Tegafur-Uracil Plus Gemcitabine Combination Chemotherapy in Patients with Advanced Non-small Cell Lung Cancer Previously Treated with Platinum

BackgroundAn open-label, single-arm prospective study was conducted to evaluate the efficacy and toxicity of the combination of gemcitabine and tegafur-uracil (UFT) in patients with advanced nonsmall-cell lung cancer (NSCLC) after the failure of previous platinum-containing regimens.Patients and MethodsPatients with advanced NSCLC received 200 mg/m2 of UFT twice daily from day 1 through 14 plus 900 mg/m2 of gemcitabine per day via intravenous injection on days 8 and 15. This regimen was repeated every 3 or 4 weeks.ResultsA total of 40 patients were enrolled. Eleven patients (28%; 95% confidence interval [CI], 15–44%) achieved a partial response. The median progression-free survival, median overall survival, and 1-year survival rate were 4.0 months (95% CI, 3.3–6.7 months), 12.6 months (95% CI, 7.0–22.3 months), and 51% (95% CI, 33–66%), respectively. The most common grade 3 or 4 toxicity was neutropenia (38%; 95% CI, 23–54%) and the rate of grade 3 or 4 nonhematologic toxicity remained at less than 5%. A multivariate Cox model showed that adenocarcinoma, nonsmoking history, and good performance status predicted better survival.ConclusionsCombination chemotherapy with UFT and gemcitabine showed a promising effectiveness and acceptable toxicity for patients with platinum-resistant NSCLC

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

Risk Factors for a Second Episode of Hemoptysis

Objectives Hemoptysis is an alarming symptom of underlying lung disease. Clinicians are often unsure how to deal with and follow up patients who have had a single episode of hemoptysis, especially if the cause remains unknown despite thorough examination, because a second, more severe episode of hemoptysis might occur despite an apparently stable condition. Investigations were done, using multivariate analyses, to see whether several clinical factors present during an initial episode of hemoptysis could be used to predict a second episode. Subjects and Methods Eighty patients with an initial episode of hemoptysis who underwent both computed tomographic and bronchoscopic examinations from 2003 through 2005 were reviewed. Results The isolation of bacteria from bronchial lavage fluid (odds ratio 13.5, P = 0.001) and the failure to determine the cause of the initial episode of hemoptysis (odds ratio 7.0, P = 0.014) were significant independent predictors of a second episode of hemoptysis. Subset analysis showed that isolation of either Pseudomonas aeruginosa or Haemophilus influenzae increased the likelihood of a second episode of hemoptysis (P = 0.077), even if colonization, representing host-bacterial equilibrium, had occurred. Furthermore, the failure to determine the etiology of an initial episode of hemoptysis was associated with an increased risk of a massive second episode (P = 0.042), regardless of the volume of the initial episode. Conclusions In patients with bacterial colonization of the respiratory tract or an initial episode of hemoptysis of unknown etiology, there is an increased possibility of a second episode of hemoptysis

Establishment and characterization of a novel vincristine‐resistant diffuse large B‐cell lymphoma cell line containing the 8q24 homogeneously staining region

Chromosome band 8q24 is the most frequently amplified locus in various types of cancers. MYC has been identified as the primary oncogene at the 8q24 locus, whereas a long noncoding gene, PVT1, which lies adjacent to MYC, has recently emerged as another potential oncogenic regulator at this position. In this study, we established and characterized a novel cell line, AMU‐ML2, from a patient with diffuse large B‐cell lymphoma (DLBCL), displaying homogeneously staining regions at the 8q24 locus. Fluorescence in situ hybridization clearly detected an elevation in MYC copy numbers corresponding to the homogenously staining region. In addition, a comparative genomic hybridization analysis using high‐resolution arrays revealed that the 8q24 amplicon size was 1.4 Mb, containing the entire MYC and PVT1 regions. We also demonstrated a loss of heterozygosity for TP53 at 17p13 in conjunction with a TP53 frameshift mutation. Notably, AMU‐ML2 cells exhibited resistance to vincristine, and cell proliferation was markedly inhibited by MYC‐shRNA‐mediated knockdown. Furthermore, genes involved in cyclin D, mTOR, and Ras signaling were downregulated following MYC knockdown, suggesting that MYC expression was closely associated with tumor cell growth. In conclusion, AMU‐ML2 cells are uniquely characterized by homogenously staining regions at the 8q24 locus, thus providing useful insights into the pathogenesis of DLBCL with 8q24 abnormalities

幼稚園教育のいくつかの課題 : 「幼稚園教育が直面する複合課題に関する共同的研究」まとめとして

幼稚園教育がかかえる複合的な課題を検討する目的で,1幼稚園を対象に共同研究を実施した。以下のような課題別に共同研究者は研究を分担した。今日的な幼稚園教育の意義を確認する意図で子どもの主体性尊重の保育を,また障害幼児や外国人幼児を含む保育の意義を検討する意図で,その具体的な保育を,さらに, 子どもや家族に幼稚園教育が果たす意義を検討する意図で,保護者からボ唆される課題について研究を実施した。幼稚園教育に寄与する諸点を見いたした。To investigate several issues on kindergarten education, we conducted collaborative research based on three themes: Child-centered education and the purpose of kindergarten education today, the concrete educational examples of children with disabilities and children from foreign counties and what education means for them, and the problems of kindergarten in the view of the parents. As a result, some findings were made which will be useful for the future development of kindergarten education.11KJ0000870999