一般住民コホートを用いた手指の変形性関節症の関連因子とバイオマーカーに関する多角的研究

学位の種別: 課程博士審査委員会委員 : （主査）東京大学教授 芳賀 信彦, 東京大学准教授 筑田 博隆, 東京大学准教授 須佐美 隆史, 東京大学准教授 池田 均, 東京大学准教授 北中 幸子University of Tokyo(東京大学

Risk factors of immune checkpoint inhibitor-related interstitial lung disease in patients with lung cancer : a single-institution retrospective study

Immune checkpoint inhibitors (ICIs) elicit antitumour effects by activating the host immunity and cause immune-related adverse events (irAEs). ICI-related interstitial lung disease (ICI-ILD) is a fatal irAE that is difficult to treat; moreover, its incidence is relatively higher in patients with lung cancer. Therefore, early ICI-ILD detection and intervention are important for patient safety. However, a risk assessment method for ICI-ILD has not been established and the prediction of ICI-ILD occurrence is difficult. The aim of our study was to identify the risk factors associated with ICI-ILD. To this end, we retrospectively analysed 102 patients with lung cancer who first received ICI and completed the treatment between April 2016 and December 2019 at Tokushima University Hospital. Nineteen patients had all grades of ICI-ILD and 10 had grade ≥ 3 ICI-ILD. The 30-day mortality rate of patients with grade ≥ 3 ICI-ILD was the highest among all patients (P < 0.01). The multivariate logistic analysis indicated that the performance status ≥ 2 alone and both performance status ≥ 2 and ≥ 50 pack-year were independent risk factors of ICI-ILD of grade ≥ 3 and all grades, respectively. Overall, our study provides insights to predict ICI-ILD occurrence

Catalogue and Systematics of Pliensbachian, Toarcian and Aalenian Radiolarian Genera and Species

This volume comprises a catalogue of 90 genera, 274 species and 13 subspecies of Pliensbachian, Toarcian and Aalenian Radiolaria. Two genera, 37 species and 3 subspecies are new formal descriptions, 24 species are described in open nomenclature. Each taxon is presented with a complete and up-to-date synonymy, original description and original remarks (translated into English where necessary), subsequent emendations, remarks by the authors of this catalogue, and etymology. Descriptions of species/subspecies further contain the original measurements, type locality, and data on geographic distribution. Plates illustrate the holotype and one or several specimens from our material, from different paleogeographic realms where possible. The material was collected from 30 measured sections in the Circum-Pacific belt (Baja California Peninsula, Oregon, British Columbia, Japan) and the Tethyan realm (Oman, Turkey, Slovenia, Austria). Abbreviated locality information and a list of all treated taxa are given in the last two chapters.A useful book for paleontologists interested in taxonomy of Jurassic radiolarians.Katalog obsega 90 rodov, 274 vrst in 13 podvrst radiolarijev iz treh stopenj v spodnji in srednji juri: pliensbachija, toarcija in aalenija. Dva rodova, 37 vrst in 3 podvrste so formalno opisani novi taksoni, 24 vrst je opisanih v odprti nomenklaturi. Vsak takson je predstavljen z vso dosedanjo sinonimiko, originalnim opisom in originalnimi opombami (v prevodu, če originalni jezik ni angleščina), poznejšimi revizijami, pripombami avtorjev tega kataloga in etimologijo. Opisi vrst in podvrst vsebujejo še originalne meritve, ime tipične lokalitete in podatke o geografski razširjenosti. Vsaka vrsta ali podvrsta je predstavljena s samostojno tablo, na kateri so slike holotipa in več primerkov iz naših vzorcev. Kjer je mogoče, so ilustrirani primerki z različnih paleogeografskih območij. Vzorci so bili pobrani na 30 profilih, posnetih v cirkumpacifiškem pasu (Kalifornijski polotok, Oregon, Britanska Kolumbija, Japonska) in v območju Tetide (Oman, Turčija, Slovenija, Avstrija). Dodatek na koncu knjige vsebuje kratek opis vzorčevanih profilov in seznam vseh obravnavanih taksonov

マウスにおける動脈硬化性急性大動脈症候群の発症に対するケルセチンの予防効果

Atherosclerosis-related acute aortic syndromes, such as aortic aneurysms or aortic dissection are life-threatening diseases. Since they develop suddenly and progress rapidly, the establishment of preventive strategies is urgently needed. Quercetin, a flavonoid abundant in various vegetables and fruits, is suggested to reduce the risk of cardiovascular disease. Therefore, in this study, the preventive effect of quercetin was evaluated using a mouse model of aortic aneurysm and dissection. The model was established by administering angiotensin II (Ang II) and β-aminopropionitrile (BAPN), a lysyl oxidase inhibitor, to mice to induce hypertension and degeneration of the elastic lamina, which would eventually result in the onset of an aortic aneurysm. Ang II, BAPN, and a nitric oxide synthase inhibitor was administered to induce aortic dissection via endothelial dysfunction. Quercetin (60 mg/kg/day) was administered 2 weeks before inducing aortic diseases by the end of the experiments (8 weeks in the aneurysm model, 6 weeks in the dissection model). It was found to reduce the incidence of aneurysm (from 72 to 45%), dissection (from 17 to 10%), and rupture (from 33 to 15%) in mice. Elastin degradation was ameliorated in the quercetin-treated mice compared to that in the mice without quercetin treatment (degradation score 2.9 ± 0.3 vs 2.2 ± 0.2). Furthermore, quercetin suppressed the expression of vascular cell adhesion molecule-1, macrophage infiltration, and pro-matrix metalloproteinase-9 activity. Our results suggest that quercetin might prevent the onset of atherosclerosis-related acute aortic syndromes through its anti-inflammatory and endothelial cell-protective effects

A Comprehensive Study of Short Bursts from SGR 1806-20 and SGR 1900+14 Detected by HETE-2

We present the results of temporal and spectral studies of the short burst (less than a few hundred milliseconds) from the soft gamma repeaters (SGRs) 1806-20 and 1900+14 using the HETE-2 samples. In five years from 2001 to 2005, HETE-2 detected 50 bursts which were localized to SGR 1806-20 and 5 bursts which were localized to SGR 1900+14. Especially SGR 1806-20 was active in 2004, and HETE-2 localized 33 bursts in that year. The cumulative number-intensity distribution of SGR 1806-20 in 2004 is well described by a power law model with an index of -1.1+/-0.6. It is consistent with previous studies but burst data taken in other years clearly give a steeper distribution. This may suggest that more energetic bursts could occur more frequently in periods of greater activity. A power law cumulative number-intensity distribution is also known for earthquakes and solar flares. It may imply analogous triggering mechanisms. Although spectral evolution during bursts with a time scale of > 20 ms is not common in the HETE-2 sample, spectral softening due to the very rapid (< a few milliseconds) energy reinjection and cooling may not be excluded. The spectra of all short bursts are well reproduced by a two blackbody function (2BB) with temperatures ~4 and ~11 keV. From the timing analysis of the SGR 1806-20 data, a time lag of 2.2+/-0.4 ms is found between the 30-100 keV and 2-10 keV radiation bands. This may imply (1) a very rapid spectral softening and energy reinjection, (2) diffused (elongated) emission plasma along the magnetic field lines in pseudo equilibrium with multi-temperatures, or (3) a separate (located at < 700 km) emission region of softer component (say, ~4 keV) which could be reprocessed X-rays by higher energy (> 11 keV) photons from an emission region near the stellar surface.Comment: 50 pages, 14 figures, accepted for publication in PAS

An Optically Dark GRB Observed by HETE-2: GRB 051022

GRB 051022 was detected at 13:07:58 on 22 October 2005 by HETE-2. The location of GRB 051022 was determined immediately by the flight localization system. This burst contains multiple pulses and has a rather long duration of about 190 seconds. The detections of candidate X-ray and radio afterglows were reported, whereas no optical afterglow was found. The optical spectroscopic observations of the host galaxy revealed the redshift z = 0.8. Using the data derived by HETE-2 observation of the prompt emission, we found the absorption N_H = 8.8 -2.9/+3.1 x 10^22 cm^-2 and the visual extinction A_V = 49 -16/+17 mag in the host galaxy. If this is the case, no detection of any optical transient would be quite reasonable. The absorption derived by the Swift XRT observations of the afterglow is fully consistent with those obtained from the early HETE-2 observation of the prompt emission. Our analysis implies an interpretation that the absorbing medium could be outside external shock at R ~ 10^16 cm, which may be a dusty molecular cloud.Comment: 6 pages, 2 figures, accepted for publication in PASJ lette

Spectral Lag Relations in GRB Pulses Detected with HETE-2

Using a pulse-fit method, we investigate the spectral lags between the traditional gamma-ray band (50-400 keV) and the X-ray band (6-25 keV) for 8 GRBs with known redshifts (GRB 010921, GRB 020124, GRB 020127, GRB 021211, GRB 030528, GRB 040924, GRB 041006, GRB 050408) detected with the WXM and FREGATE instruments aboard the HETE-2 satellite. We find several relations for the individual GRB pulses between the spectral lag and other observables, such as the luminosity, pulse duration, and peak energy (Epeak). The obtained results are consistent with those for BATSE, indicating that the BATSE correlations are still valid at lower energies (6-25 keV). Furthermore, we find that the photon energy dependence for the spectral lags can reconcile the simple curvature effect model. We discuss the implication of these results from various points of view.Comment: 13 pages, 9 figures, accepted for the publication in PASJ (minor corrections

Preclinical evaluation of the efficacy of an antibody to human SIRPα for cancer immunotherapy in humanized mouse models

Tumor-associated macrophages (TAMs) are abundant in the tumor microenvironment and are considered potential targets for cancer immunotherapy. To examine the antitumor effects of agents targeting human TAMs in vivo, we here established preclinical tumor xenograft models based on immunodeficient mice that express multiple human cytokines and have been reconstituted with a human immune system by transplantation of human CD34$^{+}$ hematopoietic stem and progenitor cells (HIS-MITRG mice). HIS-MITRG mice supported the growth of both human cell line (Raji)- and patient-derived B cell lymphoma as well as the infiltration of human macrophages into their tumors. We examined the potential antitumor action of an antibody to human SIRPα (SE12C3) that inhibits the interaction of CD47 on tumor cells with SIRPα on human macrophages and thereby promotes Fcγ receptor-mediated phagocytosis of the former cells by the latter. Treatment with the combination of rituximab (antibody to human CD20) and SE12C3 inhibited Raji tumor growth in HIS-MITRG mice to a markedly greater extent than did rituximab monotherapy. This enhanced antitumor effect was dependent on human macrophages and attributable to enhanced rituximab-dependent phagocytosis of lymphoma cells by human macrophages. Treatment with rituximab and SE12C3 also induced reprogramming of human TAMs toward a proinflammatory phenotype. Furthermore, the combination treatment essentially prevented the growth of patient-derived diffuse large B cell lymphoma in HIS-MITRG mice. Our findings thus support the study of HIS-MITRG mice as a model for the preclinical evaluation in vivo of potential therapeutics, such as antibodies to human SIRPα, that target human TAMs

Heliocentric Distance Dependence of Zodiacal Light Observed by Hayabusa2#

Zodiacal light (ZL) is sunlight scattered by interplanetary dust particles (IDPs) at optical wavelengths. The spatial distribution of IDPs in the Solar System may hold an important key to understanding the evolution of the Solar System and material transportation within it. The number density of IDPs can be expressed as $n(r) \sim r^{-\alpha}$, and the exponent $\alpha \sim 1.3$ was obtained by previous observations from interplanetary space by Helios 1/2 and Pioneer 10/11 in the 1970s and 1980s. However, no direct measurements of $\alpha$ based on ZL observations from interplanetary space outside Earth's orbit have been performed since then. Here, we introduce initial results for the radial profile of the ZL at optical wavelengths observed over the range 0.76-1.06 au by ONC-T aboard the Hayabusa2# mission in 2021-2022. The ZL brightness we obtained is well reproduced by a model brightness, although there is a small excess of the observed ZL brightness over the model brightness at around 0.9 au. The radial power-law index we obtained is $\alpha = 1.30 \pm 0.08$, which is consistent with previous results based on ZL observations. The dominant source of uncertainty arises from the uncertainty in estimating the diffuse Galactic light (DGL).Comment: 22 pages, 19 figures, 4 tables, accepted for publication by Earth, Planets and Spac

HETE-2 Observations of the X-Ray Flash XRF 040916

A long X-ray flash was detected and localized by the instruments aboard the High Energy Transient Explorer II (HETE-2) at 00:03:30 UT on 2004 September 16. The position was reported to the GRB Coordinates Network (GCN) approximately 2 hours after the burst. This burst consists of two peaks separated by 200 s, with durations of 110 s and 60 s. We have analyzed the energy spectra of the 1st and 2nd peaks observed with the Wide Field X-Ray Monitor (WXM) and the French Gamma Telescope (FREGATE). We discuss the origin of the 2nd peak in terms of flux variabilities and timescales. We find that it is most likely part of the prompt emission, and is explained by the long-acting engine model. This feature is similar to some bright X-ray flares detected in the early afterglow phase of bursts observed by the Swift satellite.Comment: 9 pages, 4 figures, Accepted for publication in PAS