Malignant Ovarian Tumors with Induced Expression of Carbonyl Reductase Show Spontaneous Regression

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Loss of ICG uptake in the process of rat hepatocarcinogenesis correlates to the disappearance of glutathione-S-transferase alpha subunit.

Reduced indocyanine green (ICG) uptake is one of the functional changes of human hepatocellular carcinoma (HCC). To clarify the mechanisms of loss of ICG uptake, and determine which subunit of glutathione-S-transferase (GST), alpha or pi, plays a role in ICG transport in hepatocytes, an experimental HCC model was developed that used nodules induced by 2-acetylamino-fluorene (2-AAF) administration. Many of the ICG stained nodules, which consisted of benign and borderline lesions, were GST-alpha positive. However, the percentage of GST-alpha positive cells tended to decrease according to the disappearance of ICG staining in the process of hepatocarcinogenesis. HCCs unstained by ICG were also GST-alpha negative. GST-pi, not detected in normal rat hepatocytes, appeared in an earlier stage of hepatocarcinogenesis before the disappearance of GST-alpha, and was not observed in HCCs. No significant relationship between ICG staining and GST-pi was recognized. These results suggest that GST-alpha synthesis is disturbed in the process of hepatocarcinogenesis and results in loss of ICG uptake in HCCs, and also indicate that GST-pi may be useful for early diagnosis of preneoplastic hepatocytes showing no roles in ICG transport.</p

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

Ly49 and C-type lectin receptors on dendritic cells regulate T-cell differentiation as co-stimulatory molecules

The C-type lectin receptors (CLRs) expressed on dendritic cells (DCs) participate in T-cell polarization by recognizing pathogen-associated molecular patterns and activating signaling pathways for cytokine production. In addition, some CLRs expressed on DCs function as co-stimulatory molecules via recognition of endogenous ligands on T cells and regulate proliferation and/or differentiation of T cells. We recently showed that killer cell lectin-like receptor Ly49s3 is expressed in rat thymic DCs and recognizes MHC class I molecules on T cells, for differentiation into naturally occurring regulatory T cells (nTregs). Upon binding to MHC class I molecules on T cells, Ly49s3 seems to stimulate signal transduction pathway(s) leading to up-regulation of the MHC class II genes and then functions as a co-stimulatory molecule. The signaling pathway(s) is supposed to involve Dap12, Syk/Zap70, Lat, Plc-gamma, PKC, PU.1 and C2ta proteins to attain MHC class II expression. Other than Ly49s3, Ly49Q and Ly49B have been shown to be expressed in myeloid cells including DCs and macrophages, raising the possibility that they may be involved in the regulation of T-cell differentiation through recognition of MHC class I molecules on T cells. In humans, immunoglobulin (Ig)-like receptors binding to MHC class I molecules take the place of Ly49 receptors. Among them, expression of the KIR2DL4 gene has been reported to be induced in antigen-presenting cells, although its biological significance is obscure, and immunoglobulin-like transcript 4 (ILT4) expressed in DCs has been shown to down-regulate expression of MHC class II molecules on the same cells, upon binding to MHC class I molecules. They may also be involved in regulation of T-cell differentiation. Some other CLRs are expressed on DCs and possibly function as co-stimulatory molecules. For example, dectin-1, dectin-2 and Dcal-1 have been shown to promote T-cell proliferation, Treg differentiation and IL-4 production of T cells, respectively, through binding to unidentified ligands on T cells. DC-Sign, which recognizes ICAM3 on T cells, is also suggested to be involved in T-cell differentiation. Further investigation of the functional roles of CLRs on DCs will provide insight into the regulatory mechanisms of T-cell differentiation, essential processes for regulating immune responses