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

Association of increasing gross tumor volume dose with tumor volume reduction and local control in fractionated stereotactic radiosurgery for unresected brain metastases

Abstract Background Fractionated stereotactic radiosurgery (fSRS) is an important treatment strategy for unresected brain metastases. We previously reported that a good volumetric response 6 months after fSRS can be the first step for local control. Few studies have reported the association between gross tumor volume (GTV) dose, volumetric response, and local control in patients treated with the same number of fractions. Therefore, in this study, we aimed to investigate the GTV dose and volumetric response 6 months after fSRS in five daily fractions and identify the predictive GTV dose for local failure (LF) for unresected brain metastasis. Methods This retrospective study included 115 patients with 241 unresected brain metastases treated using fSRS in five daily fractions at our hospital between January 2013 and April 2022. The median prescription dose was 35 Gy (range, 30–35 Gy) in five fractions. The median follow-up time after fSRS was 16 months (range, 7–66 months). Results GTV D80 > 42 Gy and GTV D98 > 39 Gy were prognostic factors for over 65% volume reduction (odds ratio, 3.68, p  42 Gy was also a prognostic factor for LF (hazard ratio, 0.37; p = 0.01). Conclusions GTV D80 > 42 Gy in five fractions led to better volume reduction and local control. The goal of planning an inhomogeneous dose distribution for fSRS in brain metastases may be to increase the GTV D80 and GTV D98. Further studies on inhomogeneous dose distributions are required

Failure patterns after adjuvant chemoradiotherapy following endoscopic resection for superficial esophageal squamous cell carcinoma

Abstract Background This study evaluated the locations of lymph node recurrence and their association with irradiation fields used for radiotherapy after adjuvant chemoradiotherapy following endoscopic resection for superficial esophageal squamous cell carcinoma. Methods Medical records of 96 consecutive patients with superficial esophageal squamous cell carcinoma who underwent adjuvant chemoradiotherapy following endoscopic resection were reviewed. Computed tomography was used to identify whether nodal recurrences were within the elective nodal irradiation field. The cumulative incidence of recurrence was calculated, accounting for death as a competing risk. Univariate and multivariate analyses identified factors predicting nodal recurrence. Results The median follow‐up period was 61 months (range: 6‐137 months). Seven patients (7.3%) developed lymph node recurrence only; two patients (2.1%) developed nodal plus local recurrence. Six of the seven cases without local recurrence involved the elective nodal irradiation field, with five cases involving the recurrent nerve lymph nodes. The 5‐year cumulative incidence of lymph node recurrence was higher for T1b tumors with lymphovascular invasion than for T1a tumors with lymphovascular invasion (17.6% vs 6.2%, P = 0.086; HR: 3.74, 95% CI: 0.80‐17.52, P = 0.094) and T1b tumors without lymphovascular invasion (17.6% vs 3.3%, P = 0.031; HR: 6.78, 95% CI: 0.80‐57.63, P = 0.080). Conclusions Lymph node recurrence frequently involved the elective nodal irradiation field, with recurrent nerve lymph nodes being common metastasis sites. The high incidence of nodal recurrence for T1b tumors with lymphovascular invasion highlights a need for new strategies for treating this subset of superficial esophageal squamous cell carcinomas

Improvement of image quality and assessment of respiratory motion for hepatocellular carcinoma with portal vein tumor thrombosis using contrast-enhanced four-dimensional dual-energy computed tomography.

To assess the objective and subjective image quality, and respiratory motion of hepatocellular carcinoma with portal vein tumor thrombosis (PVTT) using the contrast-enhanced four-dimensional dual-energy computed tomography (CE-4D-DECT). For twelve patients, the virtual monochromatic image (VMI) derived from the CE-4D-DECT with the highest contrast to noise ratio (CNR) was determined as the optimal VMI (O-VMI). To assess the objective and subjective image quality, the CNR and five-point score of the O-VMI were compared to those of the standard VMI at 77 keV (S-VMI). The respiratory motion of the PVTT and diaphragm was measured based on the exhale and inhale phase images. The VMI at 60 keV yielded the highest CNR (4.8 ± 1.4) which was significantly higher (p = 0.02) than that in the S-VMI (3.8 ± 1.2). The overall image quality (4.0 ± 0.6 vs 3.1 ± 0.5) and tumor conspicuity (3.8 ± 0.8 vs 2.8 ± 0.6) of the O-VMI determined by three radiation oncologists was significantly higher (p < 0.01) than that of the S-VMI. The diaphragm motion in the L-R (3.3 ± 2.5 vs 1.2 ± 1.1 mm), A-P (6.7 ± 4.0 vs 1.6 ± 1.3mm) and 3D (8.8 ± 3.5 vs 13.1 ± 4.9 mm) directions were significantly larger (p < 0.05) compared to the tumor motion. The improvement of objective and subjective image quality was achieved in the O-VMI. Because the respiratory motion of the diaphragm was larger than that of the PVTT, we need to be pay attention for localizing target in radiotherapy

External validation of a multifactorial normal tissue complication probability model for tube feeding dependence at 6 months after definitive radiotherapy for head and neck cancer

Background and purpose: The purpose of this study was to externally validate a previously published normal tissue complication probability (NTCP) model for tube feeding dependence at 6 months (TUBEM6) after completion of (chemo) radiotherapy. Materials and methods: This study evaluated 122 head and neck cancer patients treated by definitive (chemo) radiotherapy. The closed testing procedure was used to select the appropriate method for updating the NTCP model. In this procedure, the likelihood ratio test was used to compare the updated model against the original model. Results: Mean predicted NTCP was 12.2% (95% CI: 9.9%-14.5%) when using the original NTCP model for TUBEM6. TUBEM6 at our institute was 5.7% (95% CI: 1.8-9.6%) for the 122 patients evaluated. The test for the model revision against the original NTCP model was statistically significant (p = 0.032). The test for the model revision against the model adjusting intercept only was not statistically significant (p = 0.240). According to the closed testing procedure, the model required adjusting the intercept only. Conclusions: TUBEM6 at our institute was lower than that predicted by the original NTCP model. The closed testing procedure indicated that only an adjustment of the intercept was needed indicating the importance of external validation. (C) 2018 Elsevier B.V. All rights reserved