Intraperitoneal administration of nanoparticles containing tocopheryl succinate prevents peritoneal dissemination

Intraperitoneal administration of anticancer nanoparticles is a rational strategy for preventing peritoneal dissemination of colon cancer due to the prolonged retention of nanoparticles in the abdominal cavity. However, instability of nanoparticles in body fluids causes inefficient retention, reducing its anticancer effects. We have previously developed anticancer nanoparticles containing tocopheryl succinate, which showed high in vivo stability and multifunctional anticancer effects. In the present study, we have demonstrated that peritoneal dissemination derived from colon cancer was prevented by intraperitoneal administration of tocopheryl succinate nanoparticles. The biodistribution of tocopheryl succinate nanoparticles was evaluated using inductively coupled plasma mass spectroscopy and imaging analysis in mice administered quantum dot encapsulated tocopheryl succinate nanoparticles. Intraperitoneal administration of tocopheryl succinate nanoparticles showed longer retention in the abdominal cavity than by its intravenous (i.v.) administration. Moreover, due to effective biodistribution, tumor growth was prevented by intraperitoneal administration of tocopheryl succinate nanoparticles. Furthermore, the anticancer effect was attributed to the inhibition of cancer cell proliferation and improvement of the intraperitoneal microenvironment, such as decrease in the levels of vascular endothelial growth factor A, interleukin 10, and M2-like phenotype of tumor-associated macrophages. Collectively, intraperitoneal administration of tocopheryl succinate nanoparticles is expected to have multifaceted antitumor effects against colon cancer with peritoneal dissemination

Bronchial damage and diffuse alveolar hemorrhage following chlorine gas inhalation: A case report

Chlorine is a toxic inhalant and sources of exposure for individuals include accidental releases of chlorine vapor due to industrial or chemical transportation accidents. Inhalation of a large quantity of gas may cause circulatory and respiratory disorders or even mortality; however, the effects of a small amount of chlorine gas may be asymptomatic. The present case study presents a successfully treated 55‑year‑old male patient exposed to chlorine gas, resulting in bronchial damage and diffuse alveolar hemorrhage. Endobronchial and alveolar injuries were evaluated by direct observation using fiberoptic bronchoscopy (FB) and analyzing bronchoalveolar lavage fluid obtained by FB. Taking a precise medical history from the patient is crucial to correctly diagnose toxic gas inhalation. In addition, a timely and proper evaluation with chest imaging as well as FB may provide useful clinical information. Therefore, clinicians should consider performing FB if the circumstances permit

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

Metallopolymer-block-oligosaccharide for sub-10 nm microphase separation

High-chi (where chi is the Flory-Huggins interaction parameter) block copolymers (BCPs) have great potential to achieve ultra-small microphase-separated structures with domain spacings (d) of <10 nm, which in turn are promising for nanofabrication applications. However, when considering their practical application in next generation lithographic processes, sufficient heat resistance and high etching selectivity are also required to attain high-chi BCPs for precise pattern transfer to the substrate. Herein, we report novel high-chi BCPs comprising poly(vinyl ferrocene) (PVFc) and an oligosaccharide (maltotriose and maltohexaose), which simultaneously accomplish small d values, sufficient thermal stability, and high etching selectivity. These novel BCPs, which displayed different architectures and saccharide volume fractions, were synthesized by combining living anionic polymerization and the "click" reaction. Small angle X-ray scattering measurements revealed that PVFc-b-maltohexaose and PVFc-b-(maltotriose)(2) formed hexagonal cylinder morphology with d values of similar to 8 nm. Furthermore, a lamellar morphology with d values of 9.3 nm was realized by mixing PVFc-b-(maltotriose)(2) and glucose. The thermal properties and etching resistance of PVFc and the oligosaccharides were also investigated. As expected, PVFc displayed a high thermal stability (PVFc: T-g, similar to 140 degrees C and decomposition temperature, similar to 350 degrees C) and higher etching resistance than the oligosaccharides

Downsizing feature of microphase-separated structures via intramolecular crosslinking of block copolymers

A novel strategy for downsizing the feature of microphase-separated structures was developed via the intramolecular crosslinking reaction of block copolymers (BCPs) without changing the molecular weight. A series of BCPs consisting of poly[styrene-st-(p-3-butenyl styrene)] and poly(rac-lactide) (SBS-LA) was subjected to Ru-catalyzed olefin metathesis under highly diluted conditions to produce intramolecularly crosslinked BCPs (SBS(cl)-LAs). Small-angle X-ray scattering measurement and transmission electron microscopy observation of the SBS(cl)-LAs revealed feature size reduction in lamellar (LAM) and hexagonally close-packed cylinder (HEX) structures in the bulk state, which was surely due to the restricted chain dimensions of the intramolecularly crosslinked SBS block. Notably, the degree of size reduction was controllable by varying the crosslink density, with a maximum decrease of 22% in the LAM spacing. In addition, we successfully observed the downsizing of the HEX structure in the thin film state using atomic force microscopy, indicating the applicability of the present methodology to nextgeneration lithography technology

Highly asymmetric lamellar nanostructures from nanoparticle-linear hybrid block copolymers

The highly asymmetric lamellar (A-LAM) nanostructure is one of the most important template geometries for block copolymer (BCP) lithography. However, A-LAM is unattainable from conventional BCPs, and there is no general molecular design strategy for A-LAM-forming BCP. Herein, a nanoparticle-linear hybrid BCP system is reported, which is designed based on the intramolecular crosslinking technique, as a remarkably effective platform to obtain the A-LAM morphology. The hybrid BCPs consisting of polystyrene single-chain nanoparticles and linear polylactide segments show a remarkable capability to form the A-LAM morphology in bulk, where a maximum width ratio of 4.1 between the two domains is obtained. This unusual phase behavior is attributed to the bulky and rigid characteristics of the nanoparticle block. Furthermore, the thin films of these hybrid BCPs show perpendicularly oriented A-LAM morphology on a chemically modified Si substrate, allowing promising application in the fabrication of asymmetric line-and-space nanopatterns

Effect of Topography on Glossiness and Surface Color for a 5052 Aluminum Alloy * 1

The effect of topography on the glossiness and surface color of aluminum alloy A5052 specimens was experimentally investigated. The surfaces of the specimens were machined using either a vertical milling machine, a horizontal milling machine or a shaping machine. Four specimens were produced by each machine so that the arithmetical mean roughness value, Ra, was less than 1 mm under four different cutting conditions. The experimental results revealed that the vertical and horizontal milling glossiness values were nearly the same, while the glossiness values of the shaped surface was less than half of this value. The surface color of all of the specimens was gray, although the lightness value of the surface color, L Ã , for the horizontal milling surface had the highest value. Based on the experimental results, it was determined that the surface texture of specimens produced by these machines could be characterized by their glossiness and surface color. These results could prove an effective indicator for choosing the most appropriate machining method by providing surface texture values