Essential roles of the interaction between cancer cell-derived chemokine, CCL4, and intra-bone CCR5-expressing fibroblasts in breast cancer bone metastasis

From a murine breast cancer cell line, 4T1, we established a subclone, 4T1.3, which consistently metastasizes to bone upon its injection into the mammary fat pad. 4T1.3 clone exhibited similar proliferation rate and migration capacity as the parental clone. However, the intra-bone injection of 4T1.3 clone caused larger tumors than that of the parental cells, accompanied with increases in fibroblast, but not osteoclast or osteoblast numbers. 4T1.3 clone displayed an enhanced expression of a chemokine, CCL4, but not its specific receptor, CCR5. CCL4 shRNA-transfection of 4T1.3 clone had few effects on its in vitro properties, but reduced the tumorigenicity arising from the intra-bone injection. Moreover, intra-bone injection of 4T1.3 clone caused smaller tumors in mice deficient in CCR5 or those receiving CCR5 antagonist than in wild-type mice. The reduced tumor formation was associated with attenuated accumulation of CCR5-positive fibroblasts expressing connective tissue growth factor (CTGF)/CCN2. Tumor cell-derived CCL4 could induce fibroblasts to express CTGF/CCN2, which could support 4T1.3 clone proliferation under hypoxic culture conditions. Thus, the CCL4-CCR5 axis can contribute to breast cancer metastasis to bone by mediating the interaction between cancer cells and fibroblasts in bone cavity. © 2016 Elsevier Ireland Ltd.Embargo Period 12 month

Poster Session

International Symposium on Tumor Biology in Kanazawa & Symposium on Drug Discoverry in Academics 2014 [DATE]: January 23(Thu)-24(Fri),2014, [Place]:Kanazawa Excel Hotel Tpkyu, Kanazawa, Japan, [Organizers]:Kanazawa Association of Tumor Biologists / Cancer Research Institute, Kanazawa Universit

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

01-G.Nishimura-4.01

Abstract Vanilla planifolia Jacks. ex Andrews has the sclerotic seed coat, an exceptional character state of seed coat in the Orchidaceae. We observed seed coat formation of the species in every 10 days after pollination. The ovule develops into a nucellar filament with 6 to 8 nucellar cells at the time of anthesis prior to artificial pollination. The inner integument differentiates at 20 days after pollination. The outer integument differentiates at 30 days after pollination. The cells of the outermost layer of the outer integument start to thicken at 40 days after pollination. Dark material starts to accumulate in the outer and lateral cell walls of the outermost layer of the outer integument at 50 days after pollination. The dark material accumulates further at 60 to 80 days, while the inner integument has degenerated at 80 days. The thickened cell walls with dark material occupy the whole cell cavity and the cells become sclerotic at 120 days after pollination. The inner layer cells of the outer integument have degenerated and only the outermost layer of the outer integument remains as the seed coat at 180 days after pollination when the seed matures

Effects of Image Processing Using Honeycomb-Removal and Image-Sharpening Algorithms on Visibility of 27-Gauge Endoscopic Vitrectomy

Endoscopic vitrectomy with small gauge probes has clinical potentials, but intraocular visibility is inherently limited by low resolution and dim illumination due to the reduced number of optic fibers. We investigated whether honeycomb-removal and image-sharpening algorithms, which enable real-time processing of live images with a delay of 0.004 s, can improve the visibility of 27-gauge endoscopic vitrectomy. A total of 33 images during endoscopic vitrectomy were prepared, consisting of 11 original images, 11 images after the honeycomb-removal process, and 11 images after both honeycomb-removal and image-sharpening procedures. They were randomly presented to 18 vitreous surgeons, who rated each image on a 10-point scale. The honeycomb-removal algorithm almost completely suppressed honeycomb artifacts without degrading the background image quality. The implementation of image-sharpening algorithms further improved endoscopic visibility by optimizing contrast and augmenting image clarity. The visibility score was significantly improved from 4.27 ± 1.78 for the original images to 4.72 ± 2.00 for the images after the honeycomb-removal process (p < 0.001, linear mixed effects model), and to 5.40 ± 2.10 for the images after both the honeycomb-removal and image-sharpening procedures (p < 0.001). When the visibility scores were analyzed separately for 10 surgeons who were familiar with endoscopic vitrectomy and 8 surgeons who were not, similar results were obtained. Image processing with honeycomb-removal and image-sharpening algorithms significantly improved the visibility of 27-gauge endoscopic vitrectomy