Selective targeting of neuroblastoma tumour-initiating cells by compounds identified in stem cell-based small molecule screens

Neuroblastoma (NB) is the most deadly extra-cranial solid tumour in children necessitating an urgent need for effective and less toxic treatments. One reason for the lack of efficacious treatments may be the inability of existing drugs to target the tumour-initiating or cancer stem cell population responsible for sustaining tumour growth, metastases and relapse. Here, we describe a strategy to identify compounds that selectively target patient-derived cancer stem cell-like tumour-initiating cells (TICs) while sparing normal paediatric stem cells (skin-derived precursors, SKPs) and characterize two therapeutic candidates. DECA-14 and rapamycin were identified as NB TIC-selective agents. Both compounds induced TIC death at nanomolar concentrations in vitro, significantly reduced NB xenograft tumour weight in vivo, and dramatically decreased self-renewal or tumour-initiation capacity in treated tumours. These results demonstrate that differential drug sensitivities between TICs and normal paediatric stem cells can be exploited to identify novel, patient-specific and potentially less toxic therapies

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

Reverse water gas shift reaction using supported ionic liquid phase catalysts

The reverse water gas shift reaction (RWGSR) using a supported ionic liquid-phase (SILP) catalyst consisting of Ru catalyst, ionic liquid (1-butyl-3-methylimidazolium chloride ([C(4)mim]Cl)), and porous silica gel support, was investigated. The catalytic activity of the SILP catalyst toward RWGSR strongly depends on the kind of Ru catalyst and amount of IL. Among the three kinds of Ru catalysts ([RuCl2(CO)(3)](2), Ru-3(CO)(12), and RuC13), [RuCl2(CO)(3)](2) exhibits the best catalytic activity. Brunauer Emmett Teller (BET) surface area analysis and diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) analyses of the SILP catalyst based on [RuCl2(CO)(3)](2) and [C(4)mim]Cl revealed that both the solvation of the active catalytic Ru species and the surface area of the ionic liquid phase strongly affect catalytic activity. Hence, these factors help to determine the optimum amount of [C(4)mim]Cl in the SILP catalyst. The resulting SILP catalyst, with an optimum constitution, exhibited greater catalytic activity than the homogeneous system in which the same amounts of [RuCl2(CO)(3)](2) and [C(4)mim]Cl were employed. Catalytically active Ru species during RWGSR in both systems were investigated by means of electrospray ionization-mass spectrometry (ESI-MS). Interestingly, the rate-determining step in the two systems was different, implying that the silica support lowers the activation energy of the protonation reaction in the catalytic cycle. Therefore, the facilitation of the RWGSR by a SILP catalyst system can be realized by good mass transport, derived from the large surface area, as well as the effect of the silica support on activation energy. Furthermore, 20 cycles of the RWGSR using the SILP catalyst were accomplished

Mesonephric adenocarcinoma of the uterine corpus with intracystic growth completely confined to the myometrium: a case report and literature review

Abstract Background Mesonephric adenocarcinoma (MA) is a rare tumor believed to arise from mesonephric remnants occurring mostly in the uterine cervix and, to a lesser extent, the corpus. Since the first case report of MA in the corpus in 1995, only 16 cases have been reported in the English literature. A recent report suggested that MA originates in Müllerian tissue and exhibits the mesonephric differentiation phenotype. Case presentation An asymptomatic 61-year-old woman was referred to our hospital because of elevated levels of tumor markers. Imaging revealed an intramural lesion of the uterine corpus exhibiting fluorodeoxyglucose uptake. A total hysterectomy and bilateral salpingo-oophorectomy were performed. The tumor was completely confined to the corpus wall and was composed of an intracystic bulky component and an invasive component in the myometrial layer. The tumor exhibited a variety of growth patterns, including a characteristic tubular pattern with dense eosinophilic secretion reminiscent of the thyroid, as well as a variety of morphologies, such as acinar, papillary, and ductal structures. The structures were immunoreactive for CK7, vimentin, CD10, calretinin, PAX8, and GATA3 and almost completely negative for ER/PgR. CA125 and CA19–9 antigen expression was also detected. Conclusion A case of MA with a unique growth pattern of an intracystic mass within the corpus wall is presented. The histogenesis and differential diagnoses are discussed. The histogenesis of MA is not yet clear. We hypothesize two different pathways involved: 1) direct development from the mesonephric remnants and/or 2) mesonephric transformation of Müllerian adenocarcinoma

Evaluation of the Repolished Surface Properties of a Resin Composite Employing Structural Coloration Technology

Resin composites employing structural coloration have recently been developed. These resins match to various tooth shades despite being a single paste. To accomplish this, the filler and base resin are tightly bonded, which is thought to provide excellent discoloration resistance. Here, we investigated the surface properties of one of these resins, including the discoloration of the repolished surface. We developed an innovative in vitro method to adjust the repolished surface, in which structural degradation is removed according to scanning electron microscopy (SEM) observation rather than by the naked eye. The resin samples (20 mm (length) × 10 mm (width) × 4 mm (depth)) were manufactured using this resin material. After accelerated aging of the resin by alkaline degradation, the resin was repolished and the discoloration (ΔE*ab), surface roughness (the arithmetic mean roughness (Ra)), and glossiness (the 60° specular) were measured. SEM observation showed that the appearance of the bond between the organic composite filler and base resin on the repolished surface was different from that on the mirror-polished surface. This revealed that according to our in vitro method it was difficult to make the repolished surface structurally identical to the mirror-polished surface. Among the properties of the repolished surface, the degree of discoloration did not change despite the rougher and less glossy surface. It can be concluded that the factors that induce discoloration in this resin composite are independent of the surface roughness and glossiness