External validation of the myocardial-ischaemic-injury-index machine learning algorithm for the early diagnosis of myocardial infarction: a multicentre cohort study

Article

Author: Miro, Oscar ; Bima, Paolo ; Breidthardt, Tobias ; Nestelberger, Thomas ; Spagnuolo, Carlos C ; Wildi, Karin ; Boeddinghaus, Jasper ; Glaeser, Jonas ; Strebel, Ivo ; Christ, Michael ; Koechlin, Luca ; Keller, Dagmar I ; Zimmermann, Tobias ; Champetier, Arnaud ; Mueller, Christian ; Lopez-Ayala, Pedro ; Martin-Sanchez, Francisco Javier

BACKGROUNDThe myocardial-ischaemic-injury-index (MI³) is a novel machine learning algorithm for the early diagnosis of type 1 non-ST-segment elevation myocardial infarction (NSTEMI). The performance of MI³, both when using early serial blood draws (eg, at 1 h or 2 h) and in direct comparison with guideline-recommended algorithms, remains unknown. Our aim was to externally validate MI³ and compare its performance with that of the European Society of Cardiology (ESC) 0/1h-algorithm.METHODSIn this secondary analysis of a multicentre international diagnostic cohort study, adult patients (age >18 years) presenting to the emergency department with symptoms suggestive of myocardial infarction were prospectively enrolled from April 21, 2006, to Feb 27, 2019 in 12 centres from five European countries (Switzerland, Spain, Italy, Poland, and Czech Republic). Patients were excluded if they presented with ST-segment-elevation myocardial infarction, did not have at least two serial high-sensitivity cardiac troponin I (hs-cTnI) measurements, or if the final diagnosis remained unclear. The final diagnosis was centrally adjudicated by two independent cardiologists using all available medical records, including serial hs-cTnI measurements and cardiac imaging. The primary outcome was type 1 NSTEMI. The performance of MI³ was directly compared with that of the ESC 0/1h-algorithm.FINDINGSAmong 6487 patients, (median age 61·0 years [IQR 49·0-73·0]; 2122 [33%] female and 4365 [67%] male), 882 (13·6%) patients had type 1 NSTEMI. The median time difference between the first and second hs-cTnI measurement was 60·0 mins (IQR 57·0-70·0). MI³ performance was very good, with an area under the receiver-operating-characteristic curve of 0·961 (95% CI 0·957 to 0·965) and a good overall calibration (intercept -0·09 [-0·2 to 0·02]; slope 1·02 [0·97 to 1·08]). The originally defined MI³ score of less than 1·6 identified 4186 (64·5%) patients as low probability of having a type 1 NSTEMI (sensitivity 99·1% [95% CI 98·2 to 99·5]; negative predictive value [NPV] 99·8% [95% CI 99·6 to 99·9]) and an MI³ score of 49·7 or more identified 915 (14·1%) patients as high probability of having a type 1 NSTEMI (specificity 95·0% [94·3 to 95·5]; positive predictive value [PPV] 69·1% [66·0-72·0]). The sensitivity and NPV of the ESC 0/1h-algorithm were higher than that of MI³ (difference for sensitivity 0·88% [0·19 to 1·60], p=0·0082; difference for NPV 0·18% [0·05 to 0·32], p=0·016), and the rule-out efficacy was higher for MI³ (11% difference, p<0·0001). Specificity and PPV for MI³ were superior (difference for specificity 3·80% [3·24 to 4·36], p<0·0001; difference for PPV 7·84% [5·86 to 9·97], p<0·0001), and the rule-in efficacy was higher for the ESC 0/1h-algorithm (5·4% difference, p<0·0001).INTERPRETATIONMI³ performs very well in diagnosing type 1 NSTEMI, demonstrating comparability to the ESC 0/1h-algorithm in an emergency department setting when using early serial blood draws.FUNDINGSwiss National Science Foundation, Swiss Heart Foundation, the EU, the University Hospital Basel, the University of Basel, Abbott, Beckman Coulter, Roche, Idorsia, Ortho Clinical Diagnostics, Quidel, Siemens, and Singulex.

01 Dec 2020·BMC GenomicsQ2 · BIOLOGY

Transcriptomic profiling of Solanum peruvianum LA3858 revealed a Mi-3-mediated hypersensitive response to Meloidogyne incognita

Q2 · BIOLOGY

ArticleOA

Author: Zhao, Tingting ; Du, Chong ; Yang, Huanhuan ; Li, Jingfu ; Zhao, Zhentong ; Xu, Xiangyang ; Jiang, Jingbin ; Zhang, He ; Zhang, Dongye

AbstractBackgroundThe Mi-1 gene was the first identified and cloned gene that provides resistance to root-knot nematodes (RKNs) in cultivated tomato. However, owing to its temperature sensitivity, this gene does not meet the need for breeding disease-resistant plants that grow under high temperature. In this study, Mi-3 was isolated from the wild species PI 126443 (LA3858) and was shown to display heat-stable resistance to RKNs. However, the mechanism that regulates this resistance remains unknown.ResultsIn this study, 4760, 1024 and 137 differentially expressed genes (DEGs) were enriched on the basis of pairwise comparisons (34 °C vs. 25 °C) at 0 (before inoculation), 3 and 6 days post-inoculation (dpi), respectively. A total of 7035 DEGs were identified from line LA3858 in the respective groups under the different soil temperature treatments. At 3 dpi, most DEGs were enriched in Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways related to plant biotic responses, such as “plant-pathogen interaction” and “plant hormone signal transduction”. Significantly enriched DEGs were found to encode key proteins such as R proteins and heat-shock proteins (HSPs). Moreover, other DEGs were found to participate in Ca2+ signal transduction; the production of ROS; DEGs encoding transcription factors (TFs) from the bHLH, TGA, ERF, heat-shock transcription factor (HSF) and WRKY families were highly expressed, which contribute to be involved into the formation of phytohormones, such as salicylic acid (SA), jasmonic acid (JA) and ethylene (ET), the expression of most was upregulated at 3 dpi at the 25 °C soil temperature compared with the 34 °C soil temperature.ConclusionTaken together, the results of our study revealed reliable candidate genes from wild materials LA3858, that are related to Mi-3-mediate resistance to Meloidogyne incognita. A large number of vital pathways and DEGs were expressed specifically in accession LA3858 grown at 34 °C and 25 °C soil temperatures at 3 dpi. Upon infection by RKNs, pattern-recognition receptors (PRRs) specifically recognized conserved pathogen-associated molecular patterns (PAMPs) as a result of pathogen-triggered immunity (PTI), and the downstream defensive signal transduction pathway was likely activated through Ca2+ signal channels. The expression of various TFs was induced to synthesize phytohormones and activate R proteins related to resistance, resulting in the development of effector-triggered immunity (ETI). Last, a hypersensitive response in the roots occurred, which was probably induced by the accumulation of ROS.

01 Dec 2019·Clinical EpigeneticsQ2 · MEDICINE

Co-inhibition of HDAC and MLL-menin interaction targets MLL-rearranged acute myeloid leukemia cells via disruption of DNA damage checkpoint and DNA repair

Q2 · MEDICINE

ArticleOA

Author: Lin, Fusheng ; Li, Yin ; Yu, Yong ; Zha, Jie ; Chen, Qinwei ; Dai, Yun ; Fang, Zhihong ; Xu, Bing ; Shi, Yuanfei ; Ye, Jing ; Yuan, Delin

AbstractWhile the aberrant translocation of the mixed-lineage leukemia (MLL) gene drives pathogenesis of acute myeloid leukemia (AML), it represents an independent predictor for poor prognosis of adult AML patients. Thus, small molecule inhibitors targeting menin-MLL fusion protein interaction have been emerging for the treatment of MLL-rearranged AML. As both inhibitors of histone deacetylase (HDAC) and menin-MLL interaction target the transcription-regulatory machinery involving epigenetic regulation of chromatin remodeling that governs the expression of genes involved in tumorigenesis, we hypothesized that these two classes of agents might interact to kill MLL-rearranged (MLL-r) AML cells. Here, we report that the combination treatment with subtoxic doses of the HDAC inhibitor chidamide and the menin-MLL interaction inhibitor MI-3 displayed a highly synergistic anti-tumor activity against human MLL-r AML cells in vitro and in vivo, but not those without this genetic aberration. Mechanistically, co-exposure to chidamide and MI-3 led to robust apoptosis in MLL-r AML cells, in association with loss of mitochondrial membrane potential and a sharp increase in ROS generation. Combined treatment also disrupted DNA damage checkpoint at the level of CHK1 and CHK2 kinases, rather than their upstream kinases (ATR and ATM), as well as DNA repair likely via homologous recombination (HR), but not non-homologous end joining (NHEJ). Genome-wide RNAseq revealed gene expression alterations involving several potential signaling pathways (e.g., cell cycle, DNA repair, MAPK, NF-κB) that might account for or contribute to the mechanisms of action underlying anti-leukemia activity of chidamide and MI-3 as a single agent and particularly in combination in MLL-r AML. Collectively, these findings provide a preclinical basis for further clinical investigation of this novel targeted strategy combining HDAC and Menin-MLL interaction inhibitors to improve therapeutic outcomes in a subset of patients with poor-prognostic MLL-r leukemia.

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Indication	Highest Phase	Country/Location	Organization	Date
Solid tumor	Phase 1	US	MorphImmune, Inc.Startup	05 Mar 2022

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