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

lmmunohistochemical analysis for cell proliferation-related protein expression in small cell carcinoma of the esophagus; a comparative study with small cell carcinoma of the lung and squamous cell carcinoma of the esophagus

Small cell carcinoma is a rare neoplasm in the esophagus. To evaluate cell proliferation activity and its underlying mechanisms in this tumor, we examined immunohistochemically 5 cases of small cell carcinoma of the esophagus (SCCE) for expressions of tumor suppressor proteins, oncoproteins and cell proliferation markers including p53, p21WAF1/C1P1r,e tinoblastoma (Rb) protein, bcl-2, Ki-67 and PCNA, and compared the results with those of 5 cases of small cell carcinoma of the lung (SCCL) and 10 cases of squamous cell carcinoma of the esophagus (SQCE). The prevalence and labeling index of p53-immunoreactivity tended to be higher in SCCE (415; 56.6%) and SCCL (415; 79.9%) than in SQCE (6110; 48.8%). Expression of p21wAFl/C1P1w as observed in 2 of 10 cases of SQCE. In contrast, its expression could not be detected in any cases of SCCE and SCCL examined. Expression of Rb protein was observed in 9 out of 10 cases of SQCE, but not in any cases of SCCE and SCCL. SCCE and SCCL showed more frequent and intense immunoreactivity for bcl-2 than SQCE. In expression of cell proliferation markers (Ki-67 and PCNA), no remarkable difference was observed among SCCE, SCCL and SQCE. These results suggest that SCCE and SCCL could share some genetic alternations including mutation of p53, loss of Rb gene and overexpression of bcl-2, and these may be related to the similar biological potentials between the two. Futhermore, SCCE was different from SQCE in expression of Rb protein and bcl-2, and these two types of esophageal carcinoma could arise through different molecular mechanisms

Uterine carcinosarcoma-induced pulmonary tumor thrombotic microangiopathy: A case report

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare complication of cancer. It is histologically characterized by fibrocellular intimal proliferation in small pulmonary arteries and arterioles in patients with metastatic carcinoma. It is most frequently caused by adenocarcinoma. We report a case of PTTM caused by uterine carcinosarcoma in a 62-year-old female, who exhibited reductions in blood pressure and oxygen saturation. This is the first case report about uterine carcinosarcoma-induced PTTM. Histologically, the primary uterine carcinosarcoma included serous carcinoma and homologous sarcoma components. Many tumor emboli were observed across large regions of both lungs. PTTM was found in the lower lobes. Interestingly, the embolized tumor cells were all derived from the adenocarcinoma component. Immunohistologically, the primary carcinosarcomaexhibited weak positivity for tissue factor (TF), but was negativefor vascular endothelial growth factor-A (VEGF-A). The PTTM tumor cells were positive for TF and weakly positive for VEGF-A. This case suggests that any tumor containing adenocarcinoma can cause PTTM, and immunostaining of the primary tumor might be worthless for determining whether PTTM will develop. PTTM should always be considered during the differential diagnosis of dyspnea in patients with adenocarcinoma. Keywords: Pulmonary tumor thrombotic microangiopathy, Pulmonary tumor embolism, Vascular endothelial growth factor, Tissue factor, Uterine carcinosarcom

Up-Regulation of S100A11 in Lung Adenocarcinoma - Its Potential Relationship with Cancer Progression.

We previously reported that patients with lung adenocarcinomas with KRAS gene mutations and strong proliferating activity had poorer outcomes, even in the early stage of the disease. The aim of the present study was to elucidate the potential molecular basis of these highly malignant lung tumors by focusing on S100 proteins (S100A2, S100A7, and S100A11), which are downstream targets of oncogenic KRAS and promoters of tumor progression. The immunohistochemical expression of S100 proteins was examined in 179 primary lung adenocarcinomas, and the potential relationships between their levels and clinicopathologic factors were analyzed. Among the three subtypes, S100A11 levels were significantly higher in adenocarcinomas with KRAS mutations and strong proliferating activity. They were also higher in adenocarcinomas with poorly differentiated tumors. Furthermore, higher levels of S100A11 were associated with shorter disease-free survival. These results suggest that the up-regulation of S100A11 plays a role in tumor progression, particularly in KRAS-mutated lung adenocarcinomas