小児固形腫瘍患児の非侵襲的診断バイオマーカーとしての循環遊離DNAの検討

内容の要旨 , 審査の要旨広島大学(Hiroshima University)博士(医学)Doctor of Philosophy in Medical Sciencedoctora

Pros and cons of a bone-conduction device implanted in the worse hearing ear of patients with asymmetric hearing loss

PurposeBone-conduction devices can be considered a viable treatment option for patients experiencing asymmetric hearing loss (AHL), especially those with severe to profound hearing loss (HL) present in one ear. However, there are only a few reports on the effects of bone-anchored hearing aids (BAHAs) on patients with AHL. This retrospective study analyzed in detail the effects of BAHA on softer sounds than other hearing aids and identified situations in which BAHA had a negative effect.MethodsPatients with AHL, characterized by severe to profound hearing loss in one ear with a difference of ≥45 dB from that of the contralateral ear, underwent BAHA implantation in the ear with worse hearing. The BAHA effects were evaluated by assessing the word recognition score (WRS) and speech reception threshold (SRT) using the Japanese Oldenburg Sentence Test for various signal settings and noise directions. For a subjective analysis, the Speech, Spatial and Qualities of Hearing Scale (SSQ12) score was determined.ResultsThirteen patients who underwent BAHA implantation at the Miyazaki University Hospital between 2007 and 2021 were included. The BAHA demonstrated a significant improvement in the WRS from 40 to 70 dB sound pressure levels. Although the SRT showed significant improvement in noisy environments when speech was presented to the BAHA-wearing side, it worsened significantly when noise was presented to this side. In the survey of subjective hearing ability, both the total and subscale SSQ12 scores improved significantly after wearing the BAHA.ConclusionThis study identified scenarios in which BAHAs were beneficial and detrimental to individuals with AHL. Generally used audiological tests, such as the WRS with fixed sound pressure, may underestimate the effectiveness of BAHAs for softer sounds. In addition, depending on the direction of the noise, BAHAs may have adverse effects. These results could help patients comprehend the potential benefits and limitations of bone-conduction devices for their hearing

Induction of functional xeno-free MSCs from human iPSCs via a neural crest cell lineage

iPS細胞から間葉系幹細胞の誘導方法を確立 --動物由来成分を含まず再生医療への利用に期待. 京都大学プレスリリース. 2022-09-15.A new method for inducing mesenchymal stem cells from iPS cells without using animal-derived components. 京都大学プレスリリース. 2022-09-27.Mesenchymal stem/stromal cells (MSCs) are adult multipotent stem cells. Here, we induced MSCs from human induced pluripotent stem cells (iPSCs) via a neural crest cell (NCC) lineage under xeno-free conditions and evaluated their in vivo functions. We modified a previous MSC induction method to work under xeno-free conditions. Bovine serum albumin-containing NCC induction medium and fetal bovine serum-containing MSC induction medium were replaced with xeno-free medium. Through our optimized method, iPSCs differentiated into MSCs with high efficiency. To evaluate their in vivo activities, we transplanted the xeno-free-induced MSCs (XF-iMSCs) into mouse models for bone and skeletal muscle regeneration and confirmed their regenerative potency. These XF-iMSCs mainly promoted the regeneration of surrounding host cells, suggesting that they secrete soluble factors into affected regions. We also found that the peroxidasin and IGF2 secreted by the XF-iMSCs partially contributed to myotube differentiation. These results suggest that XF-iMSCs are important for future applications in regenerative medicine

Visualization of nerve fibers around the carotid bifurcation with use of a 9.4 Tesla microscopic magnetic resonance diffusion tensor imaging with tractography

BACKGROUND: Precise imaging of nerves have been challenging in the head and neck region, mainly due to low spatial resolution. Here, we investigated how nerves in the head and neck region could be visualized using an ultra-high magnetic field MR system. METHODS: We used formol-carbol-fixed human cadaveric necks and obtained MR diffusion tensor images (DTIs) using a 9.4 Tesla (T) ultra-high magnetic field MR system. Afterward, we prepared tissue sections and checked the anatomic relationships between the neurons and the carotid artery in order to confirm that the visualized fibers are indeed neuron fibers. RESULTS: We were able to identify nerves, including the vagus nerve, the hypoglossal nerve, and the spinal-accessory nerve. Hematoxylin-eosin stained histological sections confirmed neuron fibers in the same anatomic position. CONCLUSION: This technique has the feasibility to be applied for a more accurate anatomic understanding, maybe even close to a histological level

Familial Occurrence of a Congenital Portosystemic Shunt of the Portal Vein

A congenital portosystemic shunt of the portal vein is a very rare vascular anomaly associated with the liver. We report the case of a 5-year-old girl with a patent ductus venosus and her 31-year-old mother with a congenital portosystemic shunt. The child presented with a history of an extremely low birth weight in addition to an atrial septal defect and a patent ductus venosus. At the age of 2, she underwent ligation of the ductus venosus. Her mother was also diagnosed with a congenital vascular anomaly at the age of 16. We have followed up and evaluated her asymptomatic mother for 15 years. To our knowledge, this is the first report describing the occurrence of a congenital portosystemic shunt in both a mother and her child

Adsorption and release on three-dimensional graphene oxide network structures

In this study, three-dimensional network architectures are constructed using nano-sized graphene oxide (nGO) as the building block. The cross-linking reaction of nGO is conducted in sub-micrometre water droplets in an emulsion system to control the size of the networks by restricting the reaction space. Two types of three-dimensional GO networks with different cross-linking lengths were constructed, and their methyl orange adsorption and release behaviours were investigated under external stimuli, such as thermal treatment, ultrasonic wave treatment and near-infrared light irradiation

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