生体外培養刺激系を用いた自家消化器癌特異的細胞傷害性T細胞の誘導

取得学位 : 博士（医学）, 学位授与番号 : 医博甲第998号, 学位授与年月日：平成3年3月25日,学位授与年：199

ヒト胃癌における癌抑制遺伝子p53の発現に関する研究

金沢大学がん進展制御研究所早期胃癌に対する内視鏡的治療や縮小手術の適応を考察する際に問題となるリンパ節転移を予測するため、新たな因子として胃粘膜下層浸潤癌(sm癌)の粘膜下層への浸潤の程度を細分類し検討した。すなわち粘膜下層の粘膜筋板下縁から固有筋層上縁までの距離を3等分して管腔側からそれぞれ浅層:sm1、中層:sm2、深層:sm3とし、さらにsm1については、粘膜筋板より固有筋層側へ300μmまでのごくわずかな範囲の粘膜下層にのみ浸潤を認めるものをsm1-α、それ以上のものをsm1-βとして2つに区分した。当教室で経験したsm癌切除症例235例を以上の細分類により検討すると、浸潤度sm1-αで腫瘍径30mm以下のもの、sm1-β、sm2の10mm以下のものおよび30mm以下のsm1-βで腫瘍先進部の組織型が高分化型ly(-)Ul(-)のものにリンパ節転移を認めず、この範囲のsm癌に対して根治的内視鏡的切除術の適応拡大の可能性が示唆された。一方、癌関連遺伝子の一つであるp53遺伝子の異常がp53蛋白の核内異常蓄積としてとらえられ、しかも癌の病期や進行度、予後と密接に相関していると注目されている。このような観点から表層拡大型胃癌と小型浸潤進行胃癌のp53蛋白の異常発現について検討を試みた。当教室で経験した表層拡大型胃癌(直径5cm以上、m癌)29例と小型浸潤進行胃癌(直径2cm未満、mp以上浸潤)12例を対象としp53蛋白の異常発現を検討した結果、表層拡大型胃癌と小型浸潤進行胃癌との間にはp53蛋白発現の有意差は見られなかった。またp53蛋白の発現とリンパ節転移との関係も認められなかった。現在は胃sm癌の細分類とp53蛋白の発現の関係について検討中である。研究課題/領域番号:08770965, 研究期間(年度):1996出典：研究課題「 ヒト胃癌における癌抑制遺伝子p53の発現に関する研究」課題番号08770965（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-08770965/）を加工して作

Structure and Effective Pair Potentials of Molten CuBr Estimated from the Anomalous X-ray Scattering Measurements

The anomalous x-ray scattering (AXS) measurements for molten CuBr have been made using the energies close to the Cu K(8.980 keV) and Br K (13.470 keV) absorption edges for estimating three partial structural functions, Cu-Cu, Br-Br and Cu-Br pairs by combining with the intensity data obtained at the energy of 17.0 keV, which is far from both edges. The data processing for obtaining three partials includes the help of the reverse Monte Carlo (RMC) simulation technique. The resultant structure factor of a_(Q) for cation-cation pairs was found to be rather structureless and the closest Cu-Cu distance in molten CuBr was significantly smaller than that of a_(Q) for anion-anion pairs, suggesting the like-ion penetration into the first unlike-ion coordination shell, similar to the molten CuCl case. The effective pair potentials of molten CuBr were also estimated from these experimental partial structural data by applying the modified hypernetted-chain (MHNC) equation coupled with a "predictor-corrector method" originally proposed by Reatto et al. in 1986 for a single component liquid system. It may be worth mentioning that the resultant pair potential for Cu-Cu pairs shows remarkable shielding for the Coulomb repulsion in its nearest neighbor region

Complete Ring Artifacts Reduction Procedure for Lab-Based X-ray Nano CT Systems

In this article, we introduce a new ring artifacts reduction procedure that combines several ideas from existing methods into one complex and robust approach with a goal to overcome their individual weaknesses and limitations. The procedure differentiates two types of ring artifacts according to their cause and character in computed tomography (CT) data. Each type is then addressed separately in the sinogram domain. The novel iterative schemes based on relative total variations (RTV) were integrated to detect the artifacts. The correction process uses the image inpainting, and the intensity deviations smoothing method. The procedure was implemented in scope of lab-based X-ray nano CT with detection systems based on charge-coupled device (CCD) and scientific complementary metal-oxide-semiconductor (sCMOS) technologies. The procedure was then further tested and optimized on the simulated data and the real CT data of selected samples with different compositions. The performance of the procedure was quantitatively evaluated in terms of the artifacts' detection accuracy, the comparison with existing methods, and the ability to preserve spatial resolution. The results show a high efficiency of ring removal and the preservation of the original sample's structure

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