SBRT FOR CENTRAL LUNG TUMORS WITH 56 Gy/7 fr

Stereotactic body radiotherapy (SBRT) for centrally‑located lung tumors remains a challenge because of the increased risk of treatment‑related adverse events (AEs), and uncertainty around prescribing the optimal dose. The present study reported the results of central tumor SBRT with 56 Gy in 7 fractions (fr) at the University of Tokyo Hospital. A total of 35 cases that underwent SBRT with or without volumetric‑modulated arc therapy consisting of 56 Gy/7 fr for central lung lesions between 2010 and 2016 at the University of Tokyo Hospital were reveiwed. A central lesion was defined as a tumor within 2 cm of the proximal bronchial tree (RTOG 0236 definition) or within 2 cm in all directions of any critical mediastinal structure. Local control (LC), overall survival (OS), and AEs were investigated. The Kaplan‑Meier method was used to estimate LC and OS. AEs were scored per the Common Terminology Criteria for Adverse Events Version 4.0. Thirty‑five patients with 36 central lung lesions were included. Fifteen lesions were primary non‑small cell lung cancer (NSCLC), 13 were recurrences of NSCLC, and 8 had oligo‑recurrences from other primaries. Median tumor diameter was 29 mm. Eighteen patients had had prior surgery. At a median follow‑up of 13.1 months for all patients and 18.3 months in surviving patients, 22 patients had died, ten due to primary disease (4 NSCLC), while three were treatment‑related. The 1‑ and 2‑year OS were 57.3 and 40.4%, respectively, and median OS was 15.7 months. Local recurrence occurred in only two lesions. 1‑ and 2‑year LC rates were both 96%. Nine patients experienced grade ≥3 toxicity, representing 26% of the cohort. Two of these were grade 5, one pneumonitis and one hemoptysis. Considering the background of the subject, tumor control of our central SBRT is promising, especially in primary NSCLC. However, the safety of SBRT to central lung cancer remains controversial

A Galaxy Merger Scenario for the NGC 1550 Galaxy from Metal Distributions in the X-ray Emitting Plasma

The elliptical galaxy NGC 1550 at a redshift of $z=0.01239$, identified with an extended X-ray source RX J0419+0225, was observed with {\it XMM-Newton} for 31 ks. From the X-ray data and archival near infra-red data of Two Micron All Sky survay, we derive the profiles of components constituting the NGC 1550 system; the gas mass, total mass, metal mass, and galaxy luminosity. The metals (oxygen, silicon, and iron) are extended to $\sim 200$ kpc from the center, wherein $\sim$ 70% of the $K$-band luminosity is carried by NGC 1550 itself. As first revealed with {\it ASCA}, the data reconfirms the presence of a dark halo, of which the mass ($1.6 \times 10^{13} M_{\odot}$) is typical of a galaxy group rather than of a single galaxy. Within 210 kpc, the $K$-band mass-to-light ratio reaches $75 M_{\odot}/L_{\odot}$, which is comparable to those of clusters of galaxies. The iron-mass-to-light ratio profile (silicon- and oxygen mass-to-light ratio profiles as well) exhibits about two orders of magnitude decrease toward the center. Further studies comparing mass densities of metals with those of the other cluster components reveal that the iron (as well as silicon) in the ICM traces very well the total gravitating mass, whereas the stellar component is significantly more concentrated to within several tens kpc of the NGC 1550 nucleus. Thus, in the central region, the amount of metals is significantly depleted for the luminous galaxy light. Among a few possible explanations of this effect, the most likely scenario is that galaxies in this system were initially much more extended than today, and gradually fell to the center and merged into NGC 1550.Comment: 31 pages, 10 figures, 2 table

Regulation of PD-L1 expression in non–small cell lung cancer by interleukin-1β

IntroductionProgrammed cell death–ligand 1 (PD-L1) is a biomarker for prediction of the clinical efficacy of immune checkpoint inhibitors in various cancer types. The role of cytokines in regulation of PD-L1 expression in tumor cells has not been fully characterized, however. Here we show that interleukin-1β (IL-1β) plays a key role in regulation of PD-L1 expression in non–small cell lung cancer (NSCLC).MethodsWe performed comprehensive screening of cytokine gene expression in NSCLC tissue using available single-cell RNA-Sequence data. Then we examined the role of IL-1β in vitro to elucidate its induction of PD-L1 on NSCLC cells.ResultsThe IL-1β gene is highly expressed in the tumor microenvironment, particularly in macrophages. The combination of IL-1β and interferon-γ (IFN-γ) induced a synergistic increase in PD-L1 expression in NSCLC cell lines. IL-1β and IFN-γ also cooperatively activated mitogen-activated protein kinase (MAPK) signaling and promoted the binding of downstream transcription factors to the PD-L1 gene promoter. Furthermore, inhibitors of MAPK signaling blocked upregulation of PD-L1 by IL-1β and IFN-γ.DiscussionOur study reports high levels of IL-1β in the tumor microenvironment may cooperate with IFN-γ to induce maximal PD-L1 expression in tumor cells via activation of MAPK signaling, with the IL-1β–MAPK axis being a promising therapeutic target for attenuation of PD-L1–mediated suppression of antitumor immunity

Analysis of Pharmacokinetics in the Cochlea of the Inner Ear

Sawamura S., Ogata G., Asai K., et al. Analysis of Pharmacokinetics in the Cochlea of the Inner Ear. Frontiers in Pharmacology 12, 633505 (2021); https://doi.org/10.3389/fphar.2021.633505.Hearing loss affects >5% of the global population and therefore, has a great social and clinical impact. Sensorineural hearing loss, which can be caused by different factors, such as acoustic trauma, aging, and administration of certain classes of drugs, stems primarily from a dysfunction of the cochlea in the inner ear. Few therapeutic strategies against sensorineural hearing loss are available. To develop effective treatments for this disease, it is crucial to precisely determine the behavior of ototoxic and therapeutic agents in the microenvironment of the cochlea in live animals. Since the 1980s, a number of studies have addressed this issue by different methodologies. However, there is much less information on pharmacokinetics in the cochlea than that in other organs; the delay in ontological pharmacology is likely due to technical difficulties with accessing the cochlea, a tiny organ that is encased with a bony wall and has a fine and complicated internal structure. In this review, we not only summarize the observations and insights obtained in classic and recent studies on pharmacokinetics in the cochlea but also describe relevant analytical techniques, with their strengths, limitations, and prospects

コンパクト デジタル カメラ ニヨル テンタイ キョウザイ サクセイ ノ カノウセイ ト ジュギョウ エノ ドウニュウ ノ ココロミ

情報機器類の性能向上により,パソコンを含めた情報機器類の教材製作機材としての重要度がますます高くなってきている。その中でもデジタルカメラは,高性能で安価なものが市販され,学校への普及も急速に進んでいる。本論文ではデジタルカメラの中でも特に,安価なコンパクトデジタルカメラを使って,星座の撮影の可能性について検討した。その結果,コンパクトデジタルカメラでも,十分星座写真が写せることが明らかになった。手軽な星座撮影は,新たな教材開発につながるであろう。The performance of information-processing equipment has been greatly improved, thus they become very vital tool for teaching materials. Especially, as for the digital camera, an efficient yet cheap one is marketed. As a result, it was clarified that it is possible to use a compact digital camera to take constellation photograph. the spread of the digital camera to the school is also rapidly advanced. In this paper, we examined the possibility of taking a picture of the constellation in the compact digital camera. As a result, it was clarified to be able to take the constellation photograph with the compact digital camera. It is likely to lead to the development of new teaching material if the constellation photograph can be easily taken.国立情報学研究所『研究紀要公開支援事業』により電子化

Hearing Loss Controlled by Optogenetic Stimulation of Nonexcitable Nonglial Cells in the Cochlea of the Inner Ear

Light-gated ion channels and transporters have been applied to a broad array of excitable cells including neurons, cardiac myocytes, skeletal muscle cells and pancreatic β-cells in an organism to clarify their physiological and pathological roles. Nonetheless, among nonexcitable cells, only glial cells have been studied in vivo by this approach. Here, by optogenetic stimulation of a different nonexcitable cell type in the cochlea of the inner ear, we induce and control hearing loss. To our knowledge, deafness animal models using optogenetics have not yet been established. Analysis of transgenic mice expressing channelrhodopsin-2 (ChR2) induced by an oligodendrocyte-specific promoter identified this channel in nonglial cells—melanocytes—of an epithelial-like tissue in the cochlea. The membrane potential of these cells underlies a highly positive potential in a K+-rich extracellular solution, endolymph; this electrical property is essential for hearing. Illumination of the cochlea to activate ChR2 and depolarize the melanocytes significantly impaired hearing within a few minutes, accompanied by a reduction in the endolymphatic potential. After cessation of the illumination, the hearing thresholds and potential returned to baseline during several minutes. These responses were replicable multiple times. ChR2 was also expressed in cochlear glial cells surrounding the neuronal components, but slight neural activation caused by the optical stimulation was unlikely to be involved in the hearing impairment. The acute-onset, reversible and repeatable phenotype, which is inaccessible to conventional gene-targeting and pharmacological approaches, seems to at least partially resemble the symptom in a population of patients with sensorineural hearing loss. Taken together, this mouse line may not only broaden applications of optogenetics but also contribute to the progress of translational research on deafness

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

Why Are Outcomes Different for Registry Patients Enrolled Prospectively and Retrospectively? Insights from the Global Anticoagulant Registry in the FIELD-Atrial Fibrillation (GARFIELD-AF).

Background: Retrospective and prospective observational studies are designed to reflect real-world evidence on clinical practice, but can yield conflicting results. The GARFIELD-AF Registry includes both methods of enrolment and allows analysis of differences in patient characteristics and outcomes that may result. Methods and Results: Patients with atrial fibrillation (AF) and ≥1 risk factor for stroke at diagnosis of AF were recruited either retrospectively (n = 5069) or prospectively (n = 5501) from 19 countries and then followed prospectively. The retrospectively enrolled cohort comprised patients with established AF (for a least 6, and up to 24 months before enrolment), who were identified retrospectively (and baseline and partial follow-up data were collected from the emedical records) and then followed prospectively between 0-18 months (such that the total time of follow-up was 24 months; data collection Dec-2009 and Oct-2010). In the prospectively enrolled cohort, patients with newly diagnosed AF (≤6 weeks after diagnosis) were recruited between Mar-2010 and Oct-2011 and were followed for 24 months after enrolment. Differences between the cohorts were observed in clinical characteristics, including type of AF, stroke prevention strategies, and event rates. More patients in the retrospectively identified cohort received vitamin K antagonists (62.1% vs. 53.2%) and fewer received non-vitamin K oral anticoagulants (1.8% vs . 4.2%). All-cause mortality rates per 100 person-years during the prospective follow-up (starting the first study visit up to 1 year) were significantly lower in the retrospective than prospectively identified cohort (3.04 [95% CI 2.51 to 3.67] vs . 4.05 [95% CI 3.53 to 4.63]; p = 0.016). Conclusions: Interpretations of data from registries that aim to evaluate the characteristics and outcomes of patients with AF must take account of differences in registry design and the impact of recall bias and survivorship bias that is incurred with retrospective enrolment. Clinical Trial Registration: - URL: http://www.clinicaltrials.gov . Unique identifier for GARFIELD-AF (NCT01090362)