妊娠高血圧腎症の病因におけるnectin-4の機能的役割

藤田医科大

Polarity switching of ovarian cancer cell clusters via SRC family kinase is involved in the peritoneal dissemination

Peritoneal dissemination is a predominant pattern of metastasis in patients with advanced ovarian cancer. Despite recent progress in the management strategy, peritoneal dissemination remains a determinant of poor ovarian cancer prognosis. Using various histological types of patient-derived ovarian cancer organoids, the roles of the apicobasal polarity of ovarian cancer cell clusters in peritoneal dissemination were studied. First, it was found that both ovarian cancer tissues and ovarian organoids showed apicobasal polarity, where zonula occludens-1 (ZO-1) and integrin beta 4 (ITGB4) served as markers for apical and basal sides, respectively. The organoids in suspension culture, as a model of cancer cell cluster floating in ascites, showed apical-out/basal-in polarity status, while once embedded in extracellular matrix (ECM), the organoids switched their polarity to apical-in/basal-out. This polarity switch was accompanied by the SRC kinase family (SFK) phosphorylation and was inhibited by SFK inhibitors. SFK inhibitors abrogated the adherence of the organoids onto the ECM-coated plastic surface. When the organoids were seeded on a mesothelial cell layer, they cleared and invaded mesothelial cells. In vivo, dasatinib, an SFK inhibitor, suppressed peritoneal dissemination of ovarian cancer organoids in immunodeficient mice. These results suggest SFK-mediated polarity switching is involved in peritoneal metastasis. Polarity switching would be a potential therapeutic target for suppressing peritoneal dissemination in ovarian cancer

Written Advice Given by African American Smokers to Their Peers: Qualitative Study of Motivational Messages

BACKGROUND: Although African Americans have the lowest rates of smoking onset and progression to daily smoking, they are less likely to achieve long-term cessation. Interventions tailored to promote use of cessation resources in African American individuals who smoke are needed. In our past work, we demonstrated the effectiveness of a technology-assisted peer-written message intervention for increasing smoking cessation in non-Hispanic White smokers. In this formative study, we have adapted this intervention to be specific for African American smokers. OBJECTIVE: We aimed to report on the qualitative analysis of messages written by African American current and former smokers for their peers in response to hypothetical scenarios of smokers facing cessation challenges. METHODS: We recruited African American adult current and former smokers (n=41) via ResearchMatch between April 2017 and November 2017. We asked participants to write motivational messages for their peers in response to smoking-related hypothetical scenarios. We also collected data on sociodemographic factors and smoking characteristics. Thematic analysis was conducted to identify cessation strategies suggested by the study participants. RESULTS: Among the study participants, 60% (25/41) were female. Additionally, more than half (23/41, 56%) were thinking about quitting, 29% (12/41) had set a quit date, and 27% (11/41) had used electronic cigarettes in the past 30 days. Themes derived from the qualitative analysis of peer-written messages were (1) behavioral strategies, (2) seeking help, (3) improvements in quality of life, (4) attitudes and expectations, and (5) mindfulness/religious or spiritual practices. Under the behavioral strategies theme, distraction strategies were the most frequently suggested strategies (referenced 84 times in the 318 messages), followed by use of evidence-based treatments/cessation strategies. Within the seeking help theme, subthemes included seeking help or support from family/friends or close social networks (referenced 56 times) and health care professionals (referenced 22 times). The most frequent subthemes that emerged from improvements in the quality of life theme included improving one\u27s health (referenced 22 times) and quality of life (referenced 21 times). Subthemes that emerged from the attitude and expectations theme included practicing positive self-talk (referenced 27 times), autonomy/independence from the smoking habit (referenced six times), and financial cost of smoking (referenced five times). The two subthemes that emerged from the mindfulness/religious or spiritual practices theme were use of self-awareness techniques (referenced 36 times) and religious or spiritual practices to cope (referenced 13 times). CONCLUSIONS: Our approach to adapt a prior peer-message intervention to African American smokers yielded a set of evidence-based messages that may be suitable for smokers at all phases of motivation to quit (ready to quit or not ready to quit). In future research, we plan to assess the impact of texting these messages to African American smokers in a smoking cessation trial. H Williams, Dalton Mourao, Oluwabunmi M Emidio, Maryann Davis, Lori Pbert, Sarah L Cutrona, Thomas K Houston, Rajani S Sadasivam. Originally published in JMIR Formative Research (https://formative.jmir.org), 30.04.2021

Effects of palm cooling with CoolMitt

J-GLOBAL ID : 201901002195328127J-GLOBAL ID : 201901007563059516J-GLOBAL ID : 201801004201806465J-GLOBAL ID : 200901012516528555application/pdfdepartmental bulletin pape

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

Mutations in UVSSA cause UV-sensitive syndrome and impair RNA polymerase IIo processing in transcription-coupled nucleotide-excision repair

UV-sensitive syndrome (UVSS) is a genodermatosis characterized by cutaneous photosensitivity without skin carcinoma1, 2, 3, 4. Despite mild clinical features, cells from individuals with UVSS, like Cockayne syndrome cells, are very UV sensitive and are deficient in transcription-coupled nucleotide-excision repair (TC-NER)2, 4, 5, which removes DNA damage in actively transcribed genes6. Three of the seven known UVSS cases carry mutations in the Cockayne syndrome genes ERCC8 or ERCC6 (also known as CSA and CSB, respectively)7, 8. The remaining four individuals with UVSS, one of whom is described for the first time here, formed a separate UVSS-A complementation group1, 9, 10; however, the responsible gene was unknown. Using exome sequencing11, we determine that mutations in the UVSSA gene (formerly known as KIAA1530) cause UVSS-A. The UVSSA protein interacts with TC-NER machinery and stabilizes the ERCC6 complex; it also facilitates ubiquitination of RNA polymerase IIo stalled at DNA damage sites. Our findings provide mechanistic insights into the processing of stalled RNA polymerase and explain the different clinical features across these TC-NER–deficient disorders