Reversal effects of low-dose imatinib compared with sunitinib on monocrotaline-induced pulmonary and right ventricular remodeling in rats

High-dose imatinib reverses cardiopulmonary remodeling but adverse effects limit its clinical use. Efficacy of the multi-kinase inhibitor sunitinib remains questionable. We compared anti-remodeling effects of imatinib with sunitinib on monocrotaline-induced right ventricular (RV) hypertrophy and pulmonary arterial remodeling in rats, focusing on a lower dose. Fourteen days after monocrotaline injection, oral gavage of imatinib (5, 15, or 50mg/kg), sunitinib (0.3, 1, 3, or 10mg/kg), or water for 14days was started. RV hypertrophy and b-type natriuretic peptide mRNA levels were significantly and dose-dependently reduced, much greater in imatinib- than sunitinib-treated groups. Imatinib normalized muscularization of 20–50μm intra-acinar pulmonary arteries more significantly than sunitinib. At transcript levels, sunitinib significantly upregulated pulmonary nestin, and downregulated platelet-derived growth factor receptor beta (PDGFR-β), fibroblast growth factor receptor 1, vascular endothelial growth factor receptor-2 and vascular endothelial growth factor (VEGF)-A, but not Raf-1 proto-oncogene serine/threonine kinase mRNAs. Sunitinib also suppressed VEGF-A, but not phosphorylated extra-cellular-signal-related kinase (ERK)-1/2 protein expression. The sole PDGFR-β antagonism of imatinib resulted in significant Raf-1 mRNA and phosphorylated ERK-1/2 protein downregulation, suggesting that the equivocal reversal effect of sunitinib may be due to its VEGF signaling inhibition in the lung. Imatinib's greater dose-dependent reversal on cardiopulmonary remodeling may make a low dose suitable for PAH treatment

Assessment of Culprit Lesion Morphology in Acute Myocardial Infarction Ability of Optical Coherence Tomography Compared With Intravascular Ultrasound and Coronary Angioscopy

ObjectivesThe aim of the present study was to evaluate the ability of optical coherence tomography (OCT) for assessment of the culprit lesion morphology in acute myocardial infarction (AMI) in comparison with intravascular ultrasound (IVUS) and coronary angioscopy (CAS).BackgroundOptical coherence tomography is a new intravascular imaging method with a high resolution of approximately 10 μm. This may allow us to assess the vulnerable plaques in detail in vivo.MethodsWe enrolled 30 patients with AMI, and analyzed the culprit lesion by OCT, CAS, and IVUS.ResultsThe average duration from the onset of symptom to OCT imaging was 3.8 ± 1.0 h. The incidence of plaque rupture observed by OCT was 73%, and it was significantly higher than that by CAS (47%, p = 0.035) and IVUS (40%, p = 0.009). Furthermore, OCT (23%) was superior to CAS (3%, p = 0.022) and IVUS (0%, p = 0.005) in the detection of fibrous cap erosion. The intracoronary thrombus was observed in all cases by OCT and CAS, but it was identified in 33% by IVUS (vs. OCT, p < 0.001). Only OCT could estimate the fibrous cap thickness, and it was 49 ± 21 μm. The incidence of thin cap fibroatheroma (TCFA) was 83% in this population by OCT.ConclusionsOptical coherence tomography is a feasible imaging modality in patients with AMI and allows us to identify not only plaque rupture, but also fibrous cap erosion, intracoronary thrombus, and TCFA in vivo more frequently compared with conventional imaging techniques

Secondary Torsion of Vermiform Appendix with Mucinous Cystadenoma

Torsion of the vermiform appendix is a rare disorder, which causes abdominal symptoms indistinguishable from acute appendicitis. We report a case (a 34-year-old male) of secondary torsion of the vermiform appendix with mucinous cystadenoma. This case was characterized by mild inflammatory responses, pentazocine-resistant abdominal pain, and appendiceal tumor, which was not enhanced by the contrast medium on computed tomography presumably because of reduced blood flow by the torsion. These findings may be helpful for the preoperative diagnosis of secondary appendiceal torsion

Implication of Plaque Color Classification for Assessing Plaque Vulnerability A Coronary Angioscopy and Optical Coherence Tomography Investigation

ObjectivesThe purpose of this study was to assess the relationship between plaque color evaluated by coronary angioscopy and fibrous cap thickness estimated by optical coherence tomography (OCT) in vivo.BackgroundYellow color intensity of coronary plaque evaluated by coronary angioscopy might be associated with plaque vulnerability.MethodsSeventy-seven coronary artery plaques in patients with acute coronary syndrome were observed by angioscopy and OCT. Plaque color was graded as white, light yellow, yellow, or intensive yellow.ResultsThere were significant differences among the groups classified by plaque color with respect to the fibrous cap thickness estimated by OCT: 389 ± 74 μm in white plaques, 228 ± 51 μm in light yellow plaques, 115 ± 28 μm in yellow plaques, and 59 ± 14 μm in intensive yellow plaques (p &lt; 0.0001). In Spearman rank-order correlation analysis, there was a significant negative correlation between yellow color intensity and fibrous cap thickness (p &lt; 0.0001). Furthermore, 80% of intensive yellow plaques were thin cap fibroatheroma with a cap thickness of ≤65 μm.ConclusionsThe plaque color in coronary angioscopy was determined by the fibrous cap thickness, which was assessed by OCT. Although coronary angioscopy remains a specialized research tool, it might allow us to evaluate plaque vulnerability

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target