Induced pluripotent stem cell–based Drug Repurposing for Amyotrophic lateral sclerosis Medicine (iDReAM) study : protocol for a phase I dose escalation study of bosutinib for amyotrophic lateral sclerosis patients

Introduction Amyotrophic lateral sclerosis (ALS) is a progressive and severe neurodegenerative disease caused by motor neuron death. There have as yet been no fundamental curative medicines, and the development of a medicine for ALS is urgently required. Induced pluripotent stem cell (iPSC)-based drug repurposing identified an Src/c-Abl inhibitor, bosutinib, as a candidate molecular targeted therapy for ALS. The objectives of this study are to evaluate the safety and tolerability of bosutinib for the treatment of patients with ALS and to explore the efficacy of bosutinib on ALS. This study is the first clinical trial of administered bosutinib for patients with ALS. Methods and analysis An open-label, multicentre phase I dose escalation study has been designed. The study consists of a 12-week observation period, a 1-week transitional period, a 12-week study treatment period and a 4-week follow-up period. After completion of the transitional period, subjects whose total ALS Functional Rating Scale-Revised (ALSFRS-R) score decreased by 1–3 points during the 12-week observation period receive bosutinib for 12 weeks. Three to six patients with ALS are enrolled in each of the four bosutinib dose levels (100, 200, 300 or 400 mg/day) to evaluate the safety and tolerability under a 3+3 dose escalation study design. Dose escalation and maximum tolerated dose are determined by the safety assessment committee comprising oncologists/haematologists and neurologists based on the incidence of dose-limiting toxicity in the first 4 weeks of the treatment at each dose level. A recommended phase II dose is determined by the safety assessment committee on completion of the 12-week study treatment in all subjects at all dose levels. The efficacy of bosutinib is also evaluated exploratorily using ALS clinical scores and biomarkers. Ethics and dissemination This study received full ethical approval from the institutional review board of each participating site. The findings of the study will be disseminated in peer-reviewed journals and at scientific conferences

Sfermion Mass Degeneracy, Superconformal Dynamics and Supersymmetric Grand Unified Theories

We discuss issues in a scenario that hierarchical Yukawa couplings are generated through strong dynamics of superconformal field theories (SCFTs). Independently of mediation mechanism of supersymmetry breaking, infrared convergence property of SCFTs can provide an interesting solution to supersymmetric flavor problem; sfermion masses are suppressed around the decoupling scale of SCFTs and eventually become degenerate to some degree, thanks to family-independent radiative corrections governed by the SM gaugino masses. We discuss under what conditions the degeneracy of sfermion mass can be estimated in a simple manner. We also discuss the constraints from lepton flavor violations. We then study explicitly sfermion mass degeneracy within the framework of grand unified theories coupled to SCFTs. It is found that the degeneracy for right-handed sleptons becomes worse in the conventional SU(5) model than in the MSSM. On the other hand, in the flipped SU(5) \times U(1) model, each right-handed lepton is still an SU(5)-singlet, whereas the bino mass M_1 is determined by two independent gaugino masses of SU(5) \times U(1). These two properties enable us to have an improved degeneracy for the right-handed sleptons. We also speculate how further improvement can be obtained in the SCFT approach.Comment: 24 pages, latex, 4 figure

Perceptions and attitudes of users and non-users of mental health services concerning mental illness and services in Japan

ObjectivesThere is a global movement to develop and implement community-based integrated mental health systems. The present study attempted to clarify the perceptions and attitudes of users and non-users of mental health services concerning mental illness and services in Japan.MethodsA new questionnaire was developed for this internet survey. Data from 500 outpatients with depression and 500 healthy subjects were sampled according to the demographics of the Japanese population.ResultsOver 90% of healthy subjects and over 70% of patients were unaware of the common age of onset or lifetime prevalence of mental illness. Over 90% of the healthy subjects and about 70% of the patients could not describe any services where they would feel comfortable discussing mental health problems. In both groups, “adolescents and young adults” were ranked first as a target population for mental health and illness policies. The top requirement for the integrated care systems was the promotion and awareness of correct knowledge of mental illness in both the healthy subjects and patients.ConclusionSocietal requirements could include disseminating correct knowledge, awareness-raising actions for society, and implementing services where people, especially young people, can easily consult and receive support in the community

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

Relationship between the Well-Being of Elderly Men and Cohabiting with Women Who Have Had Experience as a Health Promotion Volunteer in Japan: A Cross-Sectional Study

In Japan, there are traditionally many health promotion volunteer activities. However, the effects these activities have on the volunteers’ families are not clear. This study examined whether the well-being of Japanese elderly men was affected by cohabiting with women who have had experience as a health promotion volunteer. The study area was Suzaka City, where more than 7500 women have been elected and served as health promotion volunteers for over 60 years. A cross-sectional survey targeting all residents aged 65 years or over was conducted in 2014 using a self-administered questionnaire and 10,758 (77.7%) residents participated. Of those, married men who lived with married women were analyzed (n = 2370). Functional capacity and depressive symptoms were analyzed as outcomes respectively. Of the 2370 men, 1434 (60.5%) lived with women who had experience as a health promotion volunteer in the past. Modified Poisson regression analysis adjusting for covariates showed that living with women who had this experience was inversely associated with depressive symptoms (adjusted Prevalence Ratio; 0.84, 95% Confidence Interval; 0.73–0.97), but not with low functional capacity. These results suggest that living with women who had the experience as health promotion volunteer might affect depressive symptoms of elderly men