Angiogenesis in Cancer

New growth in the vascular network is important since the proliferation, as well as metastatic spread, of cancer cells depends on an adequate supply of oxygen and nutrients and the removal of waste products. New blood and lymphatic vessels form through processes called angiogenesis and lymphangiogenesis, respectively. Angiogenesis is regulated by both activator and inhibitor molecules. More than a dozen different proteins have been identified as angiogenic activators and inhibitors. Levels of expression of angiogenic factors reflect the aggressiveness of tumor cells. The discovery of angiogenic inhibitors should help to reduce both morbidity and mortality from carcinomas. Thousands of patients have received antiangiogenic therapy to date. Despite their theoretical efficacy, antiangiogeic treatments have not proved beneficial in terms of long-term survival. There is an urgent need for a new comprehensive treatment strategy combining antiangiogenic agents with conventional cytoreductive treatments in the control of cancer

Issues and Solutions in Introducing Western Systems to the Pre-hospital Care System in Japan

Objective: This report aims to illustrate the history and current status of Japanese emergency medical services (EMS), including development of the specialty and characteristics adapted from the U.S. and European models. In addition, recommendations are made for improvement of the current systems.Methods: Government reports and academic papers were reviewed, along with the collective experiences of the authors. Literature searches were performed in PubMed (English) and Ichushi (Japanese), using keywords such as emergency medicine and pre-hospital care. More recent and peer-reviewed articles were given priority in the selection process.Results: The pre-hospital care system in Japan has developed as a mixture of U.S. and European systems. Other countries undergoing economic and industrial development similar to Japan may benefit from emulating the Japanese EMS model.Discussion: Currently, the Japanese system is in transition, searching for the most suitable and efficient way of providing quality pre-hospital care.Conclusion: Japan has the potential to enhance its current pre-hospital care system, but this will require greater collaboration between physicians and paramedics, increased paramedic scope of medical practice, and greater Japanese societal recognition and support of paramedics.[WestJEM. 2008;9:166-170.

Low-frequency maternal novel MYH7 mosaicism mutation in recurrent fetal-onset severe left ventricular noncompaction: a case report

BackgroundLeft ventricular noncompaction (LVNC) is a rare inherited cardiomyopathy with a broad phenotypic spectrum. The genotype-phenotype correlations in fetal-onset LVNC have not yet been fully elucidated. In this report, we present the first case of severe fetal-onset LVNC caused by maternal low-frequency somatic mosaicism of the novel myosin heavy chain 7 (MYH7) mutation.Case presentationA 35-year-old pregnant Japanese woman, gravida 4, para 2, with no significant medical or family history of genetic disorders, presented to our hospital. In her previous pregnancy at 33 years of age, she delivered a male neonate at 30 weeks of gestation with cardiogenic hydrops fetalis. Fetal echocardiography confirmed LVNC prenatally. The neonate died shortly after birth. In the current pregnancy, she again delivered a male neonate with cardiogenic hydrops fetalis caused by LVNC at 32 weeks of gestation. The neonate died shortly after birth. Genetic screening of cardiac disorder-related genes by next-generation sequencing (NGS) was performed which revealed a novel heterozygous missense MYH7 variant, NM_000257.3: c.2729A > T, p.Lys910Ile. After targeted and deep sequencing by NGS, the same MYH7 variant (NM_000257.3: c.2729A > T, p.Lys910Ile) was detected in 6% of the variant allele fraction in the maternal sequence but not in the paternal sequence. The MYH7 variant was not detected by conventional direct sequencing (Sanger sequencing) in either parent.ConclusionsThis case demonstrates that maternal low-frequency somatic mosaicism of an MYH7 mutation can cause fetal-onset severe LVNC in the offspring. To differentiate hereditary MYH7 mutations from de novo MYH7 mutations, parental targeted and deep sequencing by NGS should be considered in addition to Sanger sequencing

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

The Imminent Healthcare and Emergency Care Crisis in Japan

Objectives: Japan has a universal healthcare system, and this paper describes the reality of the healthcare services provided, as well as current issues with the system.Methods: Academic, government, and press reports on Japanese healthcare systems and healthcare guidelines were reviewed.Results: The universal healthcare system of Japan is considered internationally to be both low-cost and effective because the Japanese population enjoys good health status with a long life expectancy, while healthcare spending in Japan is below the average given by the Organization for Economic Corporation and Development (OECD). However, in many regions of Japan the existing healthcare resources are seriously inadequate, especially with regard to the number of physicians and other health professionals. Because healthcare is traditionally viewed as “sacred” work in Japan, healthcare professionals are expected to make large personal sacrifices. Also, public attitudes toward medical malpractice have changed in recent decades, and medical professionals are facing legal issues without experienced support of the government or legal professionals. Administrative response to the lack of resources and collaboration among communities are beginning, and more efficient control and management of the healthcare system is under consideration.Conclusion: The Japanese healthcare system needs to adopt an efficient medical control organization to ease the strain on existing healthcare professionals and to increase the number of physicians and other healthcare resources. Rather than continuing to depend on healthcare professionals being able and willing to make personal sacrifices, the government, the public and medical societies must cooperate and support changes in the healthcare system

Association between Proximity of the Elementary School and Depression in Japanese Older Adults: A Cross-Sectional Study from the JAGES 2016 Survey

Depression among older adults is one of the most critical public health issues. The proximity of elementary schools has been positively associated with neighborhood social cohesion and quality of life. However, no studies have identified an association between the proximity of elementary school and older adults’ mental health. Therefore, this study aimed to examine the association between the proximity of elementary schools, one of the core facilities of neighborhood communities in Japan, and depression in older adults. A total of 131,871 participants (63,430 men 73.7 ± 6.1 years, 68,441 women 73.8 ± 6.2 years) were analyzed from the Japan Gerontological Evaluation Study (JAGES) 2016 survey. Logistic regression analysis showed that there was no association between distance to elementary school and depression among males. However, among females, compared with the participants living within 400 m from the nearest elementary school, the odds ratio of depression for those living between 400 and 799 m and more than 800 m away were 1.06 (95% confidence interval (CI) 1.00–1.12) and 1.07 (95% CI 1.00–1.15), respectively. The findings may be useful when considering the design of communities around elementary schools and the planning of facilities as a population-based approach to promote mental health of older women