圧縮センシングを用いた超高速撮像による乳房ダイナミック造影MRIの新たなパラメータ

京都大学新制・課程博士博士(医学)甲第23073号医博第4700号新制||医||1049(附属図書館)京都大学大学院医学研究科医学専攻(主査)教授 溝脇 尚志, 教授 黒田 知宏, 教授 増永 慎一郎学位規則第4条第1項該当Doctor of Medical ScienceKyoto UniversityDGA

Diffusion kurtosis imaging as a biomarker of breast cancer

Diffusion kurtosis imaging (DKI) is a diffusion-weighted imaging method that describes non-Gaussian signal behavior using a relatively simple mathematical model. A parameter, kurtosis K, describes the deviation of the diffusion signal decay from a Gaussian pattern. The deviation reflects the complexity of the tissue microstructure affecting water diffusion. Several studies have investigated the diagnostic performance of DKI in distinguishing malignant from benign breast lesions. DKI has been reported to correlate with subtypes and with several molecular and other factors related to the treatment and prognosis of breast cancer. Some technical considerations remain to be resolved for the clinical application of DKI in the breast

On thinking linguistically

Trabalhando durante um período de três décadas em diversos ambientes de sala de aula, buscamos introduzir os alunos à linguística, envolvendo-os em “pensar linguisticamente” sobre o conhecimento da linguagem. O trabalho é centrado em contar uma história conectada sobre a linguagem, construída a partir de conjuntos de problemas que desenvolvemos (Honda e O'Neil 2008) e do próprio trabalho dos nossos alunos. Nosso trabalho integra o ensino e a aprendizagem cooperativos com uma abordagem baseada no problema da pesquisa lingüística, a fm de estabelecer um clima intelectual na sala de aula, em que os alunos em todos os níveis possam desenvolver um estilo científco de argumentação e umaapreciação da natureza do trabalho científco . Apresentamos evidências em apoio à nossa crença de que as questões que surgem na investigação linguística representam uma forma frutífera de introduzir os alunos ao trabalho científco sobre o conhecimento da linguagem

Looking beyond English: Linguistic inquiry for English Language Learners

Is there a role for linguistic inquiry in a class of high school English Language Learners? Based on a year-long pilot project initiated by a Greater Boston high school teacher, we present evidence: (1) that examining the spoken and written languages represented in the classroom captures students' interest and engages them in critical inquiry about the nature of linguistic knowledge and about their beliefs about language; (2) that the analysis of students' home languages validates these languages in the school context, defining them as a rich resource worthy of study, rather than as a hindrance to education

Biomarkers Predictive of Distant Disease-free Survival Derived from Diffusion-weighted Imaging of Breast Cancer

Purpose: To investigate whether intravoxel incoherent motion (IVIM) and/or non-Gaussian diffusion parameters are associated with distant disease-free survival (DDFS) in patients with invasive breast cancer. Methods: From May 2013 to March 2015, 101 patients (mean age 60.0, range 28-88) with invasive breast cancer were evaluated prospectively. IVIM parameters (flowing blood volume fraction [ɪᴠɪᴍ] and pseudodiffusion coefficient [D*]) and non-Gaussian diffusion parameters (theoretical apparent diffusion coefficient [ADC] at a b value of 0 s/mm² [ADC₀] and kurtosis [K]) were estimated using a diffusion-weighted imaging series of 16 b values up to 2500 s/mm². Shifted ADC values (sADC₂₀₀-₁₅₀₀) and standard ADC values (ADC₀-₈₀₀) were also calculated. The Kaplan-Meier method was used to generate survival analyses for DDFS, which were compared using the log-rank test. Univariable Cox proportional hazards models were used to assess any associations between each parameter and distant metastasis-free survival. Results: The median observation period was 80 months (range, 35-92 months). Among the 101 patients, 12 (11.9%) developed distant metastasis, with a median time to metastasis of 79 months (range, 10-92 months). Kaplan-Meier analysis showed that DDFS was significantly shorter in patients with K > 0.98 than in those with K ≤ 0.98 ( = 0.04). Cox regression analysis showed a marginal statistical association between K and distant metastasis-free survival ( = 0.05). Conclusion: Non-Gaussian diffusion may be associated with prognosis in invasive breast cancer. A higher K may be a marker to help identify patients at an elevated risk of distant metastasis, which could guide subsequent treatment

On the origin and evolution of the asteroid Ryugu: A comprehensive geochemical perspective

Presented here are the observations and interpretations from a comprehensive analysis of 16 representative particles returned from the C-type asteroid Ryugu by the Hayabusa2 mission. On average Ryugu particles consist of 50% phyllosilicate matrix, 41% porosity and 9% minor phases, including organic matter. The abundances of 70 elements from the particles are in close agreement with those of CI chondrites. Bulk Ryugu particles show higher δ18O, Δ17O, and ε54Cr values than CI chondrites. As such, Ryugu sampled the most primitive and least-thermally processed protosolar nebula reservoirs. Such a finding is consistent with multi-scale H-C-N isotopic compositions that are compatible with an origin for Ryugu organic matter within both the protosolar nebula and the interstellar medium. The analytical data obtained here, suggests that complex soluble organic matter formed during aqueous alteration on the Ryugu progenitor planetesimal (several 10’s of km), <2.6 Myr after CAI formation. Subsequently, the Ryugu progenitor planetesimal was fragmented and evolved into the current asteroid Ryugu through sublimation

Structural basis for DNA damage-induced phosphoregulation of MDM2 RING domain

Phosphorylation of MDM2 by ATM upon DNA damage is an important mechanism for deregulating MDM2, thereby leading to p53 activation. ATM phosphorylates multiple residues near the RING domain of MDM2, but the underlying molecular basis for deregulation remains elusive. Here we show that Ser429 phosphorylation selectively enhances the ubiquitin ligase activity of MDM2 homodimer but not MDM2-MDMX heterodimer. A crystal structure of phospho-Ser429 (pS429)-MDM2 bound to E2–ubiquitin reveals a unique 310-helical feature present in MDM2 homodimer that allows pS429 to stabilize the closed E2–ubiquitin conformation and thereby enhancing ubiquitin transfer. In cells Ser429 phosphorylation increases MDM2 autoubiquitination and degradation upon DNA damage, whereas S429A substitution protects MDM2 from auto-degradation. Our results demonstrate that Ser429 phosphorylation serves as a switch to boost the activity of MDM2 homodimer and promote its self-destruction to enable rapid p53 stabilization and resolve a long-standing controversy surrounding MDM2 auto-degradation in response to DNA damage

A dehydrated space-weathered skin cloaking the hydrated interior of Ryugu

Without a protective atmosphere, space-exposed surfaces of airless Solar System bodies gradually experience an alteration in composition, structure and optical properties through a collective process called space weathering. The return of samples from near-Earth asteroid (162173) Ryugu by Hayabusa2 provides the first opportunity for laboratory study of space-weathering signatures on the most abundant type of inner solar system body: a C-type asteroid, composed of materials largely unchanged since the formation of the Solar System. Weathered Ryugu grains show areas of surface amorphization and partial melting of phyllosilicates, in which reduction from Fe3+ to Fe2+ and dehydration developed. Space weathering probably contributed to dehydration by dehydroxylation of Ryugu surface phyllosilicates that had already lost interlayer water molecules and to weakening of the 2.7 µm hydroxyl (–OH) band in reflectance spectra. For C-type asteroids in general, this indicates that a weak 2.7 µm band can signify space-weathering-induced surface dehydration, rather than bulk volatile loss

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570