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Chimerism test was evaluated to predict leukemia relapse. Increasing mixed chimerism (IMC), defined as recipient increase ≥0.1% in peripheral blood total cell chimerism, was used as a surrogate of disease activity. Combination of quantitative PCR and short-tandem repeat method was applied to achieve high assay sensitivity. Total of 184 patients received stem cell transplant for acute myeloid leukemia (N = 110), acute lymphocytic leukemia (N = 41), myelodysplastic syndrome (N = 30), and 2389 chimerism tests (median follow-up, 1054 days). Sixty-six patients relapsed, and 118 patients did not. Cumulative incidence of relapse increased after 1 IMC or ≥2 consecutive IMCs (hazard ratios, 9.9 and 44.4, respectively). Predicted percentage relapse by day 30 after IMC was 0% (0 IMC), 10% (1 IMC), and 40% (≥2 IMCs). The last chimerism results before relapse detected IMC in 57 of 66 relapsed patients (sensitivity, 86.4%). Nine patients had no IMC before relapse (false negative) because of rapidly evolving relapse (N = 4) or extramural relapse (N = 5). In 118 patients without relapse, 158 of 1873 tests detected IMC (false positive, 8.4%; specificity, 91.6%). The false-positive rates increased with higher percentage recipient T-cell chimerism levels, indicating T-cell contamination as a cause. Chimerism monitoring predicts relapse. However, caution must be taken for false-positive or false-negative IMCs. T-cell removal can improve chimerism test specificity in patients with mixed T-cell chimerism., Competing Interests: Disclosure Statement None declared., (Copyright © 2024 Association for Molecular Pathology and American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Weight loss is a critical health issue among the older population. This study aimed to explore the association between weight loss and oral health in older adults., Methods: We used cross-sectional data from the Uonuma Chronic Kidney Disease Cohort Study. The binary logistic regression models were fitted to estimate the relationship between weight loss and independent variables including the number of teeth present., Results: The participants included 1656 females and 1625 males. There were 1217 females (73.4%) and 1236 males (76.0%) with normal BMI (18.5 ≤ BMI < 25) in the previous year. Weight loss was determined over a 12-month period. Individuals with normal BMI in previous year, and those with weight loss (≥ 5%) or those whom maintained a stable weight were further analysed. The regression analysis (model 3, fully adjusted) showed that females with 0 and 1-10 teeth present had a higher likelihood of losing weight (OR = 4.07; 95% CI = 1.85-8.93, OR = 2.33; 95% CI = 1.24-4.39) compared with those with 20 or more teeth. Current smokers had a higher likelihood of losing weight (OR = 3.15; 95% CI = 1.01-9.76) than lifelong abstainers. Among males, both current and previous smokers showed a higher likelihood of losing weight (OR = 4.94; 95%CI = 1.76-13.8, OR = 3.35; 95% CI = 1.29-8.68) than those who never smoked., Conclusions: This study indicates that the number of teeth and smoking are both linked to weight loss in females. However, in males, the association between the number of teeth and weight loss may be compromised due to the high prevalence of smoking in this group., (© 2024 John Wiley & Sons Ltd.)

Rationale: Despite variants in the Dlgap1 gene having the two lowest p-value in a genome-wide association study of obsessive compulsive disorder (OCD), previous studies reported the absence of OCD-like phenotypes in Dlgap1 knockout (KO) mice. Since these studies observed behavioral phenotypes only for a short period, development of OCD-like phenotypes in these mice at older ages was still plausible., Objective: To examine the presence or absence of development of OCD-like phenotypes in Dlgap1 KO mice and their responsiveness to fluvoxamine., Methods and Results: Newly produced Dlgap1 KO mice were observed for a year. Modified SHIRPA primary screen in 2-month-old homozygous mutant mice showed only weak signs of anxiety, stress conditions and aggression. At older ages, however, these mutant mice exhibited excessive self-grooming characterized by increased scratching which led to skin lesions. A significant sex difference was observed in this scratching behavior. The penetrance of skin lesions reached 50% at 6-7 months of age and 90% at 12 months of age. In the open-field test performed just after the appearance of these lesions, homozygous mutant mice spent significantly less time in the center, an anxiety-like behavior, than did their wild-type and heterozygous littermates, none and less than 10% of which showed skin lesions at 1 year, respectively. The skin lesions and excessive self-grooming were significantly alleviated by two-week treatment with fluvoxamine., Conclusion: Usefulness of Dlgap1 KO mice as a tool for investigating the pathogenesis of OCD-like phenotypes and its translational relevance was suggested., (© 2024. The Author(s).)

Primary graft failure (PGF) and multi-lineage cytopenia (MLC) increase the risk of nonrelapse mortality in allogeneic hematopoietic cell transplants (HCT). We evaluated the impact of post-transplant cyclophosphamide (PTCy) and splenomegaly on PGF and MLC for hematological malignancies. This study included patients with PTCy (N=84) and conventional graft-vs.-host disease prophylaxis (N=199). The occurrence of splenomegaly varied widely, ranging from 17.1 % (acute myeloid leukemia) to 66.7 % (myeloproliferative neoplasms). Ten patients (N=8 in the PTCy and N=2 in the non- PTCy) developed PGF, and 44 patients developed MLC (both N=22). PTCy and severe splenomegaly (≥20 cm) were risk factors for PGF (odds ratio (OR): 10.40, p<0.01 and 6.74, p=0.01 respectively). Moreover, severe splenomegaly was a risk factor for PGF in PTCy patients (OR: 10.20, p=0.01). PTCy (hazard ratio (HR) 2.09, p=0.02), moderate (≥15, <20 cm, HR 4.36, p<0.01), and severe splenomegaly (HR 3.04, p=0.01) were independent risk factors for MLC. However, in subgroup analysis in PTCy patients, only mild splenomegaly (≥12, <15 cm, HR 4.62, p=0.01) was a risk factor for MLC. We recommend all patients be screened for splenomegaly before HCT, and PTCy is cautioned in those with splenomegaly., Competing Interests: Declaration of Competing Interest All authors declare no conflicts of interest associated with this manuscript., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: The 2018 Osaka earthquake caused severe damage to the National Cerebral and Cardiovascular Center, and the interruption to the delivery of hospital food in particular had a significant effect on patients with left ventricular assist devices (LVAD). Methods and Results: We retrospectively assessed 10 patients who had been provided with emergency rations on the day of earthquake and the next day for breakfast. Catered foods were provided thereafter. Vitamin K content was largely reduced due to emergency rations; the prothrombin time-international normalized ratio (PT-INR) on day 2 was significantly higher than on day 1. Conclusions: Close monitoring of PT-INR and assessing vitamin K content may be important for preventing complications in patients with a LVAD during a disaster., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2024, THE JAPANESE CIRCULATION SOCIETY.)

The Asian tiger mosquito, Aedes albopictus, is a significant public health concern owing to its expanding habitat and vector competence. Disease outbreaks attributed to this species have been reported in areas under its invasion, and its northward expansion in Japan has caused concern because of the potential for dengue virus infection in newly populated areas. Accurate prediction of Ae. albopictus distribution is crucial to prevent the spread of the disease. However, limited studies have focused on the prediction of Ae. albopictus distribution in Japan. Herein, we used the random forest model, a machine learning approach, to predict the current and potential future habitat ranges of Ae. albopictus in Japan. The model revealed that these mosquitoes prefer urban areas over forests in Japan on the current map. Under predictions for the future, the species will expand its range to the surrounding areas and eventually reach many areas of northeastern Kanto, Tohoku District, and Hokkaido, with a few variations in different scenarios. However, the affected human population is predicted to decrease owing to the declining birth rate. Anthropogenic and climatic factors contribute to range expansion, and urban size and population have profound impacts. This prediction map can guide responses to the introduction of this species in new areas, advance the spatial knowledge of diseases vectored by it, and mitigate the possible disease burden. To our knowledge, this is the first distribution-modelling prediction for Ae. albopictus with a focus on Japan., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Yang 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.)

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.

Background: Bacterial prophylaxis with a fluoroquinolone (FQ) during autologous stem cell transplant (ASCT) is common, although not standardized among transplant centers. The addition of doxycycline (doxy) to FQ prophylaxis was previously linked to reduced neutropenic fever and bacteremia in multiple myeloma (MM) patients undergoing ASCT although several confounders were present. We compared the incidence of neutropenic fever and bacteremia between MM patients variably receiving prophylaxis with FQ alone and FQ-doxy during ASCT., Methods: Systematic retrospective chart review of MM patients who underwent ASCT between January 2016 and December 2021. The primary objective was to determine the effect of bacterial prophylaxis on neutropenic fever and bacteremia within 30 days of ASCT. Multivariable logistic regression for neutropenic fever and univariate logistic regression for bacteremia accounted for differences in subject characteristics between groups., Results: Among 341 subjects, 121 received FQ and 220 received FQ-doxy for prophylaxis. Neutropenic fever developed in 67 (55.4%) and 87 (39.5%) subjects in the FQ and FQ-doxy groups, respectively (p = .005). Bacteremia was infrequent, with 5 (4.1%) and 5 (2.3%) cases developing in the FQ and FQ-doxy groups, respectively (p = .337). Among Gram-negative bacteremia events, 7/7 Escherichia coli strains were FQ-resistant, and 5/7 were ceftriaxone-resistant., Conclusion: The FQ-doxy prophylaxis group had fewer cases of neutropenic fever than the FQ group, however, there was no significant difference in bacteremia. High rates of antibiotic resistance were observed. An updated randomized controlled trial investigating appropriate prophylaxis for ASCT in the context of current oncology standards and changing antimicrobial resistance rates is warranted., (© 2024 The Authors. Transplant Infectious Disease published by Wiley Periodicals LLC.)

We found a novel gene, named "transformed follicular lymphoma" (TFL), in a patient who developed diffuse large B-cell lymphoma from follicular lymphoma. TFL modulates several cytokines and chemokines by binding their 3'UTR region of mRNA with its unique RNase motif. TFL is part of a family called zinc finger CCCH-type containing 12A-D. Due to its unique RNase motif, the TFL family is also called regulatory RNase (Regnase 1-4). TFL is expressed in lymphoid tissue and is upregulated by an inflammatory response, contributing to autoimmune diseases such as multiple sclerosis via IL-17 in CNS and worsening inflammation (cachexia) due to lymphoma progression through CXCL-13. Loss of TFL expression is reported to be a valuable biomarker for various cancers, including lung adenocarcinoma, endometrial cancer, and possibly lymphoma. In addition to its mRNA modulation function, Regnase1 is known to have deubiquitinase activity for TRAF2, 3, and 6, attenuating JNK and NFκB activity, and TFL captures and transports naked nonvesicular extracellular mRNA of IL-1β to the nucleus, enhancing the tumor-killing activity in NK cells. Based on its potential to modulate inflammation, TFL could be a future treatment target for autoimmune diseases and cancer.

Amyotrophic lateral sclerosis (ALS) is a devastating motor disease with limited treatment options. A domestic fungal extract library was screened using three assays related to the pathophysiology of ALS with the aim of developing a novel ALS drug. 2(3H)-dihydrofuranolactones 1 and 2, and five known compounds 3-7 were isolated from Pleosporales sp. NUH322 culture media, and their protective activity against the excitotoxicity of β-N-oxalyl-L-α,β-diaminopropionic acid (ODAP), an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamatergic agonist, was evaluated under low mitochondrial glutathione levels induced by ethacrynic acid (EA) and low sulfur amino acids using our developed ODAP-EA assay. Additional assays evaluated the recovery from cytotoxicity caused by transfected SOD1-G93A, an ALS-causal gene, and the inhibitory effect against reactive oxygen species (ROS) elevation. The structures of 1 and 2 were elucidated using various spectroscopic methods. We synthesized 1 from D-ribose, and confirmed the absolute structure. Isolated and synthesized 1 displayed higher ODAP-EA activities than the extract and represented its activity. Furthermore, 1 exhibited protective activity against SOD1-G93A-induced toxicity. An ALS mouse model, SOD1-G93A, of both sexes, was treated orally with 1 at pre- and post-symptomatic stages. The latter treatment significantly extended their lifespan (p = 0.03) and delayed motor deterioration (p = 0.001-0.01). Our result suggests that 1 is a promising lead compound for the development of ALS drugs with a new spectrum of action targeting both SOD1-G93A proteopathy and excitotoxicity through its action on the AMPA-type glutamatergic receptor., (© 2023. The Author(s) under exclusive licence to The Japanese Society of Pharmacognosy.)

Allogeneic hematopoietic stem cell transplantation (alloSCT) is, in many clinical settings, the only curative treatment for acute myeloid leukemia (AML). The clinical benefit of alloSCT greatly relies on the graft-versus-leukemia (GVL) effect. However, AML relapse remains the top cause of posttransplant death; this highlights the urgent need to enhance GVL. Studies of human GVL have been hindered by the lack of optimal clinically relevant models. In this article, we report, the successful establishment of a novel (to our knowledge) humanized GVL model system by transplanting clinically paired donor PBMCs and patient AML into MHC class I/II knockout NSG mice. We observed significantly reduced leukemia growth in humanized mice compared with mice that received AML alone, demonstrating a functional GVL effect. Using this model system, we studied human GVL responses against human AML cells in vivo and discovered that AML induced T cell depletion, likely because of increased T cell apoptosis. In addition, AML caused T cell exhaustion manifested by upregulation of inhibitory receptors, increased expression of exhaustion-related transcription factors, and decreased T cell function. Importantly, combined blockade of human T cell-inhibitory pathways effectively reduced leukemia burden and reinvigorated CD8 T cell function in this model system. These data, generated in a highly clinically relevant humanized GVL model, not only demonstrate AML-induced inhibition of alloreactive T cells but also identify promising therapeutic strategies targeting T cell depletion and exhaustion for overcoming GVL failure and treating AML relapse after alloSCT., (Copyright © 2023 by The American Association of Immunologists, Inc.)

Acute myeloid leukemia (AML) is a devastating blood cancer with poor prognosis. Novel effective treatment is an urgent unmet need. Immunotherapy targeting T cell exhaustion by blocking inhibitory pathways, such as PD-1, is promising in cancer treatment. However, results from clinical studies applying PD-1 blockade to AML patients are largely disappointing. AML is highly heterogeneous. Identification of additional immune regulatory pathways and defining predictive biomarkers for treatment response are crucial to optimize the strategy. CD26 is a marker of T cell activation and involved in multiple immune processes. Here, we performed comprehensive phenotypic and functional analyses on the blood samples collected from AML patients and discovered that CD26 low PD-1 + CD8 T cells were associated with AML progression. Specifically, the percentage of this cell fraction was significantly higher in patients with newly diagnosed AML compared to that in patients achieved completed remission or healthy controls. Our subsequent studies on CD26 low PD-1 + CD8 T cells from AML patients at initial diagnosis demonstrated that this cell population highly expressed inhibitory receptors and displayed impaired cytokine production, indicating an exhaustion status. Importantly, CD26 low PD-1 + CD8 T cells carried features of terminal exhaustion, manifested by higher frequency of T EMRA differentiation, increased expression of transcription factors that are observed in terminally exhausted T cells, and high level of intracellular expression of granzyme B and perforin. Our findings suggest a prognostic and predictive value of CD26 in AML, providing pivotal information to optimize the immunotherapy for this devastating cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhou, Jia, Annageldiyev, Minagawa, Zhao, Mineishi, Ehmann, Naik, Cioccio, Wirk, Songdej, Rakszawski, Nickolich, Shen and Zheng.)

Objectives: To simultaneously estimate how the risk of incident dementia nonlinearly varies with the administration period and cumulative dose of benzodiazepines, the duration of disorders with an indication for benzodiazepines, and other potential confounders, with the goal of settling the controversy over the role of benzodiazepines in the development of dementia., Methods: The classical hazard model was extended using the techniques of multiple-kernel learning. Regularised maximum-likelihood estimation, including determination of hyperparameter values with 10-fold cross-validation, bootstrap goodness-of-fit test, and bootstrap estimation of confidence intervals, was applied to cohorts retrospectively extracted from electronic medical records of our university hospitals between 1 November 2004 and 31 July 2020. The analysis was mainly focused on 8160 patients aged 40 or older with new onset of insomnia, affective disorders, or anxiety disorders, who were followed up for 4.10 ± 3.47 years., Results: Besides previously reported risk associations, we detected significant nonlinear risk variations over 2-4 years attributable to the duration of insomnia and anxiety disorders, and to the administration period of short-acting benzodiazepines. After nonlinear adjustment for potential confounders, we observed no significant risk associations with long-term use of benzodiazepines., Conclusions: The pattern of the detected nonlinear risk variations suggested reverse causation and confounding. Their putative bias effects over 2-4 years suggested similar biases in previously reported results. These results, together with the lack of significant risk associations with long-term use of benzodiazepines, suggested the need to reconsider previous results and methods for future analysis., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2023.)

Statement of Significance: Loss of TFL , found in several types of lymphoma, induces excessive CXCL13 secretion through RNA dysregulation contributing to body weight loss and early death in lymphoma model mice. Follicular lymphoma (FL) is associated with overexpressed BCL-2 and other genetic aberrations, including 6q-. We identified a novel gene on 6q25, " Transformed follicular lymphoma ( TFL )," from a transformed FL. TFL regulates several cytokines via mRNA degradation, which has been suggested to underlie resolving inflammation. Fluorescence in situ hybridization revealed a deletion of TFL occurred in 13.6% of various B-cell lymphoma samples. We developed VavP- bcl2 transgenic, TFL deficit mice ( Bcl2 -Tg/ Tfl -/- ) to seek how TFL affects disease progression in this lymphoma model. While Bcl2 -Tg mice developed lymphadenopathy and died around 50 weeks, Bcl2 -Tg/ Tfl -/- mice lost body weight around 30 weeks and died about 20 weeks earlier than Bcl2 -Tg mice. Furthermore, we found a unique B220 - IgM + cell population in the bone marrow of Bcl2 -Tg mice. cDNA array in this population revealed that Cxcl13 mRNA in Bcl2 -Tg/ Tfl -/- mice expressed significantly higher than Bcl2 -Tg mice. In addition, bone marrow extracellular fluid and serum showed an extremely high Cxcl13 concentration in Bcl2 -Tg/ Tfl -/- mice. Among bone marrow cells, the B220 - IgM + fraction was the main producer of Cxcl13 in culture. A reporter assay demonstrated TFL regulates CXCL-13 via induction of 3'UTR mRNA degradation in B lineage cells. These data suggest Tfl regulates Cxcl13 in B220 - IgM + cells in the bone marrow, and a very high concentration of serum Cxcl13 arising from these cells may contribute to early death in lymphoma-bearing mice. Since several reports have suggested the association of CXCL13 expression with lymphoma, these findings provide new insights into cytokine regulation via TFL in lymphoma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Minagawa, Wakahashi, Fukui, Kawano, Kawano, Suzuki, Ishii, Sada, Nishikawa, Asada, Katayama and Matsui.)

Background: Acute kidney injury (AKI), with an increase in serum creatinine, is a common adverse drug event. Although various clinical studies have investigated whether a combination of two nephrotoxic drugs has an increased risk of AKI using traditional statistical models such as multivariable logistic regression (MLR), the evaluation metrics have not been evaluated despite the fact that traditional statistical models may over-fit the data. The aim of the present study was to detect drug-drug interactions with an increased risk of AKI by interpreting machine-learning models to avoid overfitting. Methods: We developed six machine-learning models trained using electronic medical records: MLR, logistic least absolute shrinkage and selection operator regression (LLR), random forest, extreme gradient boosting (XGB) tree, and two support vector machine models (kernel = linear function and radial basis function). In order to detect drug-drug interactions, the XGB and LLR models that showed good predictive performance were interpreted by SHapley Additive exPlanations (SHAP) and relative excess risk due to interaction (RERI), respectively. Results: Among approximately 2.5 million patients, 65,667 patients were extracted from the electronic medical records, and assigned to case ( N = 5,319) and control ( N = 60,348) groups. In the XGB model, a combination of loop diuretic and histamine H 2 blocker [mean (|SHAP|) = 0.011] was identified as a relatively important risk factor for AKI. The combination of loop diuretic and H 2 blocker showed a significant synergistic interaction on an additive scale (RERI 1.289, 95% confidence interval 0.226-5.591) also in the LLR model. Conclusion: The present population-based case-control study using interpretable machine-learning models suggested that although the relative importance of the individual and combined effects of loop diuretics and H 2 blockers is lower than that of well-known risk factors such as older age and sex, concomitant use of a loop diuretic and histamine H 2 blocker is associated with increased risk of AKI., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Akimoto, Hayakawa, Nagashima, Minagawa, Takahashi and Asai.)

Full donor T-cell chimerism (FDTCC) after allogeneic stem cell transplant (allo-SCT) has been associated with improved outcomes in hematologic malignancy. We studied if donor human leukocyte antigen (HLA) mismatch improves achievement of FDTCC because mismatched HLA promotes donor T-cell proliferation where recipient T-cells had been impaired by previous treatment. Patients (N = 138) received allo-SCT with reduced-intensity conditioning (RIC) from 39 HLA mismatched donors (16 unrelated; 23 haploidentical) with post-transplant cyclophosphamide (PTCy) or 99 matched donors (21 siblings; 78 unrelated) with PTCy (N = 18) or non-PTCy (N = 81). Achievement of FDTCC by day 100 was higher with HLA mismatched donors than matched donors (82.1% vs. 27.3%, p < 00,001), which was further improved with 200 cGy total body irradiation (87.9%) or lymphoid (versus myeloid) malignancy (93.8%). Since all mismatched transplants used PTCy, FDTCC was higher with PTCy than non-PTCy (68.4% vs. 25.7%, p < 0.00001), but not in the matched transplant with PTCy (38.9%), negating PTCy as the primary driver. Lymphocyte recovery was delayed with PTCy than without (median on day + 30: 100 vs. 630/µL, p < 0.0001). The benefit of FDTCC was not translated into survival outcomes, especially in myeloid malignancies, possibly due to the insufficient graft-versus-tumor effects from the delayed lymphocyte recovery. Further studies are necessary to improve lymphocyte count recovery in PTCy transplants., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The isoalloxazine ring system, called flavin, was successfully immobilized on poly(methacrylic acid)s, PMAAs, with different tacticity via post-polymerization modification under suitable conditions. The resulting flavin-containing polymers showed catalytic activity for aerobic oxidation reactions, in which the polymer stereoregularity clearly influenced their catalytic activity.

Gene-modified cellular therapies carry inherent risks of severe and potentially fatal adverse events, including the expansion of alloreactive cells or malignant transformation due to insertional mutagenesis. Strategies to mitigate uncontrolled proliferation of gene-modified cells include co-transfection of a suicide gene, such as the inducible caspase 9 safety switch (ΔiC9). However, the activation of the ΔiC9 fails to completely eliminate all gene-modified cells. Therefore, we tested a two suicide gene system used independently or together, with the goal of complete cell elimination. The first approach combined the ΔiC9 with an inducible caspase 8, ΔiC8, which lacks the endogenous prodomain. The rationale was to use a second caspase with an alternative and complementary mechanism of action. Jurkat cells co-transduced to co-express the ΔiC8, activatable by a BB homodimerizer, and the ΔiC9 activatable by the rapamycin analog sirolimus were used in a model to estimate the degree of inducible cell elimination. We found that both agents could activate each caspase independently, with enhanced elimination with superior reduction in cell regrowth of gene-modified cells when both systems were activated simultaneously. A second approach was employed in parallel, combining the ΔiC9 with the RQR8 compact suicide gene. RQR8 incorporates a CD20 mimotope, targeted by the anti-CD20 monoclonal antibody rituxan, and the QBend10, a ΔCD34 selectable marker. Likewise, enhanced cell elimination with superior reduction in cell regrowth was observed when both systems were activated together. A dose-titration effect was also noted utilizing the BB homodimerizer, whereas sirolimus remained very potent at minimal concentrations. Further in vivo studies are needed to validate these novel combination systems, which may play a role in future cancer therapies or regenerative medicine., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Falcon, Smith, Al-Obaidi, Abu Zaanona, Purvis, Minagawa, Athar, Salzman, Bhatia, Goldman and Di Stasi.)

Drug-induced liver injury (DILI) is a common adverse drug reaction, with abnormal elevation of serum alanine aminotransferase (ALT). Several clinical studies have investigated whether a combination of two drugs alters the reporting frequency of DILI using traditional statistical methods such as multiple logistic regression (MLR), but this model may over-fit the data. This study aimed to detect a synergistic interaction between two drugs on the risk of abnormal elevation of serum ALT in Japanese adult patients using three machine-learning algorithms: MLR, logistic least absolute shrinkage and selection operator (LASSO) regression, and extreme gradient boosting (XGBoost) algorithms. A total of 58,413 patients were extracted from Nihon University School of Medicine's Clinical Data Warehouse and assigned to case ( N = 4,152) and control ( N = 54,261) groups. The MLR model over-fitted a training set. In the logistic LASSO regression model, three combinations showed relative excess risk due to interaction (RERI) for abnormal elevation of serum ALT: diclofenac and famotidine (RERI 2.427, 95% bootstrap confidence interval 1.226-11.003), acetaminophen and ambroxol (0.540, 0.087-4.625), and aspirin and cilostazol (0.188, 0.135-3.010). Moreover, diclofenac (adjusted odds ratio 1.319, 95% bootstrap confidence interval 1.189-2.821) and famotidine (1.643, 1.332-2.071) individually affected the risk of abnormal elevation of serum ALT. In the XGBoost model, not only the individual effects of diclofenac (feature importance 0.004) and famotidine (0.016), but also the interaction term (0.004) was included in important predictors. Although further study is needed, the combination of diclofenac and famotidine appears to increase the risk of abnormal elevation of serum ALT in the real world., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Akimoto, Nagashima, Minagawa, Hayakawa, Takahashi and Asai.)

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.)

Antidepressants are known to cause hyponatremia, but conflicting evidence exists regarding specific antidepressants. To identify antidepressants less likely to cause hyponatremia, we conducted a triangulation study integrating retrospective cohort, disproportionality, and pharmacodynamic studies. In the retrospective cohort study of patients (≥ 60 years) in Nihon University School of Medicine's Clinical Data Warehouse (2004-2020), a significant decrease in serum sodium levels was observed within 30 days after initiation of a selective serotonin reuptake inhibitor (SSRI; mean change -1.00 ± 0.23 mmol/L, P < 0.001) or serotonin-noradrenaline reuptake inhibitor (SNRI; -1.01 ± 0.31 mmol/L, P = 0.0013), whereas no decrease was found for a noradrenergic and specific serotonergic antidepressant (mirtazapine; +0.55 ± 0.47 mmol/L, P = 0.24). Within-class comparison revealed no decrease in serum sodium levels for fluvoxamine (+0.74 ± 0.75 mmol/L, P = 0.33) among SSRIs and milnacipran (+0.08 ± 0.87 mmol/L, P = 0.93) among SNRIs. In the disproportionality analysis of patients (≥ 60 years) in the Japanese Adverse Drug Event Report database (2004-2020), a significant increase in hyponatremia reports was observed for SSRIs (reporting odds ratio 4.41, 95% confidence interval 3.58-5.45) and SNRIs (5.66, 4.38-7.31), but not for mirtazapine (1.08, 0.74-1.58), fluvoxamine (1.48, 0.94-2.32), and milnacipran (0.85, 0.45-1.62). Finally, pharmacoepidemiological-pharmacodynamic analysis revealed a significant correlation between the decrease in serum sodium levels and binding affinity for serotonin transporter (SERT; r = -0.84, P = 0.02), suggesting that lower binding affinity of mirtazapine, fluvoxamine, and milnacipran against SERT is responsible for the above difference. Although further research is needed, our data suggest that mirtazapine, fluvoxamine, and milnacipran are less likely to cause hyponatremia., (© 2022 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Herein, we present the first study on the polyaddition reaction of biscarbodiimides with chiral diamines, which focuses on a definite case using optically active trans -4a,8a-decahydroquinoxaline and 1,4-phenylenebis(arylcarbodiimide)s, which readily react with each other under ambient and catalyst-free conditions. The specific reactivity allows for facile access to not only the corresponding chiral polyguanidines under balanced stoichiometry but also their oligomeric analogues under imbalanced stoichiometry via a step-by-step procedure. Spectroscopic, chromatographic, and computational characterization of the novel molecular chains containing arrayed guanidines have revealed their structural, optical, and conformational properties as well as the mechanism of polymerization assisted by molecular association. Their potential use as asymmetric catalysts is also described., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

Bed bug control highly depends on insecticides with a limited number of modes of action, especially since the global prevalence of pyrethroid resistance. De facto insecticide options against bed bugs in Japan are acetylcholinesterase inhibitors (AChEis) that consist of organophosphates and carbamates. However, the status of AChEi resistance and the mechanisms involved have not been ascertained. An amino acid substitution mutation, F348Y (or F331Y in standard numbering), occurring at an acyl-binding site of the paralogous AChE gene (p-Ace), was identified among AChEi-resistant colonies of both common and tropical bed bugs (Cimex lectularius and C. hemipterus, respectively). This mutation was genetically associated with propoxur and fenitrothion resistance in F348Y-segregating colonies of C. hemipterus. Inhibition of heterologously expressed C. lectularius p-Ace with insecticides revealed that the sensitivities of F348Y-carrying AChE decreased by orders of 10- to more than 100-fold for diazoxon, carbaryl, fenitroxon, paraoxon, chlorpyrifos-methyl, malaoxon, azamethiphos, methyl-paraoxon, and propoxur. In contrast, the mutant AChE showed a slightly decreased degree of sensitivity for dichlorvos and almost unchanged sensitivity for metoxadiazone. Further studies are needed to ascertain whether the practical efficacies of dichlorvos and metoxadiazone are ensured against F348Y-carrying bed bugs and whether other resistance mechanisms are involved., (Copyright © 2021. Published by Elsevier Ltd.)

We have synthesized a cyan fluorescent benzothiazole-pyridinium salt composite based on D-π-A architecture. This salt was found to work as not only a two- and three-photon excitable fluorophore but also a degradation agent against amyloid fibrils under LED irradiation conditions., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Acute myeloid leukemia (AML) relapse after allogeneic stem cell transplant (alloSCT) remains a major therapeutic challenge. While patients with longer remission after initial alloSCT are recommended to receive cell therapy (CT) such as 2 nd alloSCT or donor lymphocyte infusion (DLI), survival for patients who relapse within 6 months of alloSCT has been dismal. We evaluated the outcomes of AML relapse after alloSCT to assess the impact of different treatments on long-term survival. One hundred and seventy-two patients with AML underwent alloSCT at the Penn State Cancer Institute from January 2014 to August 2019. Sixty-nine patients relapsed (median age, 60 years; range, 10-75). Of these, 4 patients underwent 2 nd alloSCT, and 26 received DLI. One-year overall survival (OS) in all cases was 20.3% (95% CI: 11.8-30.4%). Patients with ECOG performance status (PS) 0-2 at relapse showed a better 1-year OS than those with PS 3-4. Median OS for patients who received chemotherapy only or chemotherapy with CT was 74 or 173.5 days, respectively (p < 0.001). Relapsed patients receiving conventional re-induction chemotherapy were categorized as the high-intensity chemotherapy (H) group, while those receiving treatments such as hypomethylating agents or targeted agents were categorized as the low-intensity chemotherapy (L) group. The H group showed a better 1-year OS compared with the L group. Patients who received H + CT showed a better 1-year OS of 52.9% than the other 3 groups (p < 0.001). Even for patients with post-alloSCT remission duration of less than 6 months, the statistical significance was preserved. Factors including age, donor source at 1 st alloSCT, time to relapse, blast counts, PS at relapse, and treatment type after post-alloSCT relapse were used for a multivariate analysis, and matched or mismatched related donor and H + CT after alloSCT were identified as independent factors associated with OS. These findings support the use of H + CT as the treatment option of choice for AML patients who relapse after alloSCT when feasible., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Longer cumulenes have come to draw considerable attention due to their unique properties and reactivities, leading to various hydrocarbons. In this manuscript, we describe the reaction of tetrakis( p -methoxyphenyl)[5]cumulene with iodine to afford poly-functionalized fulvenes via unexpected migration of a terminal aryl ring under ambient conditions. The obtained iodinated fulvenes were utilized in Suzuki-Miyaura cross-coupling reactions affording penta- and fully-arylated fulvenes successfully.

We have synthesized a cyan fluorescent boron complex based on a tridentate imidazo[1,5- a ]pyridine ligand. The boron complex was found to have potential applications as not only a chiroptical material but also a heavy-atom-free mitochondria-targeted photosensitizer for cancer treatment., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

RNA in extracellular vesicles (EVs) are uptaken by cells, where they regulate fundamental cellular functions. EV-derived mRNA in recipient cells can be translated. However, it is still elusive whether "naked nonvesicular extracellular mRNA" (nex-mRNA) that are not packed in EVs can be uptaken by cells and, if so, whether they have any functions in recipient cells. Here, we show the entrance of nex-mRNA in the nucleus, where they exert a translation-independent function. Human nex-interleukin-1β (IL1β)-mRNA outside cells proved to be captured by RNA-binding zinc finger CCCH domain containing protein 12D (ZC3H12D)-expressing human natural killer (NK) cells. ZC3H12D recruited to the cell membrane binds to the 3'-untranslated region of nex-IL1β-mRNA and transports it to the nucleus. The nex-IL1β-mRNA in the NK cell nucleus upregulates antiapoptotic gene expression, migration activity, and interferon-γ production, leading to the killing of cancer cells and antimetastasis in mice. These results implicate the diverse actions of mRNA.

The mobilization efficiency of hematopoietic stem/progenitor cells from bone marrow (BM) to circulation by granulocyte colony-stimulating factor (G-CSF) is dramatically dispersed in humans and mice with no mechanistic lead for poor mobilizers. The regulatory mechanism for mobilization efficiency by dietary fat was assessed in mice. Fat-free diet (FFD) for 2 weeks greatly increased mobilization compared to normal diet (ND). The BM mRNA level of peroxisome proliferator-activated receptor δ (PPARδ), a receptor for lipid mediators, was markedly up-regulated by G-CSF in mice fed with ND and displayed strong positive correlation with widely scattered mobilization efficiency. It was hypothesized that BM fat ligand for PPARδ might inhibit mobilization. The PPARδ agonist inhibited mobilization in mice fed with ND and enhanced mobilization by FFD. Treatment with the PPARδ antagonist and chimeric mice with PPARδ+/- BM showed enhanced mobilization. Immunohistochemical staining and flow cytometry revealed that BM PPARδ expression was enhanced by G-CSF mainly in mature/immature neutrophils. BM lipid mediator analysis revealed that G-CSF treatment and FFD resulted in the exhaustion of ω3-polyunsaturated fatty acids such as eicosapentaenoic acid (EPA). EPA induced the up-regulation of genes downstream of PPARδ, such as carnitine palmitoyltransferase-1α and angiopoietin-like protein 4 (Angptl4), in mature/immature neutrophils in vitro and inhibited enhanced mobilization in mice fed with FFD in vivo. Treatment of wild-type mice with the anti-Angptl4 antibody enhanced mobilization together with BM vascular permeability. Collectively, PPARδ signaling in BM mature/immature neutrophils induced by dietary fatty acids negatively regulates mobilization, at least partially, via Angptl4 production.

Fibroblast growth factor 23 (FGF-23) hormone is produced by bone-embedded osteocytes and regulates phosphate homeostasis in kidneys. We found that administration of granulocyte colony-stimulating factor (G-CSF) to mice induced a rapid, substantial increase in FGF-23 messenger RNA in bone marrow (BM) cells. This increase originated mainly from CD45-Ter119+CD71+ erythroblasts. FGF-23 protein in BM extracellular fluid was markedly increased during G-CSF-induced hematopoietic progenitor cell (HPC) mobilization, but remained stable in the blood, with no change in the phosphate level. Consistent with the BM hypoxia induced by G-CSF, low oxygen concentration induced FGF-23 release from human erythroblast HUDEP-2 cells in vitro. The efficient mobilization induced by G-CSF decreased drastically in both FGF-23-/- and chimeric mice with FGF-23 deficiency, only in hematopoietic cells, but increased in osteocyte-specific FGF-23-/- mice. This finding suggests that erythroblast-derived, but not bone-derived, FGF-23 is needed to release HPCs from BM into the circulation. Mechanistically, FGF-23 did not influence CXCL-12 binding to CXCR-4 on progenitors but interfered with their transwell migration toward CXCL-12, which was canceled by FGF receptor inhibitors. These results suggest that BM erythroblasts facilitate G-CSF-induced HPC mobilization via FGF-23 production as an intrinsic suppressor of chemoattraction., (© 2021 by The American Society of Hematology.)

A subset of prostate cancer displays a poor clinical outcome. Therefore, identifying this poor prognostic subset within clinically aggressive groups (defined as a Gleason score (GS) ≧8) and developing effective treatments are essential if we are to improve prostate cancer survival. Here, we performed a bioinformatics analysis of a TCGA dataset (GS ≧8) to identify pathways upregulated in a prostate cancer cohort with short survival. When conducting bioinformatics analyses, the definition of factors such as "overexpression" and "shorter survival" is vital, as poor definition may lead to mis-estimations. To eliminate this possibility, we defined an expression cutoff value using an algorithm calculated by a Cox regression model, and the hazard ratio for each gene was set so as to identify genes whose expression levels were associated with shorter survival. Next, genes associated with shorter survival were entered into pathway analysis to identify pathways that were altered in a shorter survival cohort. We identified pathways involving upregulation of GRB2. Overexpression of GRB2 was linked to shorter survival in the TCGA dataset, a finding validated by histological examination of biopsy samples taken from the patients for diagnostic purposes. Thus, GRB2 is a novel biomarker that predicts shorter survival of patients with aggressive prostate cancer (GS ≧8).

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.)

Drug-induced liver injury (DILI) is a common adverse drug event. Spontaneous reporting systems such as the Japanese Adverse Event Report Database (JADER) have been used to evaluate the association between drugs and adverse drug events. However, the association of drugs with adverse drug events may be overestimated due to reporting biases. Therefore, it is important to objectively evaluate the association using liver function test values. The aim of the present study was to predict potential hepatotoxic drugs using real-world data including electronic medical records and the JADER database. A total of 70009 (2779 with DILI and 67230 without DILI) and 438515 (10235 with DILI and 428280 without DILI) Japanese adult patients were extracted from electronic medical records and the JADER database, respectively. Drugs with ≥100 DILI patients in both of the two databases were regarded as suspected drugs for DILI. We used multivariate logistic regression to evaluate the association between the suspected drugs and increased risk of DILI. Among the suspected drugs, broad-spectrum antibiotics such as meropenem, tazobactam/piperacillin and ceftriaxone were significantly associated with an increased risk of DILI, and meropenem had a greater risk of DILI in both of the two databases. Additionally, there were significant associations of mosapride and L-carbocisteine with increased risk of DILI. In addition to well-known associations between antibiotic drugs and DILI, mosapride and L-carbocisteine were found to be new potential signals of drugs causing hepatotoxicity. This study indicates potential hepatotoxic drugs that require further causality assessment.

The coronavirus disease 2019 (COVID-19) pandemic has exerted a considerable impact in our region; thus, we have been performing only emergency transplants in March 2020. At present, all inpatients and surgical patients are being tested and screened for COVID-19. If they are found to be positive, they are transferred to the COVID-19 ward, where a specialized team manages them. Team-based care allows the hematology/oncology teams to perform their regular duties. In particular, for post-transplant patients, treatment decisions are made through discussion with infectious disease specialists, and in principle, the patients are treated using the same protocol as that used for the general COVID-19 infected patients. Currently, vaccination is being promoted at a rapid pace based on the Centers for Disease Control and Prevention Guidelines (CDC) guidelines. At our institution, when a situation of suspected nosocomial COVID-19 infection occurred, all healthcare workers were tested. Thereafter, all hospitalized patients were tested every week for COVID-19, and we were able to overcome the situation. Although definitive measures for COVID-19 are yet to be established, signs of an end to the infection are beginning to appear with a wider availability of vaccines.

We have synthesized a series of quaternized imidazo[1,2-a]pyridines in three steps from commercially available reagents. These compounds exhibit blue fluorescence emission at around 425 nm with good quantum yields. In addition, one specific compound was found to work as not only a two- and three-photon excitable mitochondria imaging agent, but also a therapeutic agent upon continuous irradiation conditions.

A novel lipopeptide antibiotic, stalobacin I ( 1 ), was discovered from a culture broth of an unidentified Gram-negative bacterium. Stalobacin I ( 1 ) had a unique chemical architecture composed of an upper and a lower half peptide sequence, which were linked via a hemiaminal methylene moiety. The sequence of 1 contained an unusual amino acid, carnosadine, 3,4-dihydroxyariginine, 3-hydroxyisoleucine, and 3-hydroxyaspartic acid, and a novel cyclopropyl fatty acid. The antibacterial activity of 1 against a broad range of drug-resistant Gram-positive bacteria was much stronger than those of "last resort" antibiotics such as vancomycin, linezolid, and telavancin (MIC 0.004-0.016 μg/mL). Furthermore, compound 1 induced a characteristic morphological change in Gram-positive and Gram-negative strains by inflating the bacterial cell body. The absolute configuration of a cyclopropyl amino acid, carnosadine, was determined by the synthetic study of its stereoisomers, which was an essential component for the strong activity of 1 .

We present that thioacetalization of aldehydes can be induced by blue light irradiation in the presence of a catalytic amount of riboflavin tetraacetate (RFTA) under aerobic conditions. Several control experiments have suggested that the reaction is more likely to be catalyzed by acidic species generated in situ upon light irradiation. We have proposed that single electron transfer from a thiol (RSH) to the excited state of RFTA can take place to give a one-electron oxidized thiol (RSH+˙) and the one-electron reduced RFTA (RFTA-˙), which can be trapped by molecular oxygen to be stabilized as Brønsted acids including the protonated RFTA-˙ (RFTAH˙). Finally, we have demonstrated that such acidic species can be prepared in advance as a solution and used as Brønsted acid catalysts for not only thioacetalization but also Mannich-type reactions.

Both inhalational and intravenous anesthetics affect myocardial remodeling, but the precise effect of each anesthetic on molecular signaling in myocardial remodeling is unknown. Here, we performed in silico analysis to investigate signaling alterations in cardiomyocytes induced by inhalational [sevoflurane (Sevo)] and intravenous [propofol (Prop)] anesthetics. Bioinformatics analysis revealed that nuclear factor-kappa B (NF-kB) signaling was inhibited by Sevo and promoted by Prop. Moreover, nuclear accumulation of p65 and transcription of NF-kB-regulated genes were suppressed in Sevo-administered mice, suggesting that Sevo inhibits the NF-kB signaling pathway. Our data demonstrate that NF-kB signaling is inhibited by Sevo and promoted by Prop. As NF-kB signaling plays an important role in myocardial remodeling, our results suggest that anesthetics may affect myocardial remodeling through NF-kB., (© 2020 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)

Neurolathyrism is a motor neuron disease that is caused by the overconsumption of grass peas (Lathyrus sativus L.) under stressful conditions. The neuro-excitatory β-N-oxalyl-L-α,β-diaminopropionic acid present in grass peas was proposed the causative agent of spastic paraparesis of the legs. Historical reports of neurolathyrism epidemics, studies of neurolathyrism animal models, and in vitro studies on the mechanism of β-N-oxalyl-L-α,β-diaminopropionic acid toxicity support the hypothesis that stress increases susceptibility to neurolathyrism. To elucidate the role of stress in neurolathyrism-induced motor dysfunction, we focused on the hypothalamic-pituitary-adrenal axis in a rodent model of neurolathyrism. Our results implicated increased glucocorticoid and neuroinflammation in the motor dysfunction (paraparesis) exhibited by the stress loaded rat models of neurolathyrism., (Copyright © 2019 Elsevier B.V. All rights reserved.)

An isoalloxazine (flavin) ring system and a secondary amine have been integrated through a short peptide linker with the aim of using photons as efficiently as possible in photoredox/enamine dual catalysis. We herein report a peptide-bridged flavin-amine hybrid that can catalyze α-oxyamination of aldehydes with TEMPO under weak blue light irradiation to achieve an extremely high quantum yield of reaction (Φ = 0.80).

Background: People with chronic kidney disease (CKD) may have an increased risk of periodontal disease, but longitudinal evidence is sparse., Methods: This 4-year cohort study assessed the association between CKD and changes in periodontal health status, defined by attachment loss (AL) progression, among older adults. Participants were 388 community-dwelling Japanese adults who were 70 years old at baseline with 7053 teeth. Estimated glomerular filtration rate (eGFR) was calculated by using baseline serum creatinine concentration. AL at six sites for every tooth was recorded at baseline and follow-up examinations. Multilevel logistic regression models estimated the tooth-specific risk of AL progression (≥1 site exhibiting a ≥3 mm increase in AL) with baseline CKD (eGFR < 60 mL/min/1.73 m 2 ) as the principal exposure., Results: At baseline, 27.8% of the study population (108/388 participants) had CKD. After 4 years, 21.8% of the studied teeth (1537/7053 teeth) exhibited AL progression. After applying inverse probability weighting and adjusting for potential confounders, including sex, use of devices for interdental cleaning, smoking, diabetes, tooth location, abutment for a removable denture, and highest AL, CKD was associated with significantly higher odds of AL progression (adjusted odds ratio: 1.73; 95% confidence interval: 1.15-2.60)., Conclusions: The results suggest that CKD increases the risk of periodontal disease progression in older community-dwelling Japanese adults. Additional studies with more complete information, as well as in other geographic areas and age groups, are necessary to further generalize the findings., (© 2019 American Academy of Periodontology.)

Myelofibrosis in myeloproliferative neoplasms (MPNs) with mutations such as JAK2V617F is an unfavorable sign for uncontrollable disease progression in the clinic and is complicated with osteosclerosis whose pathogenesis is largely unknown. Because several studies have revealed that macrophages are an indispensable supporter for bone-forming osteoblasts, we speculated that macrophages might play a significant role in the proliferation of collagen-producing myofibroblasts in marrow fibrotic tissues. Here, we show that myelofibrosis critically depends on macrophages whose differentiation is skewed by vitamin D receptor (VDR) signaling. In our novel myelofibrosis model established by transplantation of VDR +/+ hematopoietic stem/progenitor cells into VDR -/- mice, donor-derived F4/80 + macrophages proliferated together with recipient-derived α-smooth muscle actin-positive myofibroblasts, both of which comprised fibrotic tissues with an indistinguishable spindle-shaped morphology. Interfering VDR signals, such as low vitamin D diet and VDR deficiency in donor cells as well as macrophage depletion prevented myelofibrosis in this model. These interventions also ameliorated myelofibrosis in JAK2V617F-driven murine MPNs likely in a transforming growth factor-β1- or megakaryocyte-independent manner. These results suggest that VDR and macrophages may be novel therapeutic targets for MPNs with myelofibrosis., (© 2019 by The American Society of Hematology.)