Organic carboxylate salt-enabled alternative synthetic routes for bio-functional cyclic carbonates and aliphatic polycarbonates

Simple and efficient synthetic routes for functionalized cyclic carbonates are indispensable for the practical application of side-chain bio-functionalized aliphatic polycarbonates as biodegradable functional biomaterials. In this study, a six-membered cyclic carbonate with a triethylammonium carboxylate has been prepared in one step from 2,2-bis(methylol)propionic acid (bis-MPA). We have demonstrated the suitability of the organic carboxylate salt of the bis-MPA cyclic carbonate for esterification with alkyl bromides via the SN2 mechanism, leading to the formation of functionalized cyclic carbonate monomers. The esterification of the organic carboxylate salt proceeds efficiently when alkyl bromides with α-carbonyl, allyl, and benzyl groups are used. This approach enables a two-step synthesis of functionalized cyclic carbonates from bis-MPA. The organocatalyzed ring-opening polymerization of the resultant functionalized cyclic carbonates is effectively controlled, indicating that the synthetic process involving the organic carboxylate salt does not influence their polymerizability. The ether-functionalized aliphatic polycarbonates obtained from the organic carboxylate salt exhibit good antiplatelet properties, comparable to those of a previously developed blood-compatible aliphatic polycarbonate. The synthetic pathways exploiting organic carboxylate salts enable alternative shortcuts to functionalized cyclic carbonates from bis-MPA

Helical tomotherapy for asymptomatic chemotherapy-refractory or -unfit multiple (3 or more) metastases

Background: Despite chemotherapy innovations, prognosis of patients with chemotherapy-refractory or -unfit multiple metastases (CRMM/CUMM) remains poor. In this prospective study, the efficacy and toxicity of helical tomotherapy for CRMM/CUMM were evaluated. Materials and methods: Between 2014 and 2020, asymptomatic patients with CRMM/CUMM with ≥ 3 lesions and no prior radiotherapy of the targets were enrolled. Patients who had intolerable toxicities to chemotherapy and those who refused chemotherapy were included in the CRMM and CUMM groups, respectively. Prostate cancer patients and patients with metastases mainly localized in the liver, lung, or brain were excluded. By helical tomotherapy, up to 10 lesions per patient were irradiated in order of volume. The standard dose was 50–60 Gy in 25–30 fractions. Results: Forty-five patients (median age, 63 years; 35 CRMM/10 CUMM) were enrolled. Primary tumors included lung, gynecological, and gastrointestinal cancers. The most frequently treated targets were lymph node metastases, followed by peritoneal/pleural disseminations and bone tumors. The 1-year survival rate was 51% (median, 12.5 months). In the 35 patients with CRMM, the median survival time was 12.5 months, and the median pre-radiation chemotherapy period was 8.8 months (p > 0.05). The 6-month target control rate was 78%. Acute adverse events (grade ≥ 2) occurred in 33 patients: hematologic toxicities in 23, dermatitis in 6, and others in 8. Late grade ≥ 2 toxicities occurred in 6 patients: pneumonitis in 4 and gastric hemorrhage in 2. Conclusion: Tomotherapy for CRMM/CUMM resulted in median survival times > 1 year. This treatment should be investigated further in larger prospective studies

PARP Inhibitor PJ34 Suppresses Osteogenic Differentiation in Mouse Mesenchymal Stem Cells by Modulating BMP-2 Signaling Pathway

Poly(ADP-ribosyl)ation is known to be involved in a variety of cellular processes, such as DNA repair, cell death, telomere regulation, genomic stability and cell differentiation by poly(ADP-ribose) polymerase (PARP). While PARP inhibitors are presently under clinical investigation for cancer therapy, little is known about their side effects. However, PARP involvement in mesenchymal stem cell (MSC) differentiation potentiates MSC-related side effects arising from PARP inhibition. In this study, effects of PARP inhibitors on MSCs were examined. MSCs demonstrated suppressed osteogenic differentiation after 1 μM PJ34 treatment without cytotoxicity, while differentiation of MSCs into chondrocytes or adipocytes was unaffected. PJ34 suppressed mRNA induction of osteogenic markers, such as Runx2, Osterix, Bone Morphogenetic Protein-2, Osteocalcin, bone sialoprotein, and Osteopontin, and protein levels of Bone Morphogenetic Protein-2, Osterix and Osteocalcin. PJ34 treatment also inhibited transcription factor regulators such as Smad1, Smad4, Smad5 and Smad8. Extracellular mineralized matrix formation was also diminished. These results strongly suggest that PARP inhibitors are capable of suppressing osteogenic differentiation and poly(ADP-ribosyl)ation may play a physiological role in this process through regulation of BMP-2 signaling. Therefore, PARP inhibition may potentially attenuate osteogenic metabolism, implicating cautious use of PARP inhibitors for cancer treatments and monitoring of patient bone metabolism levels

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

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

Computational Study of the Effect of π-Congestion on the Singlet Biradical Character and Stacked Antiaromaticity in Acene Dimers

We demonstrated the computational study of the π-congestion effects in benzene, naphthalane, anthracene, teteracene, and pentacene dimers close with two positions at Ca···Ca’ and Cb···Cb’ to elucidate the singlet biradical characters as well as the stacked antiaromaticity. By extending the π-system from benzene to pentacene, the singlet biradical character increase whereas the stacked antiaromaticity decrease at near the transition state of [4+4]pericyclic reaction in ground state. Especially, the pentacene dimer exhibits large biradical character y0 = 61% with a weak antiaromaticity of NICSxx = +11 ppm at the distance of 2.80 Å between π-planes. These calculated results provided a unique idea to extract the similar electronic and magnetic natures as seen in transition state where the bond-order of the sp2 and sp3 carbon changes, like the graphite-to-diamond transformation

Stacked Antiaromaticity in the π-Congested Space Between the Aromatic Rings in the Anthracene Dimer

Substance containing two π-congested aromatic systems are attractive targets in synthetic studies as well as efforts designed to explore the unique properties that originate from π-congestion. Since the time of the computational studies by Schleyer and Warner, the concept of stacked aromaticity created by the encounter of two antiaromatic rings has received much attention. In contrast, questions about what happens when two aromatic rings are closely stacked have remained unanswered. To the best of our knowledge, only one computational study has been performed by Herges, the results of which suggest that [2.2]paracyclophane, possessing short distance (<3.00 Å) between two aromatic ring planes, has a paratropic ring current between two the benzene rings. This observation is consistent with the conclusion that stacked antiaromaticity exists within the π-congested space between aromatic rings. Herein, we investigated the antiaromaticity of highly π-congested anthracene dimers using anthracenophane, which possesses a short inter-plane carbon-carbon distance of ca. 2.80 Å. The absorption spectrum of this substance contains a weak broad band from 450 to 550 nm that is attributed from HOMO-LUMO transition. These properties exist in planar cyclooctatetraene derivatives that having 8π-electron antiaromaticity. The results of nucleus-independent chemical shift and anisotropy of the induced current density calculations indicate that relatively weak antiaromatic character exists between the central six-membered rings of the two anthracene moieties in anthracenophane. In addition, an attempt to enhance the stacked antiaromaticity of anthracenophane using pressure to enhance π-congestion using was unsuccessful