Combination chemotherapy with anticancer agents and OK-432

Antitumor effects of the combination chemotherapy with hemolytic streptococcus preparation, OK-432, and various anticancer agents were observed on experimental tumors and human cancers. Experimental studies revealed that combined use of OK-432 with Mitomycin C, Nitrogen mustard N-Oxide or Bleomycin was remarkably effective on rodent transplantable tumors such as Ehrlich carcinoma, sarcoma-lOO and rat ascitic hepatoma AH-66. As for the mode of action of OK-432, besides a direct action on cancer cells, a host-mediated action appears to be also involved. Clinical trials were made on 14 cases with various advanced cancers, and favorable response was obtained in 5 with lung cancer. Fever was the major side effect of OK-432 and there was no evidence of bone marrow suppression.</p

Direct Observation of Radical States and the Correlation with Performance Degradation in Organic Light-Emitting Diodes During Device Operation

Microscopic characterization of radical states in organic light‐emitting diodes (OLEDs) during device operation is useful for elucidating the degradation mechanism because the radical formation has been considered as non‐radiative recombination centers. Electron spin resonance (ESR) spectroscopy is suitable for such characterization because it can directly observe radicals in OLEDs. In this work, the detailed ESR investigation into the radical states in OLEDs during device operation is firstly reported using a typical light‐emitting Alq3‐based OLEDs. The simultaneous measurements of the ESR signal and the luminance of the same OLED are performed to study the direct correlation between the radical states and the performance degradation. These characteristics show that the luminance monotonically decreases and an ESR signal concomitantly increases as the duration of the device operation increases after operating the OLED. Using the analysis of density functional theory (DFT) calculation, the origin of the newly emerged ESR signal is ascribed to the cationic species due to decomposed Alq3 molecules. The elucidation of the radical species formed in OLEDs during device operation has been demonstrated at a molecular level for the first time. This ESR analysis would provide useful knowledge for understanding the degradation mechanism in the OLEDs at the molecular level

Tumor-Derived Microvesicles Induce Proangiogenic Phenotype in Endothelial Cells via Endocytosis

Background: Increasing evidence indicates that tumor endothelial cells (TEC) differ from normal endothelial cells (NEC). Our previous reports also showed that TEC were different from NEC. For example, TEC have chromosomal abnormality and proangiogenic properties such as high motility and proliferative activity. However, the mechanism by which TEC acquire a specific character remains unclear. To investigate this mechanism, we focused on tumor-derived microvesicles (TMV). Recent studies have shown that TMV contain numerous types of bioactive molecules and affect normal stromal cells in the tumor microenvironment. However, most of the functional mechanisms of TMV remain unclear. Methodology/Principal Findings: Here we showed that TMV isolated from tumor cells were taken up by NEC through endocytosis. In addition, we found that TMV promoted random motility and tube formation through the activation of the phosphoinositide 3-kinase/Akt pathway in NEC. Moreover, the effects induced by TMV were inhibited by the endocytosis inhibitor dynasore. Our results indicate that TMV could confer proangiogenic properties to NEC partly via endocytosis. Conclusion: We for the first time showed that endocytosis of TMV contributes to tumor angiogenesis. These findings offer new insights into cancer therapies and the crosstalk between tumor and endothelial cells mediated by TMV in the tumor microenvironment

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

Intertrochanteric curved varus osteotomy for subchondral fracture of the femoral head: a case series

Abstract Although favorable results have been reported with total hip arthroplasty, joint-preserving treatment should be the first choice for subchondral fracture of the femoral head (SFF) in young patients. This study reviewed four young male patients with SFF who underwent intertrochanteric curved varus osteotomy (CVO). The patients had a mean age of 32.3 years (range: 18–49 years). Conservative treatment was initially attempted in all cases, but failed to alleviate the pain, leading to surgical intervention at an average time of 6 months (range: 4–10 months) after symptom onset. As the fracture sites were located medial to the lateral edge of the acetabulum in all cases, CVO was performed to achieve a postoperative intact ratio of ≥ 34% in the weight-bearing region of the femoral head. The average follow-up period after surgery lasted 4.3 years (range: 2–7 years). Clinical and radiographic assessments were performed pre- and postoperatively. At the latest follow-up, the mean Harris hip score improved from 67.3 preoperatively to 99.5 postoperatively. The average preoperative intact ratio of the weight-bearing region of the femoral head was 12.3%, which increased to 44.3% postoperatively. No progression to femoral head collapse or joint space narrowing was observed on the plain radiographs. CVO is a simple, less-invasive, and beneficial approach for treating SFF in young patients whose fractures occur medial to the lateral edge of the acetabulum

Application of POLARIC (TM) fluorophores in an in vivo tumor model

Fluorescent and luminescent tools are commonly used to study the dynamics of cancer progression and metastases in real-time. Fluorophores have become essential tools to study biological events. However, few can sustain fluorescence long enough during long-term studies. In the present study, we focused on a series of new amphiphilic fluorophores known as POLARIC (TM), which emit strong fluorescence in lipid bilayers and can be readily modified using the Suzuki-Miyaura cross-coupling reaction. Appropriate chemical modifications of substituent groups can improve target-site specificity, reduce cytotoxicity and prolong emission. Therefore, in contrast to conventional fluorescent probes, these fluorophores show promise for long-term monitoring of biological processes. In the present study, we conducted long-term observations of tumor growth and metastasis using a POLARIC derivative as a novel fluorescent probe. For this purpose, we studied the metastatic melanoma cell line A375-SM, which proliferates at a high rate. We compared the characteristics of the POLARIC probe with the commercially available fluorescent dye PKH26 and fluorescent protein mRFP1. A375-SM cells were labeled with these fluorescent probes and orthotopically implanted into nude mice. The fluorescence emitted by POLARIC was detected more than five weeks after implantation without causing detectable harmful effects on tumor growth. By contrast, fluorescence of cells labeled with PKH26 could not be detected at this same time. Furthermore, POLARIC-, but not PKH26-labeled cells, were also detected in lung metastases. These results indicate that labeling cells with POLARIC fluorophores can significantly extend the time course of in vivo studies on tumor cell growth