Superficial Depressed Type (IIc) Early Cancer of the Colon : Report of Two Cases

Two cases of superficial depressed type (IIc) early cancer of the colon are reported. Case 1 was a 65-year-old male and case 2 a 69-year old male. The lesion was located in the descending colon in both cases, and was removed by strip biopsy endoscopically in the former and surgically in the latter. The size of the lesion after resection was 6 mm in case 1 and 5 mm in case 2. Histopathologically, both cases were well differentiated adenocarcinoma without adenomatous components, and carcinoma developed de novo by submucosal (sm) invasion. As to the immunohistochemical staining of the cancer tissue by tumor associated antigen, case 1 showed a strong expression of carcinoembrionic antigen (CEA) and partial expression of sialyl Lewisx, and case 2 showed expressions of both CEA and sialyl Lewisx . The nuclear DNA content by flow cytometry was aneuploid only in case 1. Thus, although the two cases were morphologically the same IIc type cancer, the process of carcinogenesis and secondary phenomena varied

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

Remarkable Differences in Calcification between the Primary Tumor and Metastatic Lymph Nodes in a Patient with ALK-Positive Non-Small-Cell Lung Cancer

Calcified bilateral mediastinal lymph nodes are not common in malignant tumors. A 51-year-old woman presented to our hospital with a 20 mm nodule in the lower left lobe of the lung and extensive calcification in the bilateral mediastinal lymph nodes. Computed tomography indicated no calcification of the primary lesion. Immunohistochemical staining and fluorescent in situ hybridization detected an anaplastic lymphoma kinase (ALK) fusion. Treatment with alectinib, an ALK inhibitor, led to a significant reduction in tumor size and calcification in the lymph nodes. This case shows that different degrees of calcification can be associated with malignant tumors and may be reversible in some cases

Modulation of Murine Macrophage TLR7/8-Mediated Cytokine Expression by Mesenchymal Stem Cell-Conditioned Medium

Increasing evidence suggests that mesenchymal stem cells (MSCs) play anti-inflammatory roles during innate immune responses. However, little is known about the effect of MSCs or their secretions on the ligand response of Toll-like receptor (TLR) 7 and TLR8, receptors that recognize viral single-stranded RNA (ssRNA). Macrophages play a critical role in the innate immune response to ssRNA virus infection; therefore, we investigated the effect of MSC-conditioned medium on cytokine expression in macrophages following stimulation with TLR7/8 ligands. After stimulation with TLR7/8 ligand, bone marrow-derived macrophages cultured with MSCs or in MSC-conditioned medium expressed lower levels of tumor necrosis factor (TNF) α and interleukin (IL) 6 and higher levels of IL-10 compared to macrophages cultured without MSCs or in control medium, respectively. The modulations of cytokine expression were associated with prostaglandin E2 (PGE2) secreted by the MSCs. PGE2 enhanced extracellular signal-related kinase (ERK) signaling and suppressed nuclear factor-κB (NF-κB) signaling. Enhanced ERK signaling contributed to enhanced IL-10 production, and suppression of NF-κB signaling contributed to the low production of TNF-α. Collectively, these results indicate that MSCs and MSC-conditioned medium modulate the cytokine expression profile in macrophages following TLR7/8-mediated stimulation, which suggests that MSCs play an immunomodulatory role during ssRNA virus infection