lin, Suraj Kapa, Daniel Borgeson, Paul Friedman, Francisco Lopez-Jimenez
Journal: Journal of the American College of Cardiology (2021)
Albumin influences the inhibitory effect exerted by celecoxib on cellular viability in WiDR and CAOV3 cancer cell lines
Authors: Victor S. Vital-Reyes, Cristina Rodriguez-Burford, Denise K. Oelschlager, William E. Grizzle
Journal: Cancer Research (2005)

6083  Background: Fetal Bovine Serum (FBS) is the most common component used in cell culture medium allowing cells a supply of nutrients for growth. FBS is a complex mix of albumins and growth factors. Nevertheless, the albumin concentration of serum can impair some cytotoxicity experiments linking it with drugs and involving a cellular response. Objetive: Our study examines the cellular viability of two different carcinoma cells lines exposed to celecoxib using 8 different media conditions containing diverse albumin concentrations. Methods: WiDR colon and OVCAR ovarian carcinoma cell lines were obtained from ATCC and maintained in DMEM medium containing 10% FBS, 2mM L-Glutamine, antibiotic-antimycotic solution, and MEM vitamin solution and placed in a humidified atmosphere containing 5% CO2 at 37°C. After each cell line reached a confluency of 70-80%, 5000 cells/well were seeded on flat bottomed 96 well plates in 100 μl media/per well for 24 hrs in 8 different conditions: DMEM+10% FBS, DMEM+FBS+ITS 100X (insulin-transferrin-selenium), DMEM+ITS 100X, DMEM+Albumin 1% (AlbuMax I (Lipid-Rich Bovine Serum Albumin), DMEM+Albumin 2%, DMEM+Albumin 3%, DMEM+Albumin 4% and DMEM+BSA 10%. A stock solution of COX-2 inhibitor, Celecoxib (Celebrex ®), dissolved in ethanol was prepared at various concentrations (0, 10, 30, 50, 70 and 100 μM) for each different media condition. Each cell line was exposed to celecoxib for 72 Hrs. Cellular proliferation was performed using a Tetrazolium Conversion Assay (Promega Corporation) according to manufacturer’s instructions. Results: A significant decrease in the cell viability compared with controls was observed in both carcinoma cells lines exposed to celecoxib at 50, 70 and 100 μM for 72 hrs with DMEM+FBS10%. When the cells lines were exposed to different concentrations of Celecoxib in DMEM media containing 1, 2, 3, 4 and 10% albumin, the inhibitory effect of celecoxib observed before with DMEM+FBS 10% was absent. In contrast, when the cell lines were exposed to DMEM+ITS without serum, the cells were more sensitive to an inhibitory effect exerted by celecoxib in cellular viability. Conclusions: Our data shows that Celecoxib affects cellular viability in vitro in a dose-dependent manner in two different carcinoma cell lines. However, when we increased the concentration of albumin in culture media, the inhibitory effect in cellular viability exerted by Celecoxib was lost. This observation supports the interaction between Celecoxib and albumin that has been described in in vivo studies indicating that celecoxib is highly protein bound. Our results indicate that the inhibitory effect of celecoxib in cellular viability may be affected by the concentration of albumin in culture media; hence, these data may have implications when cytotoxicity studies are planned.
Integrated in silico formulation design of self-emulsifying drug delivery systems
Authors: Haoshi Gao, Haoyue Jia, Jie Dong, Xinggang Yang, Haifeng Li, Defang Ouyang
Journal: Acta Pharmaceutica Sinica B (2021)

The drug formulation design of self-emulsifying drug delivery systems (SEDDS) often requires numerous experiments, which are time- and money-consuming. This research aimed to rationally design the SEDDS formulation by the integrated computational and experimental approaches. 4495 SEDDS formulation datasets were collected to predict the pseudo-ternary phase diagram by the machine learning methods. Random forest (RF) showed the best prediction performance with 91.3% for accuracy, 92.0% for sensitivity and 90.7% for specificity in 5-fold cross-validation. The pseudo-ternary phase diagrams of meloxicam SEDDS were experimentally developed to validate the RF prediction model and achieved an excellent prediction accuracy (89.51%). The central composite design (CCD) was used to screen the best ratio of oil-surfactant-cosurfactant. Finally, molecular dynamic (MD) simulation was used to investigate the molecular interaction between excipients and drugs, which revealed the diffusion behavior in water and the role of cosurfactants. In conclusion, this research combined machine learning, central composite design, molecular modeling and experimental approaches for rational SEDDS formulation design. The integrated computer methodology can decrease traditional drug formulation design works and bring new ideas for future drug formulation design.
CORONARY ARTERY PSEUDOANEURYSM IN SPONTANEOUS CORONARY ARTERY DISSECTION AS SEEN ON CORONARY CT IMAGING, A RARE FINDING IN A RARE DIAGNOSIS
Authors: Stacy Tsai, Melody Hermel, Christina Adams, Curtiss Stinis, George Wesbey, Jorge Gonzalez, Austin Robinson
Journal: Journal of the American College of Cardiology (2021)
SEX, GENDER AND CARDIOVASCULAR HEALTH, AN ANALYSIS OF SYNTHETIC DATA FROM A POPULATION BASED STUDY
Authors: Zahra Azizi, Louise Pilote, Valeria Raparelli, Colleen Norris, Karolina Kublickiene, Maria Trinidad Herrero, Alexandra Kautzky-Willer, Khaled El Emam
Journal: Journal of the American College of Cardiology (2021)
SYNERGISTIC EFFECT OF EZETIMIBE AND STATIN ON LIPOPROTEINS IN PATIENTS WITH TYPE 2 DIABETES MELLITUS-A SYSTEMATIC REVIEW AND META ANALYSIS
Authors: Aminah Abdul Razzack, Faiza Ahmed, Andre Thompson, Sri Mandava, Veronica Alexandra Abraham, Priyanka Panday, Faris Pacha
Journal: Journal of the American College of Cardiology (2021)
GENETIC TESTING FOR HYPERTRIGLYCERIDEMIA - A MULTI-CENTER STUDY
Authors: Trevor Hadley, Ali Agha, Vishnu Priya Pulipati, Kent Brummel, Corey Rearick, Anne Nugent, Mendel Roth, Patrick Moriarty, Michael Davidson, Christie Ballantyne
Journal: Journal of the American College of Cardiology (2021)
PREVALENCE OF ECG TESTING AND CHARACTERISTICS AMONG NEW HYDROXYCHLOROQUINE AND CHLOROQUINE PRESCRIPTIONS WITHIN A LARGE MULTI-CENTER TERTIARY CARE CENTER
Authors: Brittany Weber, May Choi, Emma Stevens, Hongshu Guan, Jack Ellrodt, Marcelo Di Carli, Usha Tedrow, William Sauer, Karen Costenbader
Journal: Journal of the American College of Cardiology (2021)
INITIAL EXPERIENCE, SAFETY AND EFFICACY OF CATHETER ABLATION OF PAROXYSMAL ATRIAL FIBRILLATION AT A COMMUNITY HOSPITAL AND THE IMPACT ON DIAGNOSIS TO ABLATION TIME
Authors: Antonio J. Navarrete Casas, Ali Iqtidar, Nate Lambert, Gary Fisch, Shannon Colter, Mark Fisch, Makran Hajj
Journal: Journal of the American College of Cardiology (2021)
RACIAL/ETHNIC DIFFERENCES IN THE PREVALENCE OF AORTIC VALVE STENOSIS AND AORTIC VALVE REPLACEMENT BY ECHOCARDIOGRAPHY: THE MULTI-ETHNIC STUDY OF ATHEROSCLEROSIS (MESA)
Authors: Matthew J. Czarny, Sanjiv Shah, Seamus Whelton, Rimsky Denis, Michael Tsai, Michael Blaha, Alain Bertoni, Wendy Post
Journal: Journal of the American College of Cardiology (2021)
SEX DIFFERENCES IN TREATMENT AND OUTCOMES AMONGPATIENTS HOSPITALIZED FOR NON-ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION IN CHINA: 2006-2015
Authors: Weihong Guo, Xue Du, Shuang Hu, Yuan Lu, Rachel Dreyer, Erica Spatz, Frederick Masoudi, Harlan Krumholz, Xin Zheng
Journal: Journal of the American College of Cardiology (2021)
MACHINE LEARNING ALGORITHM ACCURATELY PREDICTS HEART FAILURE HOSPITALIZATION EVENTS IN POST- TRANSCATHETER AORTIC VALVE PLACEMENT PATIENTS
Authors: Chieh Ju Chao, Chia-Chun Chiang, Pradyumna Agasthi, Marlene Girardo, Matthew Buras, Anusha Shanbhag, George (YuXiang) Wang, Amith Reddy Seri, John Sweeney, F. David Fortuin, David Holmes, Reza Arsanjani
Journal: Journal of the American College of Cardiology (2021)
Abstract 16507: Peak Heart Rate During Exercise Stress Testing Predicts Symptomatic Status in Patients With Congenital Long QT Syndrome
Authors: Conor M Lane, J. M Bos, Ram K Rohatgi, Michael J Ackerman
Journal: Circulation (2018)

Introduction: Despite advances in the diagnosis and management of congenital long QT syndrome (LQTS), predicting the risk of LQTS-triggered cardiac events remains an important challenge. Exercise s...
SEASONAL DIFFERENCE OF MORTALITY IN PATIENTS WITH CARDIAC ARREST A PROPENSITY MATCHED STUDY OF NATIONAL INPATIENT SAMPLE
Authors: Adrija Hajra, Neelkumar Patel, Subrat Das, Dhrubajyoti Bandyopadhyay, Sandipan Chakraborty, Birendra Amgai
Journal: Journal of the American College of Cardiology (2021)
ONE-YEAR COST-EFFECTIVENESS OF CYP2C19- GUIDED DE-ESCALATION AND ESCALATION OF P2Y12 INHIBITORS IN VETERANS WITH ACUTE CORONARY SYNDROMES UNDERGOING PERCUTANEOUS CORONARY INTERVENTION
Authors: Olivia Dong, Kevin Friede, Catherine Chanfreau-Coffinier, Deepak Voora
Journal: Journal of the American College of Cardiology (2021)
Phase I–II Open-Label Multicenter Study of Palbociclib + Vemurafenib in <i>BRAF</i>V600MUT Metastatic Melanoma Patients: Uncovering CHEK2 as a Major Response Mechanism
Authors: Baptiste Louveau, Matthieu Resche-Rigon, Thierry Lesimple, Laetitia Da Meda, Marc Pracht, Barouyr Baroudjian, Julie Delyon, Mona Amini-Adle, Caroline Dutriaux, Coralie Reger de Moura, Aurélie Sadoux, Fanélie Jouenne, Zineb Ghrieb, Paul Vilquin, Didier Bouton, Annick Tibi, Samuel Huguet, Keyvan Rezai, Maxime Battistella, Samia Mourah, Céleste Lebbe
Journal: Clinical Cancer Research (2021)

In BRAFV600MUT metastatic melanoma, cyclin D-CDK4/6-INK4-Rb pathway alterations are involved in resistance to MAPK inhibitors, suggesting a clinical benefit of cyclin-dependent kinase 4 (CDK4) inhibitors. In this phase I-II study, we aimed to establish the MTD of palbociclib when added to vemurafenib.Patients with BRAFV600E/KMUT metastatic melanoma harboring CDKN2A loss and RB1 expression were included and stratified into two groups according to previous BRAF inhibitor treatment (no:strata 1; yes:strata 2). Treatment comprised palbociclib once daily for 14 days followed by a 7-day break + continuous dosing of vemurafenib. The primary endpoint was the occurrence of dose-limiting toxicity (DLT), and the secondary endpoints included the best response, survival, pharmacokinetics, and tumor molecular profiling.Eighteen patients were enrolled, with 15 in strata 2. Characteristics at inclusion were American Joint Committee on Cancer stage IVM1c (N = 16; 88.9%), high lactate dehydrogenase (N = 9; 50.0%), and median number of previous treatments of 2. One and 5 patients experienced DLT in strata 1 and 2, respectively, defining the MTD at palbociclib 25 mg and vemurafenib 960 mg in strata 2. No significant evidence for drug-drug interactions was highlighted. The median progression-free survival was 2.8 months, and 5 (27.8%) patients showed a clinical response. The baseline differential mRNA expression analysis and in vitro data revealed the role of CHEK2 in the response to palbociclib.Although the combination of palbociclib + fixed-dose vemurafenib did not allow an increased palbociclib dosage above 25 mg, a significant clinical benefit was achieved in pretreated patients with melanoma. An association between the transcriptomic data and clinical response was highlighted.
CD1a selectively captures endogenous cellular lipids that broadly block T cell response
Authors: Rachel N. Cotton, Marcin Wegrecki, Tan-Yun Cheng, Yi-Ling Chen, Natacha Veerapen, Jérôme Le Nours, Dennis P. Orgill, Bohdan Pomahac, Simon G. Talbot, Richard Willis, John D. Altman, Annemieke de Jong, Ildiko Van Rhijn, Rachael A. Clark, Gurdyal S. Besra, Graham Ogg, Jamie Rossjohn, D. Branch Moody
Journal: The Journal of Experimental Medicine (2021)

We optimized lipidomics methods to broadly detect endogenous lipids bound to cellular CD1a proteins. Whereas membrane phospholipids dominate in cells, CD1a preferentially captured sphingolipids, especially a C42, doubly unsaturated sphingomyelin (42:2 SM). The natural 42:2 SM but not the more common 34:1 SM blocked CD1a tetramer binding to T cells in all human subjects tested. Thus, cellular CD1a selectively captures a particular endogenous lipid that broadly blocks its binding to TCRs. Crystal structures show that the short cellular SMs stabilized a triad of surface residues to remain flush with CD1a, but the longer lipids forced the phosphocholine group to ride above the display platform to hinder TCR approach. Whereas nearly all models emphasize antigen-mediated T cell activation, we propose that the CD1a system has intrinsic autoreactivity and is negatively regulated by natural endogenous inhibitors selectively bound in its cleft. Further, the detailed chemical structures of natural blockers could guide future design of therapeutic blockers of CD1a response.
PROGNOSTIC IMPLICATION OF TUBULAR INJURY DEFINED BY URINARY LIVER-TYPE FATTY ACID BINDING PROTEIN IN PATIENTS WITH ACUTE HEART FAILURE
Authors: Tsutomu Sunayama, Yuya Matsue, Shoichiro Yatsu, Taishi Dotare, Sayaki Ishiwata, Shoko Suda, Takao Kato, Masaru Hiki, Takatoshi Kasai, Tohru Minamino
Journal: Journal of the American College of Cardiology (2021)
UTILIZATION AND TOLERANCE OF BETA-BLOCKERS AMONG PATIENTS WITH AL AMYLOIDOSIS
Authors: Alexandros Briasoulis, Kimon Stamatelopoulos, Ioannis Petropoulos, Fenia Theodorakakou, Maria Gavriatopoulou, Athanasios-Meletios Dimopoulos, Efstathios Kastritis
Journal: Journal of the American College of Cardiology (2021)
Abstract 13926: A Continuum in the Degree of Left Atrial Dynamics Impairment and Right Ventricular to Pulmonary Circulation Uncoupling in Left Heart Disease
Authors: Tadafumi Sugimoto, Francesco Bandera, Greta Generati, Eleonora Alfonzetti, Vincenzo Tufaro, Marco Guazzi
Journal: Circulation (2017)

Background: The left atrium (LA) behaves as a watershed between the right and left ventricles but its causative role in an impaired right heart hemodynamics is largely unexplored. Objective: We aim...
Cellular pyrimidine imbalance triggers mitochondrial DNA–dependent innate immunity
Authors: Hans-Georg Sprenger, Thomas MacVicar, Amir Bahat, Kai Uwe Fiedler, Steffen Hermans, Denise Ehrentraut, Katharina Ried, Dusanka Milenkovic, Nina Bonekamp, Nils-Göran Larsson, Hendrik Nolte, Patrick Giavalisco, Thomas Langer
Journal: Nature Metabolism (2021)

Cytosolic mitochondrial DNA (mtDNA) elicits a type I interferon response, but signals triggering the release of mtDNA from mitochondria remain enigmatic. Here, we show that mtDNA-dependent immune signalling via the cyclic GMP-AMP synthase‒stimulator of interferon genes‒TANK-binding kinase 1 (cGAS-STING-TBK1) pathway is under metabolic control and is induced by cellular pyrimidine deficiency. The mitochondrial protease YME1L preserves pyrimidine pools by supporting de novo nucleotide synthesis and by proteolysis of the pyrimidine nucleotide carrier SLC25A33. Deficiency of YME1L causes inflammation in mouse retinas and in cultured cells. It drives the release of mtDNA and a cGAS-STING-TBK1-dependent inflammatory response, which requires SLC25A33 and is suppressed upon replenishment of cellular pyrimidine pools. Overexpression of SLC25A33 is sufficient to induce immune signalling by mtDNA. Similarly, depletion of cytosolic nucleotides upon inhibition of de novo pyrimidine synthesis triggers mtDNA-dependent immune responses in wild-type cells. Our results thus identify mtDNA release and innate immune signalling as a metabolic response to cellular pyrimidine deficiencies.