Modeling immunotherapy and outcomes in acute myeloid leukemia

Very recently, we proposed an ordinary differential equation model incorporating promotion of regulatory T cell (Tregs) expansion by leukemic cells, which describes co-evolutional dynamics between leukemic and immune cells in progression of acute myeloid leukemia (AML). To evaluate the ability of our model to predict effectiveness of immunotherapy for AML, we performed Monte Carlo simulation of trajectories in phase plane and generated relapse free survival (RFS) curves, which could be compared with clinical data. The resulting RFS curves were in good accordance with clinical outcomes reported in immunotherapies of NK cells infusion with/without Tregs depletion. In addition, our simulation results focusing on consecutive cycles of cell infusion with/without cell depletion qualitatively accounts for the effectiveness of corresponding clinical immunotherapy. The present results suggest that our model may provide valuable information for future design of immunotherapy in AML

Transition from an unstable synchronization state with transient oscillation cessations to spiral rotation in a coupled chemical oscillator system

金沢大学大学教育開発・支援センターSpatiotemporal patterns of chemical wave propagation in the assemblies of nine cation-exchange beads loaded with the catalyst ferroin of Belousov-Zhabotinsky reaction are reported. The beads are immersed in the reaction mixture, on which periodic chemical waves are emerged. In the bead assemblies, abrupt changes of initiation site and direction of the periodic chemical waves were observed. In some cases, it was observed that transient oscillation cessations and the following rotating spiral wave occur. © 1997 American Institute of Physics

Deep neural networks based automated extraction of dugong feeding trails from UAV images in the intertidal seagrass beds

Dugongs (Dugong dugon) are seagrass specialists distributed in shallow coastal waters in tropical and subtropical seas. The area and distribution of the dugongs’ feeding trails, which are unvegetated winding tracks left after feeding, have been used as an indicator of their feeding ground utilization. However, current ground-based measurements of these trails require a large amount of time and effort. Here, we developed effective methods to observe the dugongs’ feeding trails using unmanned aerial vehicle (UAV) images (1) by extracting the dugong feeding trails using deep neural networks. Furthermore, we demonstrated two applications as follows; (2) extraction of the daily new feeding trails with deep neural networks and (3) estimation the direction of the feeding trails. We obtained aerial photographs from the intertidal seagrass bed at Talibong Island, Trang Province, Thailand. The F1 scores, which are a measure of binary classification model’s accuracy taking false positives and false negatives into account, for the method (1) were 89.5% and 87.7% for the images with ground sampling resolutions of 1 cm/pixel and 0.5 cm/pixel, respectively, while the F1 score for the method (2) was 61.9%. The F1 score for the method (1) was high enough to perform scientific studies on the dugong. However, the method (2) should be improved, and there remains a need for manual correction. The mean area of the extracted daily new feeding trails from September 12–27, 2019, was 187.8 m2 per day (n = 9). Total 63.9% of the feeding trails was estimated to have direction within a range of 112.5° and 157.5°. These proposed new methods will reduce the time and efforts required for future feeding trail observations and contribute to future assessments of the dugongs’ seagrass habitat use

Interaction between the immune system and acute myeloid leukemia: A model incorporating promotion of regulatory T cell expansion by leukemic cells

金沢大学国際基幹教育院高等教育開発・支援系Population dynamics of regulatory T cells (Treg) are crucial for the underlying interplay between leukemic and immune cells in progression of acute myeloid leukemia (AML). The goal of this work is to elucidate the dynamics of a model that includes Treg, which can be qualitatively assessed by accumulating clinical findings on the impact of activated immune cell infusion after selective Treg depletion. We constructed an ordinary differential equation model to describe the dynamics of three components in AML: leukemic blast cells, mature regulatory T cells (Treg), and mature effective T cells (Teff), including cytotoxic T lymphocytes. The model includes promotion of Treg expansion by leukemic blast cells, leukemic stem cell and progenitor cell targeting by Teff, and Treg-mediated Teff suppression, and exhibits two coexisting, stable steady states, corresponding to high leukemic cell load at diagnosis or relapse, and to long-term complete remission. Our model is capable of explaining the clinical findings that the survival of patients with AML after allogeneic stem cell transplantation is influenced by the duration of complete remission, and that cut-off minimal residual disease thresholds associated with a 100% relapse rate are identified in AML. © 2018 Elsevier B.V.Embargo Period 12 month

トクシマ ダイガク ビョウイン ノウソッチュウ センター ニ ハンソウ サレタ rt-PA ジョウチュウ リョウホウ ノ Drip and Ship ショウレイ ニオケル ケントウ

Recently,“Drip and Ship”treatment conducted in collaboration of a hospital in remote area and an institution capable of emergency stroke treatment under guidance by a stroke specialist has been reported to be effective. “Drip and Ship” treatment refers to initiating intravenous recombinant tissue-type plasminogen activator（rt-PA）infusion at a remote hospital（Drip）and then transporting patients to an institution capable of multimodality management and endovascular treatment of stroke（Ship）. We report here a case analysis and examinations on treatment methods, prognosis, and some other parameters in １６ patients who were transported to the Stroke Care Unit（SCU）of the Tokushima University Hospital while undergoing“Drip and Ship”treatment between June ２０１３ and November ２０１５. Occluded vessels were recanalized by rt-PA administration in ５／１２patients （４２％）. For ６ cases in which recanalization was not achieved with rt-PA, endovascular treatment was performed, and recanalization was obtained in ３ patients（５０％）. There was a marked improvement（８．４points on average）in NIHSS at the time of discharge compared to that before rt-PA administration. A representative case showed a ２６‐point improvement in NIHSS at the time of discharge compared to the pretreatment value. The advantage of“Drip and Ship”treatment is two-fold : It allows for rt-PA treatment of acute ischemic stroke patients at remote-area institutions incapable of multimodality stroke management, and also makes it possible to add endovascular treatment for rt-PA-irresponsive cases in which recanalization of occluded vessels could not be achieved with rt-PA therapy. The results suggest that the“Drip and Ship”treatment is a safe and effective means to eliminate regional disparities in intravenous rt-PA therapy and can make more contributions to the collaborative stroke care in the Tokushima prefecture in the future

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

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