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Lifestyle-related diseases, such as diabetes, are mostly caused by poor lifestyle habits; therefore, modifying these habits is important. In Japan, a system of specific health checkups (SHC) and specific health guidance (SHG) was introduced in 2008. The challenges faced include low retention rates and difficulty in maintaining results. Digital technologies can support self-management and increase patient convenience, although evidence of the usefulness of this technology for SHG is limited. This study evaluated the usefulness of nutritional guidance using a smartphone application (app) added to conventional SHG. We recruited eligible participants for SHG in Japan from November 2018 to March 2020. We assigned them to "Intervention Group: Application-Supported Nutrition Therapy" or "Control Group: Human Nutrition Therapy" based on their desire to use the app. The primary outcome was a change in non-high-density lipoprotein cholesterol (non-HDL-C) levels post-intervention. The secondary outcomes were a change in lipid profile, metabolic indices, and frequency of logins to the app. We assessed 109 participants in two cohorts: 3-month (short-term) and 6-month (long-term). The short-term cohort had 23 intervention and 29 control participants, while the long-term cohort had 35 and 22, respectively. There was a significant improvement in non-HDL-C levels in the short-term intervention group compared to the control group. There was no significant difference in non-HDL-C levels in the long-term groups or at 1 year. There were significant improvements in body weight (BW) in the short-term cohort until 1 year compared within the groups. The retention rate remained high in the short-term cohort (92%) but decreased to 57.8% at 6 months in the long-term cohort. Using an app system to facilitate dietary recordings and guidance for patients at risk of lifestyle-related diseases led to improved lipid levels and BW. These benefits persisted to some extent after 1 year. This app may partially supplement conventional SHG., Competing Interests: In a different study than this one, in which MK is the principal investigator, MK has received free use of the study participants’ applications from Asken inc. Other authors have declared that no competing interests exist., (Copyright: © 2024 Noda et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Carcinogenesis results from the sequential acquisition of oncogenic mutations that convert normal cells into invasive, metastasizing cancer cells. Colorectal cancer exemplifies this process through its well-described adenoma-carcinoma sequence, modeled previously using clustered regularly interspaced short palindromic repeats (CRISPR) to induce four consecutive mutations in wild-type human gut organoids. Here, we demonstrate that long-term culture of mismatch-repair-deficient organoids allows the selection of spontaneous oncogenic mutations through the sequential withdrawal of Wnt agonists, epidermal growth factor (EGF) agonists and the bone morphogenetic protein (BMP) antagonist Noggin, while TP53 mutations were selected through the addition of Nutlin-3. Thus, organoids sequentially acquired mutations in AXIN1 and AXIN2 (Wnt pathway), TP53, ACVR2A and BMPR2 (BMP pathway) and NRAS (EGF pathway), gaining complete independence from stem cell niche factors. Quadruple-pathway (Wnt, EGF receptor, p53 and BMP) mutant organoids formed solid tumors upon xenotransplantation. This demonstrates that carcinogenesis can be recapitulated in a DNA repair-mutant background through in vitro selection that targets four consecutive cancer pathways., Competing Interests: Competing interests: H.C. is the inventor of several patents related to organoid technology; his full disclosure is given at https://www.uu.nl/staff/JCClevers/ . The other authors declare no competing interests., (© 2024. The Author(s).)

By replicating damaged nucleotides, error-prone DNA translesion synthesis (TLS) enables the completion of replication, albeit at the expense of fidelity. TLS of helix-distorting DNA lesions, that usually have reduced capacity of basepairing, comprises insertion opposite the lesion followed by extension, the latter in particular by polymerase ζ (Pol ζ). However, little is known about involvement of Pol ζ in TLS of non- or poorly-distorting, but miscoding, lesions such as O 6 -methyldeoxyguanosine (O 6 -medG). Using purified Pol ζ we describe that the enzyme can misincorporate thymidine opposite O 6 -medG and efficiently extend from terminal mismatches, suggesting its involvement in the mutagenicity of O 6 -medG. Surprisingly, O6-medG lesions induced by the methylating agent N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) appeared more, rather than less, mutagenic in Pol ζ-deficient mouse embryonic fibroblasts (MEFs) than in wild type MEFs. This suggested that in vivo Pol ζ participates in non-mutagenic TLS of O 6 -medG. However, we found that the Pol ζ-dependent misinsertions at O 6 -medG lesions are efficiently corrected by DNA mismatch repair (MMR), which masks the error-proneness of Pol ζ. We also found that the MNNG-induced mutational signature is determined by the adduct spectrum, and modulated by MMR. The signature mimicked single base substitution signature 11 in the catalogue of somatic mutations in cancer, associated with treatment with the methylating drug temozolomide. Our results unravel the individual roles of the major contributors to methylating drug-induced mutagenesis. Moreover, these results warrant caution as to the classification of TLS as mutagenic or error-free based on in vitro data or on the analysis of mutations induced in MMR-proficient cells., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Although the percentage of the population with a high degree of obesity (body mass index [BMI] ≥ 35 kg/m 2 ) is low in Japan, the prevalence of obesity-related diseases in patients with high-degree obesity is greater than that in patients with a BMI < 35 kg/m 2 . Therefore, treatment for high-degree obesity is important. However, clinical studies have reported that 20-50% of patients with obesity discontinue weight-loss treatment in other countries. The circumstances surrounding antiobesity agents are quite different between Japan and other countries. In this study, we investigated the predictors of treatment discontinuation in Japanese patients with high-degree obesity., Methods: We retrospectively reviewed the medical charts of 271 Japanese patients with high-degree obesity who presented at Toho University Sakura Medical Center for obesity treatment between April 1, 2014, and December 31, 2017. The patients were divided into non-dropout and dropout groups. Patients who discontinued weight-loss treatment within 24 months of the first visit were defined as "dropouts." Multivariate Cox proportional hazards regression analysis and Kaplan-Meier survival analysis were performed to examine the factors predicting treatment withdrawal., Results: Among the 271 patients, 119 (43.9%) discontinued treatment within 24 months of the first visit. The decrease in BMI did not significantly differ between the two groups. No prescription of medication and residential distance from the hospital exceeding 15 km were the top contributors to treatment discontinuation, and the absence of prescription medication was the most important factor. The dropout-free rate was significantly higher in patients with medication prescriptions than in those without and in patients who lived within 15 km of the hospital than in those who lived farther than 15 km from the hospital., Conclusions: No medication prescription and longer residential distance from the hospital were associated with treatment dropout in Japanese patients with high-degree obesity; therefore, the addition of antiobesity medications and telemedicine may be necessary to prevent treatment discontinuation in such patients., (© 2024. The Author(s).)

High pathogenicity avian influenza is an acute zoonotic disease with high mortality in birds caused by a high pathogenicity avian influenza virus (HPAIV). Recently, HPAIV has rapidly spread worldwide and has killed many wild birds, including endangered species. Baloxavir marboxil (BXM), an anti-influenza agent used for humans, was reported to reduce mortality and virus secretion from HPAIV-infected chickens ( Gallus domesticus , order Galliformes) at a dosage of ≥2.5 mg/kg when administered simultaneously with viral challenge. Application of this treatment to endangered birds requires further information on potential avian-specific toxicity caused by repeated exposure to BXM over the long term. To obtain information of potential avian-specific toxicity, a 4-wk oral repeated-dose study of BXM was conducted in chickens ( n = 6 or 7 per group), which are commonly used as laboratory avian species. The study was conducted in reference to the human pharmaceutical guidelines for nonclinical repeated-dose drug toxicity studies to evaluate systemic toxicity and exposure. No adverse changes were observed in any organs examined, and dose proportional increases in systemic exposure to active pharmaceutical ingredients were noted from 12.5 to 62.5 mg/kg per day. BXM showed no toxicity to chickens at doses of up to 62.5 mg/kg per day, at which systemic exposure was approximately 71 times higher than systemic exposure at 2.5 mg/kg, the reported efficacious dosage amount, in HPAIV-infected chickens. These results also suggest that BXM could be considered safe for treating HPAIV-infected endangered birds due to its high safety margin compared with the efficacy dose. The data in this study could contribute to the preservation of endangered birds by using BXM as a means of protecting biodiversity.

To develop novel inorganic red pigments without harmful elements, we focused on the band structure of Ca 2 (Mg, Co)WO 6 and attempted to narrow its bandgap by replacing the W 6+ sites in the host structure of Mo 6+ . Ca 2 Mg 1- x Co x W 1- y Mo y O 6 (0.10 ≤ x ≤ 0.30; 0.45 ≤ y ≤ 0.60) samples were synthesized by a sol-gel method using citric acids, and the crystal structure, optical properties, and color of the samples were characterized. The Ca 2 Mg 1- x Co x W 1- y Mo y O 6 solid solution was successfully formed, which absorbed visible light at wavelengths below 600 nm. In addition, the absorption wavelength shifted to longer wavelengths with increasing Mo 6+ content. This is because a new conduction band composed of a Co 3d -W 5d -Mo 4d hybrid orbital was formed by Mo 6+ doping to reduce the bandgap energy. Thus, the color of the samples gradually changed from pale orange to dark red, with a hue angle ( h °) of less than 35°. Based on the above results, the optical absorption wavelength of the Ca 2 Mg 1- x Co x W 1- y Mo y O 6 system can be controlled to change the color by adjusting the bandgap energy.

We examined whether a machine-learning-based automated scoring system can mimic the human similarity task performance. We trained a bidirectional encoder representations from transformer-model based on the semantic similarity test (SST), which presented participants with a word pair and asked them to write about how the two concepts were similar. In Experiment 1, based on the fivefold cross validation, we showed the model trained on the combination of the responses (N = 1600) and classification criteria (which is the rubric of the SST; N = 616) scored the correct labels with 83% accuracy. In Experiment 2, using the test data obtained from different participants in different timing from Experiment 1, we showed the models trained on the responses alone and the combination of responses and classification criteria scored the correct labels in 80% accuracy. In addition, human-model scoring showed inter-rater reliability of 0.63, which was almost the same as that of human-human scoring (0.67 to 0.72). These results suggest that the machine learning model can reach human-level performance in scoring the Japanese version of the SST., (© 2024. The Author(s).)

Coproporphyrin-I (CP-I) has been investigated as an endogenous biomarker of organic anion transporting polypeptide (OATP) 1B. Here, we determined the CP-I concentrations in a cocktail drug-drug interaction (DDI) study of ensitrelvir to evaluate the OATP1B inhibitory potential because ensitrelvir had increased plasma concentrations of rosuvastatin in this study, raising concerns about breast cancer resistance protein and OATP1B inhibition. Furthermore, CP-I concentrations were compared between active and placebo groups in a first-in-human (FIH) study of ensitrelvir to verify whether the OATP1B inhibitory potential could be estimated at an early drug development stage. In the cocktail DDI study, CP-I did not differ between with/without administration of ensitrelvir, indicating that ensitrelvir has no OATP1B inhibitory effect. Although there were some individual variabilities in CP-I concentrations among the treatment groups in the FIH study, the normalization of CP-I concentrations with pre-dose values minimized these variabilities, suggesting that this normalized method would be helpful for comparing the CP-I from different participants. Finally, we concluded that CP-I concentrations were not affected by ensitrelvir in the FIH study. These results suggested that the CP-I determination in an FIH study and its normalized method can be useful for an early evaluation of the OATP1B-mediated DDI potential in humans., Competing Interests: Declaration of Competing Interest Financial support for the present study was provided by Shionogi & Co., Ltd. All authors are employees of the SHIONOGI Group (Shionogi & Co., Ltd. and Shionogi TechnoAdvance Research & Co., Ltd.)., (Copyright © 2023 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

It is known that oligosaccharyltransferase (OST) has hydrolytic activity toward dolichol-linked oligosaccharides (DLO), which results in the formation of free N-glycans (FNGs), i.e. unconjugated oligosaccharides with structural features similar to N-glycans. The functional importance of this hydrolytic reaction, however, remains unknown. In this study, the hydrolytic activity of OST was characterized in yeast. It was shown that the hydrolytic activity of OST is enhanced in ubiquitin ligase mutants that are involved in endoplasmic reticulum-associated degradation. Interestingly, this enhanced hydrolysis activity is completely suppressed in asparagine-linked glycosylation (alg) mutants, bearing mutations related to the biosynthesis of DLO, indicating that the effect of ubiquitin ligase on OST-mediated hydrolysis is context-dependent. The enhanced hydrolysis activity in ubiquitin ligase mutants was also found to be canceled upon treatment of the cells with dithiothreitol, a reagent that potently induces protein unfolding in the endoplasmic reticulum (ER). Our results clearly suggest that the hydrolytic activity of OST is enhanced under conditions in which the formation of unfolded proteins is promoted in the ER in yeast. The possible role of FNGs on protein folding is discussed., (© 2023 Federation of European Biochemical Societies.)

Aims: The present study aimed to clarify the relationships between novel and traditional anthropometric indices and insulin sensitivity (SI) in young and middle-aged Japanese persons with normal glucose tolerance (NGT), and middle-aged Japanese persons with NGT and glucose intolerance. Methods: Plasma glucose and insulin levels were measured in 1270 young (age <40 years) and 2153 middle-aged persons with NGT ( n  = 1531) and glucose intolerance ( n  = 622) during a 75-g oral glucose tolerance test. Height (Ht), weight, and waist circumference (WC) were measured. The body mass index (BMI), WC, and the WC/Ht ratio were used as traditional anthropometric indices. A body shape index (ABSI) and the body roundness index (BRI) were calculated as novel indices. Indices of SI (Matsuda index and 1/homeostasis model assessment of insulin resistance) were calculated and compared with anthropometric indices. Results: The ABSI showed a weak correlation with SI indices in all groups. The BRI showed almost the same correlation with SI indices as the BMI, WC, and WC/Ht in all groups. The inverse correlation between each of the anthropometric indices other than ABSI and SI indices was weak in young persons, at 0.16-0.27 (Spearman's ρ values), but strong in middle-aged persons, at 0.38-1.00. On receiver-operating characteristic (ROC) curve analysis for detection of insulin resistance, the ABSI had a lower area under the ROC curve (AUC) than the other anthropometric indices, and the BRI and the WC/Ht ratio showed similar AUCs. The AUCs for the BRI and WC/Ht ratio were the highest in middle-aged men with NGT and glucose intolerance. Conclusions: The BRI, not the ABSI, was better correlated with SI in young and middle-aged Japanese persons. The BRI and WC/Ht ratio were comparable in their correlations with SI and the detection of insulin resistance in the participants of the present study.

Prostate cancer (PCa) exhibits a spectrum of heterogeneity, from indolent to highly aggressive forms, with approximately 10-20% of patients experiencing metastatic PCa. Oligometastatic PCa, characterized by a limited number of metastatic lesions in specific anatomical locations, has gained attention due to advanced imaging modalities. Although patients with metastatic PCa typically receive systemic therapy, personalized treatment approaches for oligometastatic PCa are emerging, including surgical and radiotherapeutic interventions. This comprehensive review explores the latest developments in the field of oligometastatic PCa, including its biological mechanisms, advanced imaging techniques, and relevant clinical studies. Oligometastatic PCa is distinct from widespread metastases and presents challenges in patient classification. Imaging plays a crucial role in identifying and characterizing oligometastatic lesions, with new techniques such as prostate-specific membrane antigen positron emission tomography demonstrating a remarkable efficacy. The management strategies encompass cytoreductive surgery, radiotherapy targeting the primary tumor, and metastasis-directed therapy for recurrent lesions. Ongoing clinical trials are evaluating the effectiveness of these approaches. Oligometastatic PCa occupies a unique position between locally advanced and high-volume metastatic diseases. While a universally accepted definition and standardized diagnostic criteria are still evolving, emerging imaging technologies and therapeutic strategies hold promise for improving the patient outcomes in this intermediate stage of PCa.

In this study, Eu 3+ and K + co-doped Ca 3 WO 6 double perovskite, a high-color-purity red phosphor, is quantitatively investigated using synchrotron X-ray diffraction Rietveld refinement, energy dispersive X-ray spectroscopy, and high-resolution PL spectroscopy. The Eu 3+ fluorescence line-narrowing (FLN) results, used to estimate the Eu 3+ occupation at given sites (so-called A and B sites) in the host crystal (A 2 BMO 6 ; A, B = Ca; M = W), reveal that the Eu 3+ ions have a twin distribution in both the A and B sites with high asymmetry ratios of Λ A  = 9.7 and Λ B  = 10.7, respectively. More interestingly, at lower Eu 3+ doping levels, the ions are predominantly located at the B sites (≈75%), indicating that the high color purity of Ca 3 WO 6 :(Eu 3+ , K + ) is mainly caused by the high asymmetry ratios of the Eu 3+ sites. Rietveld refinement combined with the FLN technique provides more reliable results for increasing the Eu 3+ substitution at the A site with Eu 3+ and K + doping concentrations, which lower the lattice energy of Ca 3 WO 6 :(Eu 3+ , K + ). The structural distortions owing to K + co-doping in terms of the quadratic elongation and bond-angle variance exhibit good correlations with the Ca(Eu)O 12 A-site cuboctahedra and Ca(Eu)O 6 B-site octahedra, partially accounting for the higher Λ values., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

The major adrenal tumors with endocrine activity are primary aldosteronism, Cushing's syndrome/mild autonomous cortisol secretion, and pheochromocytoma/paraganglioma. Excessive aldosterone secretion in primary aldosteronism causes cardiovascular, renal, and other organ damage in addition to hypertension and hypokalemia. Cortisol hypersecretion in Cushing's syndrome/mild autonomous cortisol secretion causes obesity, hypertension, impaired glucose tolerance, and cardiometabolic syndrome. Massive secretion of catecholamines in pheochromocytoma/paraganglioma causes hypertension and cerebrocardiovascular disease due to rapid blood pressure fluctuation. Moreover, pheochromocytoma multi-system crisis is a feared and possibly fatal presentation of pheochromocytoma/paraganglioma. Thus, adrenal tumors with endocrine activity are considered an indication for adrenalectomy, and perioperative management is very important. They have a risk of perioperative complications, either due to direct hemodynamic effects of the hormone hypersecretion or due to hormone-related comorbidities. In the last decades, deliberate preoperative evaluation and advanced perioperative management have significantly reduced complications and improved outcomes. Furthermore, improvements in anesthesia and surgical techniques with the feasibility of laparoscopic adrenalectomy have contributed to reduced morbidity and mortality. However, there are still several challenges to be considered in the perioperative care of these patients. There are very few data available prospectively to guide clinical management, due to the rarity of adrenal tumors with endocrine activity. Therefore, most guidelines are based on retrospective data analyses or small case series. In this review, the latest knowledge is summarized, and practical pathways to reduce perioperative complications and improve outcomes in adrenal tumors with endocrine activity are presented., (© 2023 The Japanese Urological Association.)

The Ba 2 RE 1- x Ce x TaO 6 (RE = La, Gd, Y; 0 ≤ x ≤ 1) pigments were synthesized by a conventional solid-state reaction method to develop environmentally friendly reddish inorganic pigments. The host was the double-perovskite-type Ba 2 RETaO 6 (RE: rare-earth elements), and the color source was Ce 3+ . All Ba 2 RE 1- x Ce x TaO 6 samples were obtained in a single-phase form as solid solutions. Rietveld refinement analysis of the Ba 2 RETaO 6 (RE = La, Ce, Gd, and Y) samples revealed that the average bond length between RE 3+ and O depends on the ionic radius of RE 3+ , and the shorter the RE-O length, the stronger the crystal field surrounding Ce 3+ . A photon energy at the maximum 4f-5d absorption of Ce 3+ depended on the weighted average ionic radius ( r RE ) at the RE 3+ site (i.e., the crystal field energy around the Ce 3+ ions). In response to this phenomenon, the sample color was changed in order to orange, red, pink, and violet with a decrease in the r RE value, and a hue angle ( h °) was roughly linearly related to that. For validation of the tendency, we demonstrated the synthesis and characterization of Ba 2 La 0.5- y Y y Ce 0.5 TaO 6 to obtain a more reddish color. As we exactly expected, a more reddish color was obtained while maintaining a high C value. Furthermore, the h ° values for y = 0.1 and 0.2 were in good agreement with our estimation. In light of the above results, by controlling the intensity of the crystal field surrounding Ce 3+ and/or the concentration of Ce 3+ , the optical absorption wavelength and absorption intensity of the Ba 2 RE 1- x Ce x TaO 6 system can be changed to adjust the color.

Layered perovskite black Ca 2 (Mn,Ti)O 4 ceramics were studied by using synchrotron radiation X-rays (SRX) and density functional theory (DFT) calculations to investigate the valence states of the cations, average/local structures, and electronic states. The crystallographic data were obtained by the Rietveld refinement of the obtained synchrotron radiation X-ray powder diffraction patterns. X-ray absorption near edge structure (XANES) spectroscopy measurements revealed that the ratios of Mn 4+ and Ti 4+ were about 82 and 95%, respectively, in all samples, and the Mn/Ti valences were not affected by the introduction of Ti 4+ . In addition, two pre-edge peaks were observed in the Mn-XANES spectra, but their peak positions and intensities were affected by doping with Ti 4+ , indicating that the symmetry of the MnO 6 octahedra was changed. A comparison of the atomic distances estimated from the Rietveld analysis and radial distribution function (RDF) revealed that there were large differences between the M-M distances (M = Mn, Ti). Therefore, XANES simulations were carried out to obtain models of the local structure. The experimental and theoretical data indicate that the Mn atoms were configured in a zigzagging arrangement, and the distortion of the MnO 6 octahedra increased with the increase in the degree of Ti 4+ doping. The origin of the changes to the pre-edge peaks was not only the crystal field strength around Mn but also the symmetry of the MnO 6 octahedra.

Drug-drug interaction potentials of ensitrelvir, a novel oral inhibitor of 3C-like protease of severe acute respiratory syndrome coronavirus 2, for drug transporters were evaluated by in vitro and clinical studies. The target drug transporters assessed were P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), organic anion transporting polypeptide (OATP) 1B1, OATP1B3, organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, and multidrug and toxin extrusion 1 and 2K. In vitro study revealed that ensitrelvir is a substrate for P-gp and BCRP and inhibits P-gp, BCRP, OATP1B1, OATP1B3, OCT1, and OAT3. Based on these results, a clinical drug-drug interaction study to evaluate the effect of ensitrelvir on the pharmacokinetics of P-gp, BCRP, OATP1B1, OATP1B3, and OCT1 substrates was conducted with a cocktail approach using digoxin (P-gp substrate), rosuvastatin (BCRP, OATP1B1, and OATP1B3 substrate), and metformin (OCT1 substrate). The cocktail was administered first, and after the washout period, the cocktail was coadministered with 500 mg of ensitrelvir. No treatment-emergent adverse events were observed. Pharmacokinetic analyses demonstrated that the ratios (90% confidence intervals) of "cocktail with ensitrelvir" to "cocktail without ensitrelvir" for maximum plasma concentration and area under the plasma concentration-time curve were, respectively, 2.17 (1.72-2.73) and 1.31 (1.13-1.52) for digoxin, 1.97 (1.73-2.25) and 1.65 (1.47-1.84) for rosuvastatin, and 1.03 (0.91-1.16) and 1.02 (0.94-1.11) for metformin. The results indicate that the exposure levels of digoxin and rosuvastatin increased when coadministered with ensitrelvir, but those of metformin were not changed. In conclusion, ensitrelvir has an impact on the exposure levels of P-gp, BCRP, OATP1B1, and OATP1B3 substrates., (© 2023 The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Background/aim: Photodynamic diagnosis (PDD)-assisted transurethral resection of a bladder tumor (PDD-TURBT) in a patient receiving 5-aminolevulinic acid improved the detection of micro- and flat lesions of the bladder. This study used real-world data in Japan to examine the diagnostic accuracy of PDD-assisted targeted biopsies and white-light (WL) random biopsies and reevaluated the necessity of random biopsies., Patients and Methods: A total of 133 patients diagnosed with bladder cancer who underwent TURBT from April 2020 to March 2022 were included in the study. Biopsy specimens obtained from 407 flat lesions or normal-like lesions, excluding biopsies from elevated lesions and TUR specimens, were used to analyze diagnostic accuracy in PDD and WL findings., Results: The respective sensitivities, specificities, and negative predictive values of PDD vs. WL findings were 81.4% vs. 54.0% (p=0.0039), 70.4% vs. 81.4% (p=0.0012), and 96.4% vs. 90.6% (p=0.0144), indicating that PDD was useful for a diagnosis of exclusion. Combining the PDD and WL findings improved the detection of malignant flat lesions. Ten (PDD-positive and WL-negative) specimens from 9 patients were diagnosed as malignant. The results of PDD-assisted targeted biopsy provided an accurate assessment of the risk classification for recurrence and progression of non-muscle invasive bladder cancer (NMIBC) as defined by the Japanese Urological Association (JUA) guidelines., Conclusion: For NMIBC treatment, a more accurate diagnosis is important for postoperative treatment decisions. PDD-assisted targeted biopsy may be necessary and sufficient for diagnosis of flat lesions in patients with bladder cancer for treatment decision making based on JUA risk classification., (Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The mixed-valent spinel LiV 2 O 4 is known as the first oxide heavy-fermion system. There is a general consensus that a subtle interplay of charge, spin, and orbital degrees of freedom of correlated electrons plays a crucial role in the enhancement of quasi-particle mass, but the specific mechanism has remained yet elusive. A charge-ordering (CO) instability of V 3+ and V 4+ ions that is geometrically frustrated by the V pyrochlore sublattice from forming a long-range CO down to T = 0 K has been proposed as a prime candidate for the mechanism. Here, we uncover the hidden CO instability by applying epitaxial strain on single-crystalline LiV 2 O 4 thin films. We find a crystallization of heavy fermions in a LiV 2 O 4 film on MgO, where a charge-ordered insulator comprising of a stack of V 3+ and V 4+ layers along [001], the historical Verwey-type ordering, is stabilized by the in-plane tensile and out-of-plane compressive strains from the substrate. Our discovery of the [001] Verwey-type CO, together with previous realizations of a distinct [111] CO, evidence the close proximity of the heavy-fermion state to degenerate CO states mirroring the geometrical frustration of the V pyrochlore lattice, which supports the CO instability scenario for the mechanism behind the heavy-fermion formation.

Although the prevalence of polymerase acidic (PA)/I38T strains of influenza virus with reduced susceptibility to baloxavir acid is low, there is a possibility of emergence under selective pressure. Furthermore, the virus may be transmitted between humans. We investigated the in vivo efficacy of baloxavir acid and oseltamivir phosphate against influenza A subtypes H1N1, H1N1pdm09, and H3N2, with PA/I38T substitution, at doses simulating human plasma concentrations. A pharmacokinetic/pharmacodynamic analysis was performed to strengthen the validity of the findings and the applicability in a clinical setting. Although the antiviral effect of baloxavir acid was attenuated in mice infected with PA/I38T-substituted viral strains compared with the wild type (WT), baloxavir acid significantly reduced virus titers at higher-but clinically relevant-doses. The virus titer reduction with baloxavir acid (30 mg/kg subcutaneous single dose) was comparable to that of oseltamivir phosphate (5 mg/kg orally twice daily) against H1N1 and H1N1pdm09 PA/I38T strains in mice, as well as the H3N2 PA/I38T strain in hamsters. Baloxavir acid demonstrated an antiviral effect against PA/I38T-substituted strains, at day 6, with no further viral rebound. In conclusion, baloxavir acid demonstrated dose-dependent antiviral effects comparable to that of oseltamivir phosphate, even though the degree of lung virus titer reduction was diminished in animal models infected with PA/I38T-substituted strains.

Objectives: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become established in the human population, making the need to develop safe and effective treatments critical. We have developed the small-molecule antiviral ensitrelvir, which targets the 3C-like (3CL) protease of SARS-CoV-2. This study evaluated the in vitro and in vivo efficacy of ensitrelvir compared with that of another SARS-CoV-2 3CL PI, nirmatrelvir., Methods: Cultured cells, BALB/cAJcl mice and Syrian hamsters were infected with various SARS-CoV-2 strains, including the ancestral strain WK-521, mouse-adapted SARS-CoV-2 (MA-P10) strain, Delta strain and Omicron strain. Ensitrelvir efficacy was compared with that of nirmatrelvir. Effective concentrations were determined in vitro based on virus-induced cytopathic effects, viral titres and RNA levels. Lung viral titres, nasal turbinate titres, body-weight changes, and animal survival were also monitored., Results: Ensitrelvir and nirmatrelvir showed comparable antiviral activity in multiple cell lines. Both ensitrelvir and nirmatrelvir reduced virus levels in the lungs of mice and the nasal turbinates and lungs of hamsters. However, ensitrelvir demonstrated comparable or better in vivo efficacy than that of nirmatrelvir when present at similar or slightly lower unbound-drug plasma concentrations., Conclusions: Direct in vitro and in vivo efficacy comparisons of 3CL PIs revealed that ensitrelvir demonstrated comparable in vitro efficacy to that of nirmatrelvir in cell culture and exhibited equal to or greater in vivo efficacy in terms of unbound-drug plasma concentration in both animal models evaluated. The results suggest that ensitrelvir may become an important resource for treating individuals infected with SARS-CoV-2., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Background: Liver fibrosis or cirrhosis frequently makes parenchymal transection more difficult, but the difficulty score of laparoscopic liver resection (LLR), including the IWATE criteria, does not include a factor related to liver fibrosis. Therefore, this study aimed to evaluate M2BPGi as a predictor of the difficulty of parenchymal transection and the incidence of postoperative complications in LLR., Methods: Data from 54 patients who underwent laparoscopic partial liver resection (LLR-P) and 24 patients who underwent laparoscopic anatomical liver resection between 2017 and 2019 in our institution were retrospectively analyzed. All cases were classified according to M2BPGi scores, and reserve liver function, intraoperative blood loss, and postoperative complications were compared among these groups., Results: Sixteen cases (29.6%) were M2BPGi negative (cut-off index < 1.0), 25 cases (46.3%) were 1+ (1.0 ≤ cut-off index < 3.0), and 13 cases (24.1%) were 2+ (cut-off index ≥ 3.0). M2BPGi-positive cases had significantly worse hepatic reserve function (K-ICG: 0.16 vs 0.14 vs 0.08, p < 0.0001). Intraoperative bleeding was significantly greater in M2BPGi-positive cases [50 ml vs 150 ml vs 200 ml, M2BPGi (-) or (1+) vs M2BPGi (2+), p = 0.045]. Postoperative complications (Clavien-Dindo ≥ II) were significantly more frequent in M2BPGi-positive cases [0% vs 4% vs 33%, M2BPGi (-) or (1+) vs M2BPGi (2+), p = 0.001]., Conclusion: M2BPGi could predict surgical difficulty and complications in LLR-P. In particular, it might be better not to select M2BPGi (2+) cases as teaching cases because of the massive bleeding during parenchymal transection., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Childhood cancer survivors are confronted with various chronic health conditions like therapy-related malignancies. However, it is unclear how exposure to chemotherapy contributes to the mutation burden and clonal composition of healthy tissues early in life. Here, we studied mutation accumulation in hematopoietic stem and progenitor cells (HSPC) before and after cancer treatment of 24 children. Of these children, 19 developed therapy-related myeloid neoplasms (t-MN). Posttreatment HSPCs had an average mutation burden increase comparable to what treatment-naïve cells accumulate during 16 years of life, with excesses up to 80 years. In most children, these additional mutations were induced by clock-like processes, which are also active during healthy aging. Other patients harbored mutations that could be directly attributed to treatments like platinum-based drugs and thiopurines. Using phylogenetic inference, we demonstrate that most t-MN in children originate after the start of treatment and that leukemic clones become dominant during or directly after chemotherapy exposure., Significance: Our study shows that chemotherapy increases the mutation burden of normal blood cells in cancer survivors. Only few drugs damage the DNA directly, whereas in most patients, chemotherapy-induced mutations are caused by processes similar to those present during normal aging. This article is highlighted in the In This Issue feature, p. 1825., (©2022 The Authors; Published by the American Association for Cancer Research.)

This study examined whether or not the number of topic-attributed features affects the speakers' use of metaphor production rather than literal expressions. Across two experiments, participants were asked to produce an expression that best paraphrased a given sentence. The number of features attributed to each topic was manipulated: one feature ("Her sarcasm hurts people"), two features ("Her sarcasm hurts people and is sharp"), and three features ("Her sarcasm hurts people, is sharp, and is piercing to the heart"). Participants' responses were classified into nominal metaphor/simile, literal, other metaphor/simile, and others. In both Experiment 1 and Experiment 2, participants' nominal metaphor responses (e.g., "Her sarcasm is a knife") increased with the number of topic-vehicles that shared significant features in a given sentence. These results suggest that the number of topic-attributed features affects participants' preference for the use of metaphorical expressions. We discussed the results based on the compactness hypothesis (Ortony, Educational Theory, 25: 45-53, 1975) of metaphor production., (© 2022. The Psychonomic Society, Inc.)

Context: The role of hepatic steatosis (HS) in the initial stages of developing type 2 diabetes remains unclear., Objective: We aimed to clarify the impact of HS indexed by Fatty Liver Index (FLI) and high-normal fasting plasma glucose (FPG) as risk factors for incident prediabetes in a nonobese cohort., Methods: Data from 1125 participants with ADA-defined normal glucose metabolism (median age 52 years; BMI 23.1 kg/m 2 ) were used for retrospective analysis. In the entire population, correlation between normal FPG and FLI was evaluated by multiple regression adjusted for age and sex. Follow-up data from 599 participants in whom 75-g OGTT was repeated 3.7 years later showed that 169 developed prediabetes. This was analyzed by the multivariate Cox proportional hazards model., Results: In the entire population, FLI was positively correlated with FPG ( P  < 0.01): mean FLI increased from 15.8 at FPG 4.2 mmol/L to 31.6 at FPG 5.5 mmol/L. Analysis of the 599 participants (2061 person-years) by Cox model, adjusted for sex, age, family history of diabetes, ISI MATSUDA , and Stumvoll-1, clarified an increased risk of prediabetes with high-normal FPG and FLI. Risk was increased 2.2 times with FLI ≥ 16.5 vs FLI < 16.5, P  < 0.001, and increased 2.1 times in participants with FPG ≥ 5.3 mmol/L, P  < 0.001. Cutoff values (unadjusted) were obtained by ROC at the point of the largest Youden's index using the entire range of the variables., Conclusion: Even among nonobese individuals, HS indexed by FLI and a high-normal FPG (≥ 5.3 mmol/L) are risk factors for prediabetes, independently from insulin., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.)

Gd 3+ -doped cerium vanadates, Ce 1- x Gd x VO 4 (0 ≤ x ≤ 0.30), were synthesized as near-infrared (NIR) reflective black pigments by a conventional solid-state reaction method. Crystal structure, particle size, optical properties, and color of the samples were characterized. The Ce 1- x Gd x VO 4 (0 ≤ x ≤ 0.30) samples were obtained in a single-phase form and the lattice volume decreased with increasing Gd 3+ concentration. Optical absorption below 630 nm was observed in all samples, which corresponded to the charge-transfer transition between Ce 4f and V 3d orbitals. The absorption spectrum of Ce 1- x Gd x VO 4 was shifted to the longer wavelength side as the Gd 3+ content increased, because of the increase in the crystal field around V 5+ due to the lattice shrinkage. As a result, the sample color gradually changed from dark brown to black with increasing Gd 3+ content. Among the samples synthesized in this study, Ce 0.80 Gd 0.20 VO 4 absorbed visible light with wavelengths shorter than 650 nm and exhibited the darkest color. Furthermore, this black pigment showed a sufficient NIR reflectance value ( R = 66.3%), which was higher than those of the commercially available products ( R < 50%)., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Layered perovskite A 2 B O 4 compounds were studied by a combination of X-ray powder diffraction (XRD) analysis, Raman spectroscopy, and density functional theory (DFT) calculations. Ti 4+ -doped Ca 2 MnO 4 ceramics with high near-infrared (NIR) reflectivity were selected as a test case. After elucidating their crystal structures ( I 4 1 / acd ) by XRD analysis, Raman spectroscopy was applied. Raman peaks were observed at approximately 178, 290, 330, 463, 500, and 562 cm -1 , which were confirmed by DFT calculations, and were in modes identical to those reported for Sr 2 IrO 4 in the same space group. An additional peak was observed at approximately 780 cm -1 for the Ti 4+ -doped samples, indicating that a silent A 2g mode was activated by doping with Ti 4+ , similar to the A 1g (breathing) mode found in B -site-substituted simple perovskite and B -site-ordered double perovskite structures. The XRD patterns of the doped samples did not exhibit any additional X-ray reflections, except for the pattern typical of nondoped Ca 2 MnO 4 . Thus, these results were attributed to the presence of the Ti-Ti correlation with a certain distance. The calculated band gap energies of Ca 2 MnO 4 and Ca 2 Mn 0.75 Ti 0.25 O 4 were approximately 1.8 eV, which was in reasonable agreement with the experimental value. The DFT calculations also revealed that one of the factors contributing to the enhancement of NIR reflectivity upon introduction of Ti 4+ ions is the reduced density of states (DOS) near the Fermi level.

Background: Type 2 diabetes is a risk factor for atherosclerosis. Oxidative stress, which is a causative factor in insulin resistance, leads to atherosclerosis in patients with diabetes. Xanthine oxidoreductase (XOR) is an enzyme that catalyzes the oxidation of hypoxanthine to xanthine and xanthine to uric acid and is related to oxidative stress. We aimed to examine the influence of plasma XOR activity on arterial stiffness in patients with type 2 diabetes., Methods: In total, 458 patients with type 2 diabetes not receiving antihyperuricemic agents were enrolled and their clinical parameters including plasma XOR activity and the cardio-ankle vascular index (CAVI) were measured. Patients were divided into the liver dysfunction and absence of liver dysfunction groups. Multiple regression analysis was performed., Results: The median plasma XOR activity level was 64.3 pmol/h/mL (33.3-147.3 pmol/h/mL). Plasma XOR activity was correlated significantly and positively with aspartate transaminase and alanine transaminase (ρ > 0.5). The level of plasma XOR activity in the liver dysfunction group was eight-fold higher than that in the absence of liver dysfunction group. A significant positive correlation was observed between plasma XOR activity and the CAVI only in the liver dysfunction group (ρ = 0.3968, P < 0.0043). Multiple regression models demonstrated that plasma XOR activity was an independent predictor of the CAVI in the liver dysfunction group (P = 0.0055)., Conclusions: Our results suggest that plasma XOR activity is associated with arterial stiffness and may have a role in atherosclerosis development in patients with type 2 diabetes and liver dysfunction., Competing Interests: Declaration of Competing Interest The author has no financial or other conflicts of interest to disclose., (Copyright © 2021 Southern Society for Clinical Investigation. Published by Elsevier Inc. All rights reserved.)

Background: The collective of somatic mutations in a genome represents a record of mutational processes that have been operative in a cell. These processes can be investigated by extracting relevant mutational patterns from sequencing data., Results: Here, we present the next version of MutationalPatterns, an R/Bioconductor package, which allows in-depth mutational analysis of catalogues of single and double base substitutions as well as small insertions and deletions. Major features of the package include the possibility to perform regional mutation spectra analyses and the possibility to detect strand asymmetry phenomena, such as lesion segregation. On top of this, the package also contains functions to determine how likely it is that a signature can cause damaging mutations (i.e., mutations that affect protein function). This updated package supports stricter signature refitting on known signatures in order to prevent overfitting. Using simulated mutation matrices containing varied signature contributions, we showed that reliable refitting can be achieved even when only 50 mutations are present per signature. Additionally, we incorporated bootstrapped signature refitting to assess the robustness of the signature analyses. Finally, we applied the package on genome mutation data of cell lines in which we deleted specific DNA repair processes and on large cancer datasets, to show how the package can be used to generate novel biological insights., Conclusions: This novel version of MutationalPatterns allows for more comprehensive analyses and visualization of mutational patterns in order to study the underlying processes. Ultimately, in-depth mutational analyses may contribute to improved biological insights in mechanisms of mutation accumulation as well as aid cancer diagnostics. MutationalPatterns is freely available at http://bioconductor.org/packages/MutationalPatterns ., (© 2022. The Author(s).)

Induced pluripotent stem cells (iPSCs) hold great promise for regenerative medicine, but genetic instability is a major concern. Embryonic pluripotent cells also accumulate mutations during early development, but how this relates to the mutation burden in iPSCs remains unknown. Here, we directly compared the mutation burden of cultured iPSCs with their isogenic embryonic cells during human embryogenesis. We generated developmental lineage trees of human fetuses by phylogenetic inference from somatic mutations in the genomes of multiple stem cells, which were derived from different germ layers. Using this approach, we characterized the mutations acquired pre-gastrulation and found a rate of 1.65 mutations per cell division. When cultured in hypoxic conditions, iPSCs generated from fetal stem cells of the assessed fetuses displayed a similar mutation rate and spectrum. Our results show that iPSCs maintain a genomic integrity during culture at a similar degree as their pluripotent counterparts do in vivo ., Competing Interests: The authors declare no competing interests., (© 2022 The Authors.)

Background: Transrectal ultrasound-guided prostate biopsy (TRUSPB) is widely used to diagnose prostate cancer (PCa). The aim of this study was to evaluate the risk of multi-factorial complications (febrile genitourinary tract infection (GUTI), rectal bleeding, and urinary retention) after TRUSPB., Methods: N = 2053 patients were Japanese patients undergoing transrectal or transperineal TRUSPB for suspicious of PCa. To assess risk of febrile GUTI adequately, the patients were divided into four groups: low-risk patients before starting a rectal culture, low-risk patients after starting a rectal culture, high-risk patients, and patients undergoing transperineal TRUSPB. Furthermore, to identify risk of rectal bleeding and urinary retention, patients were divided into transrectal and transperineal group., Results: Febrile GUTI significantly decreased owing to risk classification. The frequency of rectal bleeding was 1.43% (transrectal: 25/1742), while it did not happen in transperineal group. The patients with rectal bleeding had a significantly lower body mass index (BMI) (P < 0.01). The frequency of urinary retention was 5.57% (transrectal: 97/1742), while it did not happen in transperineal group. The patients with urinary retention had a significantly higher prostate-specific antigen (PSA) (P = 0.01) in transrectal group., Conclusions: Risk classification, rectal swab culture, and selected antimicrobial prophylaxis for transrectal TRUSPB were extremely effective to reduce the risk of febrile GUTI. Furthermore, lower BMI and higher PSA were novel clinical predictors for rectal bleeding and urinary retention, respectively. When urologists perform transrectal TRUSPB to their patients, they can correctly understand and explain each complication risk to their patients based on these novel risk factors., (© 2021. Japan Society of Clinical Oncology.)

Barrett's esophagus (BE) is categorized, based on morphological appearance, into different stages, which correlate with the risk of developing esophageal adenocarcinoma. More advanced stages are more likely to acquire chromosomal instabilities, but stage-specific markers remain elusive. Here, we performed single-cell DNA-sequencing experiments (scDNAseq) with fresh BE biopsies. Dysplastic BE cells frequently contained chromosomal instability (CIN) regions, and these CIN cells carried mutations corresponding to the COSMIC mutational signature SBS17, which were not present in biopsy-matched chromosomally stable (CS) cells or patient-matched nondiseased control cells. CS cells were predominantly found in nondysplastic BE biopsies. The single-base substitution (SBS) signatures of all CS BE cells analyzed were indistinguishable from those of nondiseased esophageal or gastric cells. Single-cell RNA-sequencing (scRNAseq) experiments with BE biopsies identified two sets of marker genes which facilitate the distinction between columnar BE epithelium and nondysplastic/dysplastic stages. Moreover, histological validation confirmed a correlation between increased CLDN2 expression and the presence of dysplastic BE stages. Our scDNAseq and scRNAseq datasets, which are a useful resource for the community, provide insight into the mutational landscape and gene expression pattern at different stages of BE development.

La 3 LiMn 1- x Ti x O 7 (0 ≤ x ≤ 0.05) samples were synthesized by a solid-state reaction method, and a single-phase form was observed for the samples in the range of x ≤ 0.03. Crystal structure, optical properties, and color of the La 3 LiMn 1- x Ti x O 7 (0 ≤ x ≤ 0.03) samples were characterized. Strong optical absorption was observed at a wavelength between 400 and 550 nm, and a shoulder absorption peak also appeared around 690 nm in all samples; orange colors were also exhibited. Among the samples synthesized, the most brilliant orange color was obtained at La 3 LiMn 0.97 Ti 0.03 O 7 . The redness ( a *) and yellowness ( b *) values of this pigment were higher than those of the commercially available orange pigments. Therefore, the orange color of this pigment is brighter than those of the commercial products. Since the La 3 LiMn 0.97 Ti 0.03 O pigment is composed of non-toxic elements, it could be a new environmentally friendly inorganic orange pigment.

Genetic instability is a major concern for successful application of stem cells in regenerative medicine. However, the mutational consequences of the most applied stem cell therapy in humans, hematopoietic stem cell transplantation (HSCT), remain unknown. Here we characterized the mutation burden of hematopoietic stem and progenitor cells (HSPCs) of human HSCT recipients and their donors using whole-genome sequencing. We demonstrate that the majority of transplanted HSPCs did not display altered mutation accumulation. However, in some HSCT recipients, we identified multiple HSPCs with an increased mutation burden after transplantation. This increase could be attributed to a unique mutational signature caused by the antiviral drug ganciclovir. Using a machine learning approach, we detected this signature in cancer genomes of individuals who received HSCT or solid organ transplantation earlier in life. Antiviral treatment with nucleoside analogs can cause enhanced mutagenicity in transplant recipients, which may ultimately contribute to therapy-related carcinogenesis., Competing Interests: Declaration of interests A.R.H., A.v.L., and R.v.B. are named as inventors on a patent application filed resulting from this work., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Marketing of breastmilk substitutes (BMS) continues to undermine breastfeeding globally, and low income countries experiencing rapid economic growth are especially vulnerable as expanding BMS markets. The objective of the study was to understand the prevalence of exposure to BMS promotions among mothers of children 0-23 months, the frequency and type of contacts between BMS companies and health workers and the presence of educational/informational materials and branded equipment associated with such companies in health facilities in Abidjan using the World Health Organization's NetCode protocol. The methods included structured interviews with health workers and mothers and observations of equipment/materials in a sample of 42 facilities, 330 mothers and 129 health workers. Descriptive statistics were produced, and chi-squared tests were used to assess differences by child age and facility type. Forty-three per cent of mothers were advised to feed BMS products in the past 6 months, with a significantly higher percentage of mothers of older children (6-23 months) advised compared to infants 0-5 months. Two thirds (66%) of mothers had seen promotions outside of facilities. Among health workers, 63% were contacted by BMS companies, and only 8% were familiar with the International Code of Marketing of BMS. Differences were found between public/private facilities in the types of requests BMS companies made to health workers. Strong actions are needed in Côte d'Ivoire to prevent BMS promotion in the health system, including increasing health workers' knowledge of the International Code and national regulations, monitoring violations and reaching mothers and families to promote optimal breastfeeding practices., (© 2021 The Authors. Maternal & Child Nutrition published by John Wiley & Sons Ltd.)

Background: Presepsin is a diagnostic and prognostic biomarker of both bacterial infection and sepsis; however, elevated presepsin levels have also been observed without sepsis. We conducted several analyses to evaluate the clinical laboratory parameters affecting presepsin levels., Method: We analyzed the association between sequential organ failure assessment (SOFA) scores and plasma presepsin levels and then analyzed clinical laboratory parameters in 567 patients with univariate and multivariate regression analysis and analysis of covariance (ANCOVA). We also determined presepsin in the bile of 11 patients and examined the presepsin immunostaining in liver., Results: Spearman's rank correlation analysis with log e change revealed that presepsin levels were closely associated with log e -transformed SOFA score (ρ = 0.541), alkaline phosphatase (ALP); (ρ = 0.454) and gamma-glutamyl transferase; (ρ = 0.505). Multivariate regression analysis revealed that log e -transformed SOFA score (β-coefficient = 0.316), ALP level (β-coefficient = 0.380), and creatinine level (β-coefficient = 0.290) independently and significantly affected log e presepsin levels. ANCOVA revealed that presepsin levels were significantly higher in patients with hepatobiliary disease. Patients who presented with dilatation of the bile ducts and elevated ALP levels or total bilirubin levels exhibited high presepsin levels in the bile. Presepsin production in liver Kupffer cells was also confirmed by immunostaining., Conclusion: Presepsin levels is correlated with the elevation of biliary enzymes in patients without renal dysfunction or sepsis. Additionally, presepsin exists with high concentrations in the bile and is positive in Kupffer cells., (Copyright © 2021. Published by Elsevier B.V.)

Neuroblastomas are childhood tumors with frequent fatal relapses after induction treatment, which is related to tumor evolution with additional genomic events. Our whole-genome sequencing data analysis revealed a high frequency of somatic cytosine > adenine (C > A) substitutions in primary neuroblastoma tumors, which was associated with poor survival. We showed that increased levels of C > A substitutions correlate with copy number loss (CNL) of OGG1 or MUTYH Both genes encode DNA glycosylases that recognize 8-oxo-guanine (8-oxoG) lesions as a first step of 8-oxoG repair. Tumor organoid models with CNL of OGG1 or MUTYH show increased 8-oxoG levels compared to wild-type cells. We used CRISPR-Cas9 genome editing to create knockout clones of MUTYH and OGG1 in neuroblastoma cells. Whole-genome sequencing of single-cell OGG1 and MUTYH knockout clones identified an increased accumulation of C > A substitutions. Mutational signature analysis of these OGG1 and MUTYH knockout clones revealed enrichment for C > A signatures 18 and 36, respectively. Clustering analysis showed that the knockout clones group together with tumors containing OGG1 or MUTYH CNL. In conclusion, we demonstrate that defects in 8-oxoG repair cause accumulation of C > A substitutions in neuroblastoma, which contributes to mutagenesis and tumor evolution., Competing Interests: The authors declare no competing interest., (Copyright © 2021 the Author(s). Published by PNAS.)

Acquisition of oncogenic mutations with age is believed to be rate limiting for carcinogenesis. However, the incidence of leukemia in children is higher than in young adults. Here we compare somatic mutations across pediatric acute myeloid leukemia (pAML) patient-matched leukemic blasts and hematopoietic stem and progenitor cells (HSPCs), as well as HSPCs from age-matched healthy donors. HSPCs in the leukemic bone marrow have limited genetic relatedness and share few somatic mutations with the cell-of-origin of the malignant blasts, suggesting polyclonal hematopoiesis in pAML patients. Compared to normal HSPCs, a subset of pAML cases harbored more somatic mutations and a distinct composition of mutational process signatures. We hypothesize these cases might have arisen from a more committed progenitor. This subset had better outcomes than pAML cases with mutation burden comparable to age-matched healthy HSPCs. Our study provides insights into the etiology and patient stratification of pAML., Competing Interests: Declaration of interests Authors declare no competing interests.

Prime editing is a recently reported genome editing tool using a nickase-cas9 fused to a reverse transcriptase that directly synthesizes the desired edit at the target site. Here, we explore the use of prime editing in human organoids. Common TP53 mutations can be correctly modeled in human adult stem cell-derived colonic organoids with efficiencies up to 25% and up to 97% in hepatocyte organoids. Next, we functionally repaired the cystic fibrosis CFTR-F508del mutation and compared prime editing to CRISPR/Cas9-mediated homology-directed repair and adenine base editing on the CFTR-R785* mutation. Whole-genome sequencing of prime editing-repaired organoids revealed no detectable off-target effects. Despite encountering varying editing efficiencies and undesired mutations at the target site, these results underline the broad applicability of prime editing for modeling oncogenic mutations and showcase the potential clinical application of this technique, pending further optimization., (© 2021 Geurts et al.)

Cervical cancer is a common gynecological malignancy often caused by high-risk human papillomavirus. There is a paucity of human-derived culture systems to study the cervical epithelium and the cancers derived thereof. Here we describe a long-term culturing protocol for ecto- and endocervical epithelia that generates 3D organoids that stably recapitulate the two tissues of origin. As evidenced for HSV-1, organoid-based cervical models may serve to study sexually transmitted infections. Starting from Pap brush material, a small biobank of tumoroids derived from affected individuals was established that retained the causative human papillomavirus (HPV) genomes. One of these uniquely carried the poorly characterized HPV30 subtype, implying a potential role in carcinogenesis. The tumoroids displayed differential responses to common chemotherapeutic agents and grew as xenografts in mice. This study describes an experimental platform for cervical (cancer) research and for future personalized medicine approaches., Competing Interests: Declaration of interests H.C. is an inventor on several patents involving adult stem cell-based organoid technology. His full declaration is given at https://www.uu.nl/staff/JCClevers/., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Most known pathogenic point mutations in humans are C•G to T•A substitutions, which can be directly repaired by adenine base editors (ABEs). In this study, we investigated the efficacy and safety of ABEs in the livers of mice and cynomolgus macaques for the reduction of blood low-density lipoprotein (LDL) levels. Lipid nanoparticle-based delivery of mRNA encoding an ABE and a single-guide RNA targeting PCSK9, a negative regulator of LDL, induced up to 67% editing (on average, 61%) in mice and up to 34% editing (on average, 26%) in macaques. Plasma PCSK9 and LDL levels were stably reduced by 95% and 58% in mice and by 32% and 14% in macaques, respectively. ABE mRNA was cleared rapidly, and no off-target mutations in genomic DNA were found. Re-dosing in macaques did not increase editing, possibly owing to the detected humoral immune response to ABE upon treatment. These findings support further investigation of ABEs to treat patients with monogenic liver diseases., (© 2021. The Author(s).)

Objective: One-hour plasma glucose (1-h PG) during the oral glucose tolerance test (OGTT) is an accurate predictor of type 2 diabetes. We performed a meta-analysis to determine the optimum cutoff of 1-h PG for detection of type 2 diabetes using 2-h PG as the gold standard., Research Design and Methods: We included 15 studies with 35,551 participants from multiple ethnic groups (53.8% Caucasian) and 2,705 newly detected cases of diabetes based on 2-h PG during OGTT. We excluded cases identified only by elevated fasting plasma glucose and/or HbA 1c . We determined the optimal 1-h PG threshold and its accuracy at this cutoff for detection of diabetes (2-h PG ≥11.1 mmol/L) using a mixed linear effects regression model with different weights to sensitivity/specificity (2/3, 1/2, and 1/3)., Results: Three cutoffs of 1-h PG, at 10.6 mmol/L, 11.6 mmol/L, and 12.5 mmol/L, had sensitivities of 0.95, 0.92, and 0.87 and specificities of 0.86, 0.91, and 0.94 at weights 2/3, 1/2, and 1/3, respectively. The cutoff of 11.6 mmol/L (95% CI 10.6, 12.6) had a sensitivity of 0.92 (0.87, 0.95), specificity of 0.91 (0.88, 0.93), area under the curve 0.939 (95% confidence region for sensitivity at a given specificity: 0.904, 0.946), and a positive predictive value of 45%., Conclusions: The 1-h PG of ≥11.6 mmol/L during OGTT has a good sensitivity and specificity for detecting type 2 diabetes. Prescreening with a diabetes-specific risk calculator to identify high-risk individuals is suggested to decrease the proportion of false-positive cases. Studies including other ethnic groups and assessing complication risk are warranted., (© 2021 by the American Diabetes Association.)

(1) Background: This study aimed to evaluate the associations of lymphovascular invasion (LVI) at first transurethral resection of bladder (TURBT) and radical cystectomy (RC) with survival outcomes, and to evaluate the concordance between LVI at first TURBT and RC. (2) Methods: We analyzed 216 patients who underwent first TURBT and 64 patients who underwent RC at Toho University Sakura Medical Center. (3) Results: LVI was identified in 22.7% of patients who underwent first TURBT, and in 32.8% of patients who underwent RC. Univariate analysis identified ≥cT3, metastasis and LVI at first TURBT as factors significantly associated with overall survival (OS) and cancer-specific survival (CSS). Multivariate analysis identified metastasis (hazard ratio (HR) 6.560, p = 0.009) and LVI at first TURBT (HR 9.205, p = 0.003) as significant predictors of CSS. On the other hand, in patients who underwent RC, ≥pT3, presence of G3 and LVI was significantly associated with OS and CSS in univariate analysis. Multivariate analysis identified inclusion of G3 as a significant predictor of OS and CSS. The concordance rate between LVI at first TURBT and RC was 48.0%. Patients with positive results for LVI at first TURBT and RC displayed poorer prognosis than other patients ( p < 0.05). (4) Conclusions: We found that the combination of LVI at first TURBT and RC was likely to provide a more significant prognostic factor.

Base editors are RNA-programmable deaminases that enable precise single-base conversions in genomic DNA. However, off-target activity is a concern in the potential use of base editors to treat genetic diseases. Here, we report unbiased analyses of transcriptome-wide and genome-wide off-target modifications effected by cytidine base editors in the liver of mice with phenylketonuria. The intravenous delivery of intein-split cytidine base editors by dual adeno-associated viruses led to the repair of the disease-causing mutation without generating off-target mutations in the RNA and DNA of the hepatocytes. Moreover, the transient expression of a cytidine base editor mRNA and a relevant single-guide RNA intravenously delivered by lipid nanoparticles led to ~21% on-target editing and to the reversal of the disease phenotype; there were also no detectable transcriptome-wide and genome-wide off-target edits. Our findings support the feasibility of therapeutic cytidine base editing to treat genetic liver diseases.

Eu 2+ -doped calcium zirconates, Ca 1- x Eu x ZrO 3 (0 ≤ x ≤ 1), were synthesized as novel environmentally friendly inorganic yellow pigments by the conventional solid-state reaction method. The crystal structure, morphology, optical properties, and color were characterized. The Eu 2+ -doped samples strongly absorbed blue light in the wavelength range of 435-480 nm, which was caused by the 4f-5d allowed transition of Eu 2+ . The color of the sample gradually became brilliant yellow with increasing the Eu 2+ content. Among the samples synthesized in this study, the brightest yellow color was obtained with the Ca 0.7 Eu 0.3 ZrO 3 ( a * = +11.5 and b * = +70.7) sample. Compared with the commercially available praseodymium yellow pigment ( a * = -3.28, b * = +70.3), the yellowness value ( b *) of Ca 0.7 Eu 0.3 ZrO 3 was comparable and the redness value ( a *) was higher. As a result, this pigment exhibited a reddish yellow color as compared with praseodymium yellow. In addition, this pigment was chemically stable. Therefore, the Ca 0.7 Eu 0.3 ZrO 3 pigment has the potential to become a novel environmentally friendly inorganic yellow pigment., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Background: Baloxavir acid, the active form of the orally available prodrug baloxavir marboxil, is a novel cap-dependent endonuclease inhibitor of influenza virus. Baloxavir marboxil has been shown to rapidly reduce virus titres compared with oseltamivir in clinical studies., Objectives: We investigated the relationship between pharmacokinetic (PK) parameters and antiviral activity of baloxavir acid based on virus titre reduction in lungs of infected mice., Methods: BALB/c mice infected with a sub-lethal dose of influenza A(H1N1), A(H1N1)pdm09, A(H3N2) or type B virus were treated on day 5 with oral baloxavir marboxil (0.5-50 mg/kg q12h), subcutaneous baloxavir acid (0.25-8 mg/kg/day), oseltamivir phosphate (5 or 50 eq mg/kg q12h) or other antivirals for 1 day. Lung virus titres were assessed 24 h after initial antiviral dosing. PK testing was performed at up to 24 h post-dosing of baloxavir marboxil or baloxavir acid in A/WSN/33-infected mice and the PK/pharmacodynamic (PD) relationship was evaluated for baloxavir acid., Results: Oral baloxavir marboxil administration showed dose-dependent virus titre reductions in lungs of mice infected with the different types/subtypes of influenza viruses 24 h post-dosing. Baloxavir marboxil at 15 mg/kg q12h resulted in ≥100-fold and ≥10-fold reductions in influenza A and B virus titres, respectively, compared with oseltamivir phosphate. PK/PD analysis showed that the plasma concentration at the end of the dosing interval (Cτ) or the plasma concentration at 24 h after initial dosing (C24) was the PK parameter predicting the virus titres at 24 h post-dosing of baloxavir acid., Conclusions: PK/PD analysis of baloxavir acid based on virus titre reduction in this mouse model could be helpful in predicting and maximizing virological outcomes in clinical settings., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.)

Background: Baloxavir marboxil (BXM), the oral prodrug of baloxavir acid (BXA), greatly reduces virus titers as well as influenza symptoms of uncomplicated influenza in patients., Objectives: To investigate the pharmacokinetic profiles of BXA and its efficacy against influenza A virus infection in ferrets., Methods: Ferrets were dosed orally with BXM (10 and 30 mg/kg twice daily for 1 day), oseltamivir phosphate (OSP) (5 mg/kg twice daily for 2 days) or vehicle to measure the antiviral effects of BXM and OSP. The pharmacokinetic parameters of BXA was determined after single oral dosing of BXM., Results: The maximum plasma concentrations of BXA were observed at 1.50 and 2.00 hours with the two BXM doses, which then declined with an elimination half-life of 6.91 and 4.44 hours, respectively. BXM at both doses remained detectable in the plasma in ferrets, which may be due to higher stability in liver microsomes. BXM (10 and 30 mg/kg twice daily) treatment at Day 1 post-infection (p.i.) reduced virus titers by ≥3 log10 of the 50% tissue culture infective doses by Day 2, which was significantly different compared with vehicle or OSP. Body temperature drops over time were significantly greater with BXM than with vehicle or OSP. Significant reduction in virus titers was also demonstrated when BXM was administrated after symptom onset at Day 2 p.i. compared with vehicle and OSP, although body temperature changes largely overlapped between Day 2 and Day 4., Conclusions: The results highlight the rapid antiviral action of BXM with post-exposure prophylaxis or therapeutic dosing in ferrets and offer support for further research on prevention of influenza virus infection and transmission., (© 2020 The Authors. Influenza and Other Respiratory Viruses published by John Wiley & Sons Ltd.)