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Background: We examined whether denosumab-induced hypocalcaemia is evident in osteoporosis when given loop diuretics that promote urinary calcium excretion., Methods: Japanese Spontaneous Adverse Drug Event Reports was analyzed to examine signals for denosumab-induced hypocalcaemia co-administered loop diuretics. We retrospectively included osteoporotic patients to detect predictors for denosumab-induced hypocalcaemia (corrected calcium level < 8.5 mg/dL) using multivariate logistic regression analysis. We compared differences in corrected calcium levels (ΔCa = nadir-baseline)., Results: A significant signal for hypocalcaemia was detected (Reporting odds ratio = 865.8, 95% confidence interval [95% CI]: 596.8 to 1255.9, p < 0.0001). Among 164 patients (hypocalcaemia, 12%), loop diuretics have a significant association with hypocalcaemia (odds ratio [OR] = 6.410, 95% CI: 1.005 to 40.90, p = 0.0494). However, hypocalcaemia was found to be lower in high corrected calcium levels at baseline (OR = 0.032, 95% CI: 0.005 to 0.209, p < 0.0001) and calcium and vitamin D supplementation (OR = 0.285, 95% CI: 0.094 to 0.868, p = 0.0270). In the non-hypocalcaemia, ΔCa decreased significantly in the denosumab plus loop diuretics than in the denosumab alone (-0.9 [-1.3 to -0.7] mg/dL vs. -0.5 [-0.8 to -0.3] mg/dL, p = 0.0156). However, ΔCa remained comparable in the hypocalcaemia despite loop diuretics co-administration (-1.0 [-1.2 to -0.8] mg/dL vs. -0.8 [-1.5 to -0.7] mg/dL, p = 0.7904)., Conclusions: Loop diuretics may predispose to developing denosumab-induced hypocalcaemia., (© 2024. The Author(s).)

Background: We examined whether the pharmacodynamic drug-drug interaction between esaxerenone and trimethoprim enhances the hyperkalemic effect., Methods: A retrospective observational study was conducted to identify patients >18 years undertaking esaxerenone alone or esaxerenone plus trimethoprim at Mie University Hospital from May 2019 to December 2022. We performed propensity score-matching (1:1) to compare between-group differences in the maximum change in serum potassium levels (ΔK) using the Mann-Whitney U test. For esaxerenone plus trimethoprim, Spearman's correlation coefficients were used to examine correlations between ΔK and variables, including changes in blood urea nitrogen (ΔBUN), serum creatinine levels (ΔCr), and weekly trimethoprim cumulative dose., Results: Out of propensity score-matched groups (n=8 each), serum potassium levels significantly increased after administration of esaxerenone alone (4.4 [4.2 to 4.7] meq/L to 5.2 [4.7 to 5.4] meq/L, p=0.008) and esaxerenone plus trimethoprim (4.2 [4.0 to 5.1] meq/L to 5.4 [4.7 to 5.5] meq/L, p=0.023). ΔK did not significantly differ between the groups (esaxerenone alone; 0.6 [0.3 to 0.9] meq/L vs. esaxerenone plus trimethoprim; 1.0 [0.4 to 1.3] meq/L, p=0.342). ΔK positively correlated with ΔBUN (r=0.988, p<0.001) or ΔCr (r=0.800, p=0.017). There was a trend of correlation of ΔK with a weekly cumulative trimethoprim dose (r=0.607, p=0.110)., Conclusions: The hyperkalemic effect of the drug-drug interaction between esaxerenone and trimethoprim is not notable and related to renal function and trimethoprim dosage., (© 2024. The Author(s).)

Background: The estimation of creatinine clearance (CCr) in older adult patients with diabetes is subject to deviations from the results of actual measurements because of changes in body composition. In the present study, we aimed to create a correction for the equation used for the estimation of CCr in older adult Asian patients with diabetes using body composition parameters., Methods: We enrolled 50 older Japanese patients with diabetes in whom the measured values of CCr were compared with values estimated using the Cockcroft-Gault equation. The relationships between the error in the estimated CCr and body composition parameters were investigated, and the Cockcroft-Gault equation was corrected using the appropriate parameters. To evaluate the generalizability of the corrected equation, the utility of the Cockcroft-Gault equation, which was corrected on the basis of body composition measured using a household body composition meter, was also investigated., Results: Body fat mass (BFM) was closely correlated with the error in the estimated CCr. The BFM-corrected Cockcroft-Gault equation was more accurate than the original equation. Similarly, the error became smaller using BFM measured with a household body composition meter., Conclusion: The BFM-corrected Cockcroft-Gault equation may provide an accurate method of estimating CCr that can be used in general practice., Competing Interests: SH is employed by I & H Co., Ltd. The remaining 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 © 2024 Utsumi, Kondo, Harada, Yoshida, Nishimura, Narita, Irie, Jinnouchi, Ishitsuka and Hirata.)

Pharmacists are expected to demonstrate their expertise in clinical practice and conduct research activities to generate new evidence. However, the factors promoting research activities among pharmacists remain unclear. Therefore, we investigated the research activities of Japanese pharmacists through a questionnaire survey and examined the factors contributing to the promotion of research activities. A web-based questionnaire using Google Forms was disseminated across pharmacists working in community pharmacies, drugstores, hospitals, and clinics. The questionnaire included respondents' backgrounds, research activities, and research environments. Logistic regression analysis was used to examine the factors promoting pharmacists' research activities, with experience in research paper acceptance as the objective variable. In total, 401 responses were included in the analysis. Of the respondents, 54.1% were hospital pharmacists, and 77.1% were pharmacists with > 5 years of pharmacist experience. Furthermore, 50.4% of the pharmacists had presented at conferences, and 22.2% had experience in research paper acceptance. The influential factors were "master's degree or higher," "number of affiliated academic societies," "acquisition of specialists/certified pharmacists," and "daily availability of a consultant for writing research papers." This study revealed the factors contributing to the promotion of research activities among pharmacists. We believe that our findings will help promote research among pharmacists., (© 2024. The Author(s).)

Teicoplanin can cause acute kidney injury, but little is known about the risk of acute kidney injury when teicoplanin is co-administered with loop diuretics (a powerful diuresis), which can alter renal hemodynamics and glomerular filtration rate. We performed a signal detection analysis using a Japanese adverse event database to determine the additive impact of loop diuretics on acute kidney injury associated with teicoplanin. The dataset originated between April 2004 and August 2022. Disproportionality analysis was performed to detect the signals for acute kidney injury (the Standardized MedDRA Query) when co-administered teicoplanin or vancomycin (a positive control) with individual diuretics, including loop diuretics. Multivariate logistic regression analysis was tested to estimate the adjusted reporting odds ratio (aROR) and 95% confidence interval (95% CI). There were 147 and 515 events of acute kidney injury associated with teicoplanin and vancomycin, respectively. A significant positive signal for acute kidney injury when teicoplanin was co-administered with loop diuretics was present (aROR 4.83, 95% CI 3.52-6.61, p < 0.0001). Contrastingly, no significant signals were observed when vancomycin was co-administered with any diuretics. These findings suggest that co-administered loop diuretics may have an unfavorable effect on acute kidney injury while undertaking teicoplanin but not vancomycin., (© 2023. Springer Nature Limited.)

Background: Niemann-Pick disease type C (NPC) is a fatal neurodegenerative disorder caused by abnormal intracellular cholesterol trafficking. Cyclodextrins (CDs), the most promising therapeutic candidates for NPC, but with concerns about ototoxicity, are cyclic oligosaccharides with dual functions of unesterified cholesterol (UC) shuttle and sink that catalytically enhance the bidirectional flux and net efflux of UC, respectively, between the cell membrane and the extracellular acceptors. However, the properties of CDs that regulate these functions and how they could be used to improve treatments for NPC are unclear., Methods: We estimated CD-UC complexation for nine CD derivatives derived from native α-, β-, and γ-CD with different cavity sizes, using solubility and molecular docking analyses. The stoichiometry and complexation ability of the resulting complexes were investigated in relation to the therapeutic effectiveness and toxicity of each CD derivative in NPC experimental models., Findings: We found that shuttle and sink activities of CDs are dependent on cavity size-dependent stoichiometry and substituent-associated stability of CD-UC complexation. The ability of CD derivatives to form 1:1 and 2:1 complexes with UC were correlated with their ability to normalize intracellular cholesterol trafficking serving as shuttle and with their cytotoxicity associated with cellular UC efflux acting as sink, respectively, in NPC model cells. Notably, the ability of CD derivatives to form an inclusion complex with UC was responsible for not only efficacy but ototoxicity, while a representative derivative without this ability negligibly affected auditory function, underscoring its preventability., Conclusions: Our findings highlight the importance of strategies for optimizing the molecular structure of CDs to overcome this functional dilemma in the treatment of NPC., (© 2023 The Authors. Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.)

Mitochondria, a major source of reactive oxygen species (ROS), are intimately involved in the response to oxidative stress in the body. The production of excessive ROS affects the balance between oxidative responses and antioxidant defense mechanisms thus perturbing mitochondrial function eventually leading to tissue injury. Therefore, antioxidant therapies that target mitochondria can be used to treat such diseases and improve general health. This study reports on an attempt to establish a system for delivering an antioxidant molecule coenzyme Q 10 (CoQ 10 ) to mitochondria and the validation of its therapeutic efficacy in a model of acetaminophen (APAP) liver injury caused by oxidative stress in mitochondria. A CoQ 10 -MITO-Porter, a mitochondrial targeting lipid nanoparticle (LNP) containing encapsulated CoQ 10 , was prepared using a microfluidic device. It was essential to include polyethylene glycol (PEG) in the lipid composition of this LNP to ensure stability of the CoQ 10 , since it is relatively insoluble in water. Based on transmission electron microscope (TEM) observations and small angle X-ray scattering (SAXS) measurements, the CoQ 10 -MITO-Porter was estimated to be a 50 nm spherical particle without a regular layer structure. The use of the CoQ 10 -MITO-Porter improved liver function and reduced tissue injury, suggesting that it exerted a therapeutic effect on APAP liver injury., (© 2023. The Author(s).)

Melanogenesis is a major part of the environmental responses and tissue development of the integumentary system. The balance between reduction and oxidation (redox) governs pigmentary responses, for which coordination among epidermal resident cells is indispensable. Here, we review the current understanding of melanocyte biology with a particular focus on the "master regulator" of oxidative stress responses (i.e., the Kelch-like erythroid cell-derived protein with cap'n'collar homology-associated protein 1-nuclear factor erythroid-2-related factor 2 system) and the autoimmune pigment disorder vitiligo. Our investigation revealed that the former is essential in pigmentogenesis, whereas the latter results from unbalanced redox homeostasis and/or defective intercellular communication in the interfollicular epidermis (IFE). Finally, we propose a model in which keratinocytes provide a "niche" for differentiated melanocytes and may "imprint" IFE pigmentation., Competing Interests: The authors declare no conflict of interest.

Niemann-Pick disease type C (NPC) is a fatal disorder with abnormal intracellular cholesterol trafficking resulting in neurodegeneration and hepatosplenomegaly. A cyclic heptasaccharide with different degrees of substitution of 2-hydroxypropyl groups, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), acts as a strong cholesterol solubilizer and is under investigation for treating this disease in clinical trials, but its physicochemical properties and ototoxicity remain a concern. Here, we evaluated the potential of mono-6-O-α-maltosyl-γ-CD (G2-γ-CD), a single-maltose-branched cyclic octasaccharide with a larger cavity than HP-β-CD, for treating NPC. We identified that G2-γ-CD ameliorated NPC manifestations in model mice and showed lower ototoxicity in mice than HP-β-CD. To investigate the molecular mechanisms of action behind the differential ototoxicity of these CDs, we performed cholesterol solubility analysis, proton nuclear magnetic resonance spectroscopy, and molecular modeling, and estimated that the cholesterol inclusion mode of G2-γ-CD maintained solely the 1:1 inclusion complex, whereas that of HP-β-CD shifted to the highly-soluble 2:1 complex at higher concentrations. We predicted the associations of these differential complexations of CDs with cholesterol with the profile of disease attenuation and of the auditory cell toxicity using specific cell models. We proposed that G2-γ-CD can serve as a fine-tuned cholesterol solubilizer for treating NPC, being highly biocompatible and physicochemically suitable for clinical application., Competing Interests: Conflict of Interest Statement 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 © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The Kelch-like erythroid cell-derived protein with cap'n'collar homology-associated protein 1 (KEAP1)-nuclear factor erythroid-2-related factor 2 (NRF2) system, a thiol-based sensor-effector apparatus, exerts antioxidative and anti-inflammatory effects and maintains skin homeostasis. Thus, NRF2 activation appears to be a promising treatment option for various skin diseases. However, NRF2-mediated defense responses may deteriorate skin inflammation in a context-dependent manner. Atopic dermatitis (AD) and psoriasis are two common chronic inflammatory skin diseases caused by a defective skin barrier, dysregulated immune responses, genetic predispositions, and environmental factors. This review focuses on the role of the KEAP1-NRF2 system in the pathophysiology of AD and psoriasis and the therapeutic approaches that utilize this system.

Background: Clinical decision support systems (CDSS) are reported to be useful in preventing dosage errors in renally excreted drugs by alerting hospital pharmacists to inadequate dosages for hospitalized patients with decreased GFR. However, it is unclear whether CDSS can reduce dosage errors in renally excreted drugs in hospitalized patients. To prevent dosage errors in renally excreted drugs, we introduced a prescription checking system (PCS) for in-hospital prescriptions. This retrospective study aimed to evaluate whether a prescription audit by hospital pharmacists using the PCS reduced the rate of dosage errors in renally excreted drugs., Methods: The target drugs were allopurinol, cibenzoline, famotidine, and pilsicainide. Interrupted time series analysis was used to evaluate trends in the 4-weekly dosage error rates over 52 weeks before PCS implementation and 52 weeks after PCS implementation., Results: Before and after PCS implementation, 474 and 331 prescriptions containing one of the targeted drugs, respectively, were generated. The estimated baseline level of the 4-weekly dosage error rates was 34%. The trend before the PCS implementation was stable with no observable trend. The estimated level change from the last point in the pre-PCS implementation to the first point in the PCS implementation was -20% ( P <0.001). There was no change in the trend after PCS implementation., Conclusions: We demonstrated that a prescription audit by hospital pharmacists using the PCS reduced the rate of dosage errors in the target renally excreted drugs in hospitalized patients. Although further studies are needed to confirm whether our results can be generalized to other health facilities, our findings highlight the need for a PCS to prevent the overdose of renally excreted drugs., Competing Interests: T. Irie reports having patents or royalties with the Safety Medical System Laboratory Corporation. Y. Ishitsuka reports having patents or royalties with the Safety Medical System Laboratory Corporation. Y. Kondo reports receiving research funding from AYUMI Pharmaceutical Corporation and Safety Medical System Laboratory Corporation; having patents or royalties with the Safety Medical System Laboratory Corporation; and serving in an advisory or leadership role for Safety Medical System Laboratory Corporation (unpaid). All remaining authors have nothing to disclose., (Copyright © 2022 by the American Society of Nephrology.)

Cornification is a specialized mode of the cell-death program exclusively allowed for terrestrial amniotes. Recent investigations suggest that loricrin (LOR) is an important cornification effector. As the connotation of its name ("lorica" meaning an armor in Latin) suggests, the keratin-associated protein LOR promotes the maturation of the epidermal structure through organizing covalent cross-linkages, endowing the epidermis with the protection against oxidative injuries. By reviewing cornification mechanisms, we seek to classify ichthyosiform dermatoses based on their function, rather than clinical manifestations. We also reviewed recent mechanistic insights into the Kelch-like erythroid cell-derived protein with the cap "n" collar homology-associated protein 1/nuclear factor erythroid 2-related factor 2 (NRF2) signaling pathway in skin health and diseases, as LOR and NRF2 coordinate the epidermis-intrinsic xenobiotic metabolism. Finally, we refine the theoretical framework of cross-talking between keratinocytes and epidermal resident leukocytes, dissecting an LOR immunomodulatory function.

PD-1 is an immunoregulatory receptor that can bind PD-L1 or PD-L2 expressed on stimulated antigen-presenting cells. In this study, isolated antigen-presenting cells (macrophages and dendritic cells) were cultured with IFN-γ, IL-4, or IL-17A, and the expression of PD-L1 and PD-L2 was compared by flow cytometry. Strong upregulation of PD-L1 expression was observed on IFN-γ stimulation of both antigen-presenting cells as well as in response to IL-17A stimulation of macrophages compared with the expression in unstimulated controls. In contrast, only stimulation with IL-4 could upregulate PD-L2 expression on both antigen-presenting cells. Therefore, experiments were performed in murine models, including DNFB-induced contact hypersensitivity, calcipotriol-induced atopic dermatitis-like skin inflammation, and imiquimod-induced psoriasis-like dermatitis models, to trigger IFN-γ‒mediated T helper type (Th)1-, IL-4‒mediated Th2-, and IL-17A‒mediated Th17-type responses, respectively. In both Th1- and Th17-type immunity models, changes in ear thickness were more severe in Pd-l1‒deficient mice than in wild-type or Pd-l2‒deficient mice. In the Th2-type immunity model, changes in thickness in Pd-l2‒deficient mice were more severe than that in wild-type or Pd-l1‒deficient mice. Collectively, PD-L1 has predominant roles in Th1 and Th17 type immunity, whereas PD-L2 is involved in Th2-type immunity., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

A functional epithelial barrier necessitates protection against dehydration, and ichthyoses are caused by defects in maintaining the permeability barrier in the stratum corneum (SC), the uppermost protective layer composed of dead cells and secretory materials from the living layer stratum granulosum (SG). We have found that loricrin (LOR) is an essential effector of cornification that occurs in the uppermost layer of SG (SG1). LOR promotes the maturation of corneocytes and extracellular adhesion structure through organizing disulfide cross-linkages, albeit being dispensable for the SC permeability barrier. This review takes psoriasis and AD as the prototype of impaired cornification. Despite exhibiting immunological traits that oppose each other, both conditions share the epidermal differentiation complex as a susceptible locus. We also review recent mechanistic insights on skin diseases, focusing on the Kelch-like erythroid cell-derived protein with the cap "n" collar homology-associated protein 1/NFE2-related factor 2 signaling pathway, as they coordinate the epidermis-intrinsic xenobiotic metabolism. Finally, we refine the theoretical framework of thiol-mediated crosstalk between keratinocytes and leukocytes in the epidermis that was put forward earlier.

Arctic rivers drain ~15% of the global land surface and significantly influence local communities and economies, freshwater and marine ecosystems, and global climate. However, trusted and public knowledge of pan-Arctic rivers is inadequate, especially for small rivers and across Eurasia, inhibiting understanding of the Arctic response to climate change. Here, we calculate daily streamflow in 486,493 pan-Arctic river reaches from 1984-2018 by assimilating 9.18 million river discharge estimates made from 155,710 satellite images into hydrologic model simulations. We reveal larger and more heterogenous total water export (3-17% greater) and water export acceleration (factor of 1.2-3.3 larger) than previously reported, with substantial differences across basins, ecoregions, stream orders, human regulation, and permafrost regimes. We also find significant changes in the spring freshet and summer stream intermittency. Ultimately, our results represent an updated, publicly available, and more accurate daily understanding of Arctic rivers uniquely enabled by recent advances in hydrologic modeling and remote sensing., (© 2021. The Author(s).)

Cornification involves cytoskeletal cross-linkages in corneocytes (the brick) and the secretion of lipids/adhesion structures to the interstitial space (the mortar). Because the assembly of lipid envelopes precedes corneocyte maturation, loricrin is supposed to be dispensable for the protection against desiccation. Although the phenotypes of Lor knockout (LKO) mice are obscure, the antioxidative response on the KEAP1/NRF2 signaling pathway compensates for the structural defect in utero. In this study, we asked how the compensatory response is evoked after the defects are repaired. To this end, the postnatal phenotypes of LKO mice were analyzed with particular attention to the permeability barrier function primarily maintained by the mortar. Ultrastructural analysis revealed substantially thinner cornified cell envelopes and increased numbers of lamellar granules in LKO mice. Superficial epidermal damages triggered the adaptive repairing responses that evoke the NRF2-dependent upregulation of genes associated with lamellar granule secretion in LKO mice. We also found that corneodesmosomes are less degraded in LKO mice. The observation suggests that loricrin and NRF2 are important effectors of cornification, in which proteins need to be secreted, cross-linked, and degraded in a coordinated manner., (© 2021 The Authors.)

Competing Interests: There are no financial or other issues that might lead to conflict of interest.

The exact mechanisms of the imiquimod (IMQ)-induced antitumor effect have not been fully understood. Although both topical IMQ treatment and anti-PD-1 antibody may be used for primary skin lesions or skin metastases of various cancers, the efficacy of each monotherapy for these lesions is insufficient. Using a murine tumor model and human samples, we aimed to elucidate the detailed mechanisms of the IMQ-induced antitumor effect and analyzed the antitumor effect of combination therapy of topical IMQ plus anti-PD-1 antibody. Topical IMQ significantly suppressed the tumor growth of MC38 in wildtype mice. IMQ upregulated interferon γ (IFN-γ) expression in CD8 + T cells in both the lymph nodes and the tumor, and the antitumor effect was abolished in both Rag1-deficient mice and IFN-γ-deficient mice, indicating that IFN-γ produced by CD8 + T cells play a crucial role in the IMQ-induced antitumor effect. IMQ also upregulated PD-1 expression in T cells as well as PD-L1/PD-L2 expression in myeloid cells, suggesting that IMQ induces not only T-cell activation but also T-cell exhaustion by enhanced PD-1 inhibitory signaling. Combination therapy of topical IMQ plus anti-PD-1 antibody exerted a significantly potent antitumor effect when compared with each single therapy, indicating that the combination therapy is a promising therapy for the skin lesions of various cancers.

Background and Purpose: Niemann-Pick disease type C (NPC) is a lysosomal storage disorder with disrupted intracellular cholesterol trafficking. A cyclic heptasaccharide, 2-hydroxypropyl-β-cyclodextrin (HP-β-CD), is a cholesterol solubilizer that is being developed to treat NPC, but its ototoxicity and pulmonary toxicity remain important issues. We have characterized 2-hydroxypropyl-γ-cyclodextrin (HP-γ-CD), a cyclic octasaccharide with a larger cavity than HP-β-CD, as a candidate drug to treat NPC. However, the molecular target of HP-γ-CD with respect to NPC and its potential for clinical application are still unclear., Experimental Approach: We investigated the mode of interaction between HP-γ-CD and cholesterol by phase-solubility analysis, proton NMR spectroscopy and molecular dynamics simulations. We then evaluated the therapeutic effects of HP-γ-CD compared with HP-β-CD using cellular and murine NPC models. Mouse auditory and pulmonary function tests were also conducted., Key Results: HP-γ-CD solely formed a 1:1 inclusion complex with cholesterol with an affinity similar to that of HP-β-CD. In vitro, HP-γ-CD and HP-β-CD amelioration of NPC-related manifestations was almost equivalent at lower concentrations. However, at higher concentrations, the cholesterol inclusion mode of HP-β-CD shifted to the highly soluble 2:1 complex whereas that of HP-γ-CD maintained solely the 1:1 complex. The constant lower cholesterol solubilizing ability of HP-γ-CD conferred it with significantly reduced toxicity compared with HP-β-CD, but equal efficacy in treating a mouse model of NPC., Conclusions and Implications: HP-γ-CD can serve as a fine-tuned cholesterol solubilizer for the treatment of NPC with a wider safety margin than HP-β-CD in terms of ototoxicity and pulmonary toxicity., (© 2021 The British Pharmacological Society.)

Patients with graft-versus-host disease (GVHD) develop characteristic mucocutaneous phenomena consisting of erosive erythema with histopathological findings including interface dermatitis and keratinocyte (KC) death, resulting in widespread sclerodermatous changes. We found that KCs exhibit marked production of TGFβ1 in skin lesions of chronic GVHD but not in those of acute GVHD. To further investigate the roles of KCs, the main targets of donor T cells, in sclerodermatous changes followed by interface dermatitis, we established a murine model of chronic GVHD-like sclerodermatous changes followed by acute GVHD-like mucocutaneous injury in genetically modified mice transferred with KC-specific CD8 T cells. Although transfer of granzyme B-deficient CD8 T cells did not result in either mucocutaneous injury or sclerodermatous changes in recipients, IFN-γ-deficient CD8 T-cell recipients developed severe acute mucocutaneous injury but milder sclerodermatous changes than wild-type CD8 T-cell recipients. Moreover, IFN-γ-deficient CD8 T-cell recipients had a lower expression of TGFβ1 in the epidermis than the control. Murine primary KCs undergoing FasL-induced apoptosis and incubated with IFN-γ produced TGFβ1, the production of which was inhibited by a pan-caspase inhibitor. Our results indicate that IFN-γ promotes TGFβ1 production by apoptotic KCs, which mediates the development of widespread sclerodermatous changes in KC-targeting GVHD., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Floods can be devastating in densely populated regions along rivers, so attaining a longer forecast lead time with high accuracy is essential for protecting people and property. Although many techniques are used to forecast floods, sufficient validation of the use of a forecast system for operational alert purposes is lacking. In this study, we validated the flooding locations and times of dike breaking that had occurred during Typhoon Hagibis, which caused severe flooding in Japan in 2019. To achieve the goal of the study, we combined a hydrodynamic model with statistical analysis under forcing by a 39-h prediction of the Japan Meteorological Agency's Meso-scale model Grid Point Value (MSM-GPV) and obtained dike-break times for all flooded locations for validation. The results showed that this method was accurate in predicting floods at 130 locations, approximately 91.6% of the total of 142 flooded locations, with a lead time of approximately 32.75 h. In terms of precision, these successfully predicted locations accounted for 24.0% of the total of 542 locations under a flood warning, and on average, the predicted flood time was approximately 8.53 h earlier than a given dike-break time. More warnings were issued for major rivers with severe flooding, indicating that the system is sensitive to extreme flood events and can issue warnings for rivers subject to high risk of flooding.

Acute graft-versus-host disease (aGVHD) induced by allogenic hematopoietic stem cell transplantation is an immunological disorder in which donor lymphocytes attack recipient organs. It has been proven that recipient nonhematopoietic tissue cells, such as keratinocytes, are sufficient as immunological targets for allogenic donor T cells, whereas Langerhans cells (LCs) are potent professional hematopoietic antigen-presenting cells existing in the target epidermis and eliminated during the early phase of mucocutaneous aGVHD. Moreover, LCs have been reported to negatively regulate various types of immune responses. Here, we present data showing that initial depletion of recipient LCs exacerbates mucocutaneous lesions in a murine model of allogenic bone marrow transplantation-induced aGVHD. Furthermore, another murine model of mucocutaneous aGVHD induced in mice with keratinocytes genetically expressing chicken ovalbumin by transfer of ovalbumin-specific CD8 + OT-I cells also showed that LC-depleted recipient mice develop aggravated mucocutaneous disease owing to decreased apoptosis of skin-infiltrating OT-I cells. Moreover, coexisting LCs directly induce apoptosis and inhibit the proliferation of OT-I cells in vitro partially via B7 family proteins. Collectively, our results indicate that LCs negatively regulate mucocutaneous aGVHD-like lesions in situ by inhibiting the number of infiltrating CD8 + T cells., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Cutaneous squamous cell carcinoma (cSCC) is the second most prevalent skin cancer globally. Because most cSCC cases are manageable by local excision/radiotherapy and hardly become life-threatening, they are often excluded from cancer registries in most countries. Compared with cutaneous melanoma that originates from the melanin-producing, neural crest-derived epidermal resident, keratinocyte (KC)-derived cancers are influenced by the immune system with regards to their pathogenetic behaviour. Congenital or acquired immunosurveillance impairments compromise tumoricidal activity and raises cSCC incidence rates. Intriguingly, expanded applications of programmed death-1 (PD-1) blockade therapies have revealed cSCC to be one of the most amenable targets, particularly when compared with the mucosal counterparts arisen in the esophagus or the cervix. The clinical observation reminds us that cutaneous tissue has a peculiarly high immunogenicity that can evoke tumoricidal recall responses topically. Here we attempt to redefine cSCC biology and review current knowledge about cSCC from multiple viewpoints that involve epidemiology, clinicopathology, molecular genetics, molecular immunology, and developmental biology. This synthesis not only underscores the primal importance of the immune system, rather than just a mere accumulation of ultraviolet-induced mutations but also reinforces the following hypothesis: PD-1 blockade effectively restores the immunity specially allowed to exist within the fully cornified squamous epithelium, that is, the epidermis.

Competing Interests: There are no conflicts of interest.