Biomimetic design of an α-ketoacylphosphonium-based light-activated oxygenation auxiliary

The biomimetic design of a transition metal complex based on the iron(IV)-oxo porphyrin π-cation radical species in cytochrome P450 enzymes has been studied extensively. Herein, we translate the functions of this iron(IV)-oxo porphyrin π-cation radical species to an α-ketoacyl phosphonium species comprised of non-metal atoms and utilize it as a light-activated oxygenation auxiliary for ortho-selective oxygenation of anilines. Visible light irradiation converts the α-ketoacyl phosphonium species to the excited state, which acts as a transiently generated oxidant. The intramolecular nature of the process ensures high regioselectivity and chemoselectivity. The auxiliary is easily removable. A one-pot protocol is also described

Synthesis of tertiary alkylphosphonate oligonucleotides through light-driven radical-polar crossover reactions

光エネルギーで新しい化学修飾核酸を合成 --核酸リン原子の第三級アルキル化に成功--. 京都大学プレスリリース. 2023-11-01.Chemical modification of nucleotides can improve the metabolic stability and target specificity of oligonucleotide therapeutics, and alkylphosphonates have been employed as charge-neutral replacements for naturally-occurring phosphodiester backbones in these compounds. However, at present, the alkyl moieties that can be attached to phosphorus atoms in these compounds are limited to methyl groups or primary/secondary alkyls, and such alkylphosphonate moieties can degrade during oligonucleotide synthesis. The present work demonstrates the tertiary alkylation of the phosphorus atoms of phosphites bearing two 2’-deoxynuclosides. This process utilizes a carbocation generated via a light-driven radical-polar crossover mechanism. This protocol provides tertiary alkylphosphonate structures that are difficult to synthesize using existing methods. The conversion of these species to oligonucleotides having charge-neutral alkylphosphonate linkages through a phosphoramidite-based approach was also confirmed in this study

Constraints on the Intracluster Dust Emission in the Coma Cluster of Galaxies

We have undertaken a search for the infrared emission from the intracluster dust in the Coma cluster of galaxies by the Multiband Imaging Photometer for Spitzer. Our observations yield the deepest mid and far-infrared images of a galaxy cluster ever achieved. In each of the three bands, we have not detected a signature of the central excess component in contrast to the previous report on the detection by Infrared Space Observatory (ISO). We still find that the brightness ratio between 70 and 160 microns shows a marginal sign of the central excess, in qualitative agreement with the ISO result. Our analysis suggests that the excess ratio is more likely due to faint infrared sources lying on fluctuating cirrus foreground. Our observations yield the 2 sigma upper limits on the excess emission within 100 kpc of the cluster center as 5 x 10^-3 MJy/sr, 6 x 10^-2 MJy/sr, and 7 x 10^-2 MJy/sr, at 24, 70, and 160 microns, respectively. These values are in agreement with those found in other galaxy clusters and suggest that dust is deficient near the cluster center by more than 3 orders of magnitude compared to the interstellar medium.Comment: 10 pages, 9 figures, minor changes to match version published in Ap

Clinical responses to EGFR-tyrosine kinase inhibitor retreatment in non-small cell lung cancer patients who benefited from prior effective gefitinib therapy: a retrospective analysis

<p>Abstract</p> <p>Background</p> <p>Gefitinib was the first epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) approved for the treatment of advanced non-small cell lung cancer (NSCLC). Few treatment options are available for NSCLC patients who have responded to gefitinib treatment and demonstrated tumor progression. The present study was conducted to evaluate the efficacy and toxicity of the 2^ndEGFR-TKI administration.</p> <p>Methods</p> <p>We retrospectively analyzed 11 patients who had obtained a partial response (PR) or stable disease (SD) with gefitinib treatment and were re-treated with EGFR-TKI after failure of the initial gefitinib treatment.</p> <p>Results</p> <p>Three patients (27%) were treated with gefitinib as the 2^ndEGFR-TKI, and 8 patients (73%) received erlotinib. Only one patient (9%) showed PR, 7 (64%) achieved SD, and 3 (27%) had progressive disease. The disease control rate was 73% (95% CI, 43% - 91%) and the median progression-free survival was 3.4 months (95% CI, 2 - 5.2). The median overall survival from the beginning of the 2^ndEGFR-TKI and from diagnosis were 7.3 months (95% CI, 2.7 - 13) and 36.7 months (95% CI, 23.6 - 43.9), respectively. No statistical differences in PFS or OS were observed between gefitinib and erlotinib as the 2^ndEGFR-TKI (PFS, P = 0.23 and OS, P = 0.052). The toxicities associated with the 2^ndEGFR-TKI were generally acceptable and comparable to those observed for the initial gefitinib therapy.</p> <p>Conclusions</p> <p>Our results indicate that a 2^ndEGFR-TKI treatment can be an effective treatment option for gefitinib responders.</p

Clinical responses to EGFR-tyrosine kinase inhibitor retreatment in non-small cell lung cancer patients who benefited from prior effective gefitinib therapy: a retrospective analysis

<p>Abstract</p> <p>Background</p> <p>Gefitinib was the first epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) approved for the treatment of advanced non-small cell lung cancer (NSCLC). Few treatment options are available for NSCLC patients who have responded to gefitinib treatment and demonstrated tumor progression. The present study was conducted to evaluate the efficacy and toxicity of the 2^ndEGFR-TKI administration.</p> <p>Methods</p> <p>We retrospectively analyzed 11 patients who had obtained a partial response (PR) or stable disease (SD) with gefitinib treatment and were re-treated with EGFR-TKI after failure of the initial gefitinib treatment.</p> <p>Results</p> <p>Three patients (27%) were treated with gefitinib as the 2^ndEGFR-TKI, and 8 patients (73%) received erlotinib. Only one patient (9%) showed PR, 7 (64%) achieved SD, and 3 (27%) had progressive disease. The disease control rate was 73% (95% CI, 43% - 91%) and the median progression-free survival was 3.4 months (95% CI, 2 - 5.2). The median overall survival from the beginning of the 2^ndEGFR-TKI and from diagnosis were 7.3 months (95% CI, 2.7 - 13) and 36.7 months (95% CI, 23.6 - 43.9), respectively. No statistical differences in PFS or OS were observed between gefitinib and erlotinib as the 2^ndEGFR-TKI (PFS, P = 0.23 and OS, P = 0.052). The toxicities associated with the 2^ndEGFR-TKI were generally acceptable and comparable to those observed for the initial gefitinib therapy.</p> <p>Conclusions</p> <p>Our results indicate that a 2^ndEGFR-TKI treatment can be an effective treatment option for gefitinib responders.</p

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

Gaze measurements during viewing human dialogue scenes in adults with ADHD: Preliminary findings

Abstract Aim Eye gaze measurement to human dialogue scenes in adults with attention deficit hyperactivity disorder (ADHD) was investigated. We examined whether eye gaze measurement might be a biological marker of ADHD. Methods Twenty‐two individuals with ADHD (mean age, 34.5 years) attending the outpatient clinic of Showa University Karasuyama Hospital were included in the study, and 26 healthy individuals (mean age, 32.6 years) with no history of mental disorders were used as the control group. For the participants, intellectual functioning was estimated using the Japanese Adult Reading Test, and mental symptoms were assessed using the Autism Spectrum Quotient and Conner's Adult ADHD Rating Scale. We extracted human dialogue scenes from two classic movies as visual stimuli and recorded the participant's gaze while watching these scenes using Tobii's eye tracker. Results For gazing time, repeated measures analysis of variance showed no significant main effect of “group” and no significant interaction effect between “group” and areas of interest “(AOI).” In the normal group, gazing time at the eyes was significantly longer than those at the mouth, body, and background; in the ADHD group, gazing time at the eyes was significantly longer than only that at the background. Conclusion Given the different results obtained in the past in ASD, these results suggest that it would be necessary to directly compare the two groups to determine whether the gaze measurement shows significant differences in ASD and ADHD

Eradication of Established Murine Skin Tumors by Cyclic Chemoimmunotherapy with Cyclophosphamide and Effector T Cells

Background: Nonmyeloablative chemotherapy followed by adoptiveimmunotherapy is an attractive strategy for depleting regulatory T cells in the host. However, its efficacy is transient. Here, we aim to investigate whether cyclic chemoimmunotherapy has therapeutic efficacy against cancer. Methods:We examined the efficacy of cyclic chemoimmunotherapy with cyclophosphamide and adoptively transferred effector T cells against 5-day, established MCA205 murine skin sarcomas. Results: Cyclophosphamide administration followed by adoptive immunotherapy augmented the trafficking of effector T cells into established tumors. Further, multiple cyclophosphamide administrations helped effector T cells to persist at the sites.Chemoimmunotherapy achieved complete tumor regression even with the transfer of a limited number of effector T cells (5×106).Conclusion: Cyclic chemoimmunotherapy, which maintains adoptively transferred T cells by impairing regulatory T cells, is a potentially suitable treatment for established tumors