New Paradigms of Radiotherapy for Bone Metastasis

Proper care of patients with bone metastasis requires interdisciplinary treatments. Radiotherapy (RT) plays a central role in the management of painful bone metastasis. External beam RT can provide rapid successful palliation of painful bone metastasis in 50–80% of patients, is associated with very few adverse effects and leads to complete pain relief at the treated site in up to one‐third of patients. Intensity‐modulated RT (IMRT) or stereotactic body RT (SBRT) enables the delivery of higher doses to the target tumor while minimizing the dose to adjacent organs. Reirradiation using IMRT or SBRT is a valuable option for the management of bone metastases. A multidisciplinary team, especially one consisting of a spinal surgeon and rehabilitation physician, is particularly useful for treating patients with spinal bone metastases characterized by spinal instability. Rehabilitation intervention which increases the physical activity level and prevents deconditioning is important. Future developments in surgical procedures and RT will likely improve the management protocols for bone metastases and technology to reduce metal artifacts in radiation planning might improve the efficacy and safety of combination therapy

VLBI study of water maser emission in the Seyfert 2 galaxy NGC5793. I: Imaging blueshifted emission and the parsec-scale jet

We present the first result of VLBI observations of the blueshifted water maser emission from the type 2 Seyfert galaxy NGC5793, which we combine with new and previous VLBI observations of continuum emission at 1.7, 5.0, 8.4, 15, and 22 GHz. Maser emission was detected earlier in single-dish observations and found to have both red- and blueshifted features relative to the systemic velocity. We could image only the blueshifted emission, which is located 3.6 pc southwest of the 22 GHz continuum peak. The blueshifted emission was found to originate in two clusters that are separated by 0.7 milliarcsecond (0.16 pc). No compact continuum emission was found within 3.6 pc of the maser spot. A compact continuum source showing a marginally inverted spectrum between 1.7 and 5.0 GHz was found 4.2 pc southwest of the maser position. The spectral turnover might be due to synchrotron self-absorption caused by a shock in the jet owing to collision with dense gas, or it might be due to free-free absorption in an ionized screen possibly the inner part of a disk, foreground to the jet. The water maser may be part of a maser disk. If so, it would be rotating in the opposite sense to the highly inclined galactic disk observed in CO emission. We estimate a binding mass within 1 pc of the presumed nucleus to be on the order of 10^7 Msun. Alternatively, the maser emission could result from the amplification of a radio jet by foreground circumnuclear molecular gas. In this case, the high blueshift of the maser emission might mean that the masing region is moving outward away from the molecular gas surrounding an active nucleus.Comment: 20 pages, 6 figures, to appear in ApJ, Oct. 200

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

The Corvée System ”Yao 徭” in the Qin and Han Dynasties

特集　出土文獻と秦楚文化（Ⅱ）/編集責任　小寺

Comparative study of sub-second temporal resolution 4D-MRI and 4D-CT for target motion assessment in a phantom model

Abstract To develop and investigate the feasibility of sub-second temporal resolution volumetric T1-weighted four-dimensional (4D-) MRI in comparison with 4D-CT for respiratory-correlated motion assessment using an MRI/CT-compatible phantom. Sub-second high temporal resolution (0.5 s) gradient-echo T1-weighted 4D-MRI was developed using a volumetric acquisition scheme with compressed sensing. An MRI/CT-compatible motion phantom (simulated liver tumor) with three sinusoidal movements of amplitudes and two respiratory patterns was introduced and imaged with 4D-MRI and 4D-CT to investigate the geometric accuracy of the target movement. The geometric accuracy, including centroid position, volume, similarity index of dice similarity coefficient (DSC), and Hausdorff distance (HD), was systematically evaluated. Proposed 4D-MRI achieved a similar geometric accuracy compared with 4D-CT regarding the centroid position, volume, and similarity index. The observed position differences of the absolute average centroid were within 0.08 cm in 4D-MRI and 0.03 cm in 4D-CT, less than the 1-pixel resolution for each modality. The observed volume difference in 4D-MRI/4D-CT was within 0.73 cm3 (4.5%)/0.29 cm3 (2.1%) for a large target and 0.06 cm3 (11.3%)/0.04 cm3 (11.6%) for a small target. The observed DSC values for 4D-MRI/4D-CT were at least 0.93/0.95 for the large target and 0.83/0.84 for the small target. The maximum HD values were 0.25 cm/0.31 cm for the large target and 0.21 cm/0.15 cm for the small target. Although 4D-CT potentially exhibit superior numerical accuracy in phantom studies, the proposed high temporal resolution 4D-MRI demonstrates sub-millimetre geometric accuracy comparable to that of 4D-CT. These findings suggest that the 4D-MRI technique is a viable option for characterizing motion and generating phase-dependent internal target volumes within the realm of radiotherapy

Exosome-mediated radiosensitizing effect on neighboring cancer cells via increase in intracellular levels of reactive oxygen species

The precise mechanism of intercellular communication between cancer cells following radiation exposure is unclear. Exosomes are membrane-enclosed small vesicles comprising lipid bilayers and are mediators of intercellular communication that transport a variety of intracellular components, including microRNAs (miRNAs or miRs). The present study aimed to identify novel roles of exosomes released from irradiated cells to neighboring cancer cells. In order to confirm the presence of exosomes in the human pancreatic cancer cell line MIAPaCa-2, ultracentrifugation was performed followed by transmission electron microscopy and nanoparticle tracking analysis (NanoSight) using the exosome-specific surface markers CD9 and CD63. Subsequent endocytosis of exosomes was confirmed by fluorescent microscopy. Cell survival following irradiation and the addition of exosomes was evaluated by colony forming assay. Expression levels of miRNAs in exosomes were then quantified by microarray analysis, while protein expression levels of Cu/Zn- and Mn-superoxide dismutase (SOD1 and 2, respectively) enzymes in MIAPaCa-2 cells were evaluated by western blotting. Results showed that the uptake of irradiated exosomes was significantly higher than that of non-irradiated exosomes. Notably, irradiated exosomes induced higher intracellular levels of reactive oxygen species (ROS) and a higher frequency of DNA damage in MIAPaCa-2 cells, as determined by fluorescent microscopy and immunocytochemistry, respectively. Moreover, six up- and five downregulated miRNAs were identified in 5 and 8 Gy-irradiated cells using miRNA microarray analyses. Further analysis using miRNA mimics and reverse transcription-quantitative PCR identified miR-6823-5p as a potential candidate to inhibit SOD1, leading to increased intracellular ROS levels and DNA damage. To the best of our knowledge, the present study is the first to demonstrate that irradiated exosomes enhance the radiation effect via increasing intracellular ROS levels in cancer cells. This contributes to improved understanding of the bystander effect of neighboring cancer cells