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Abstract.: Circulating bone marrow-derived vascular progenitor cells contribute to angiogenesis, atherosclerosis, and the response to vascular injury. These vascular progenitor cells consist of two cell groups, endothelial progenitor cells (EPCs) and smooth muscle progenitor cells (SMPCs). Although HMG-CoA reductase inhibitors (statins) have been reported to inhibit atherosclerosis partially by increased EPCs, the effects of statins on SMPCs are unclear. Therefore, we investigated the relationship between EPCs and SMPCs and whether pravastatin has atheroprotective effects on SMPCs. Peripheral mononuclear cells (MNCs) were isolated and cultured on fibronectin-coated dishes in SMPC medium. MNCs were stained with acetylated low density lipoprotein and lectin, or α-smooth muscle actin, and cell numbers were counted. mRNA expression and vascular endothelial growth factor (VEGF) protein synthesis of MNCs were evaluated. Pravastatin significantly increased the number of EPC and decreased the number of SMPC. mRNA expression of VEGF, endothelial nitric oxide synthase, VEGF receptor-2 (KDR), and Akt were up-regulated, and VEGF secretion was increased by pravastatin. The present study demonstrated that pravastatin has promotive effects on the differentiation from MNCs to EPC cells, while inhibitory effects to SMPC cells. Our findings suggest a previously unreported mechanism of the effect of statin therapy on vascular progenitor cells. Keywords:: endothelial progenitor cell, smooth muscle progenitor cell, statin, atherosclerosis

Objectives: Hypertensive disorders of pregnancy (HDP) are a significant cause of morbidity and mortality. This study aimed to investigate whether preconception dietary fiber intake is associated with new-onset HDP., Study Design: We identified 84,873 (primipara, 33,712; multipara, 51,161) normotensive participants from the Japan Environmental Children's Study database who delivered between 2011 and 2014. The participants were subsequently categorized into five groups based on their preconception dietary fiber intake quintiles (Q1-Q5)., Main Outcome Measures: The main obstetric outcome was HDP, and the secondary obstetric outcomes included early-onset (Eo, <34 weeks)-HDP, late-onset (Lo, ≥34 weeks)-HDP, small for gestational age (SGA) births, and HDP with/without SGA., Results: Multiple logistic regression analysis showed that in primiparas, the risks of HDP, Lo-HDP, and HDP without SGA were lower in the Q5 group compared with the Q3 group (HDP: adjusted odds ratio [aOR] = 0.73, 95 % confidence intervals [95 % CI] = 0.58-0.93; Lo-HDP: aOR = 0.72, 95 % CI = 0.55-0.94; and HDP without SGA: aOR = 0.68, 95 % CI = 0.53-0.88). However, the risks of Eo-HDP and HDP with SGA were higher in the Q1 group compared with the Q3 group (Eo-HDP: aOR = 1.66, 95 % CI = 1.02-2.70; and HDP with SGA: aOR = 1.81, 95 % CI = 1.04-3.17). In multiparas, the risks of Lo-HDP and SGA were higher in the Q1 group compared with the Q3 group (Lo-HDP: aOR = 1.47, 95 % CI = 1.10-1.97; SGA: aOR = 1.17, 95 % CI = 1.02-1.35)., Conclusions: Preconception dietary fiber intake is beneficial in preventing HDP onset. Therefore, new recommendations should be considered to encourage higher dietary fiber intake as part of preconception care., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

The chemical constituents of Saxifraga stolonifera, S. fortunei, S. nipponica, S. cortusifolia, and S. rebunshirensis were investigated for structure and virucidal activity. In addition to the Saxifraga species-derived tannins, 30 compounds (1-30) were isolated from the five species. 5-Hydroxy-4-methoxy-3-O-(6-O-caffeoyl)-β-D-glucopyranosyl benzoic acid (1) and kaempferol 3-O-β-d-xylopyranosyl-(1 → 2)-β-D-xylopyranoside (2) were identified as undescribed compounds. Although 1 was isolated as the (E)-isomer of its caffeoyl moiety, under light it became over time a mixture of the (Z)-isomer (1a) and (E)-isomer (1). Kaempferol 3-O-β-d-xylopyranosyl-(1 → 2)-β-D-glucopyranoside (3) was an analog of 2 and a known compound, whose NMR assignment was reconsidered and described. 6-Isopropyl-5,5-dimethyldihydropyrimidine-2,4(1H,3H)-dione (30) was expected to be a racemic mixture based on its optical rotation and X-ray crystallography data. The virucidal activities of the isolated compounds (1-30) against influenza A virus, severe acute respiratory syndrome coronavirus 2, feline calicivirus, and murine norovirus were evaluated to identify the presence of compounds other than the Saxifraga species-derived tannins, which exhibited virucidal activities. Although the isolated compound activities were relatively weak compared to those of Saxifraga species-derived tannins, the potential virucidal activity of the compounds with galloyl groups was confirmed., Competing Interests: Declaration of competing interest The authors indicate that there is no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

The persistent prevalence and dissemination of drug-resistant malaria parasites continue to challenge the progress of malaria eradication efforts. As a result, there is an urgent need to search for and develop innovative therapies. In this study, we screened synthetic 2,5-diphenyloxazole analogs from Oxytropis lanata. Among 48 compounds, 14 potently inhibited the proliferation of P. falciparum strains 3D7 (chloroquine-sensitive) and K1 (multidrug-resistant) in vitro, exhibited IC 50 values from 3.38 to 12.65 μM and 1.27-6.19 μM, respectively, and were toxic to human foreskin fibroblasts at 39.53-336.35 μM. Notably, Compounds 31 (2-(2',3'-dimethoxyphenyl)-5-(2″-hydroxyphenyl)oxazole) and 32 (2-(2',3'-dimethoxyphenyl)-5-(2″-benzyloxyphenyl)oxazole) exhibited the highest selectivity indices (SIs) against both P. falciparum strains (3D7/K1), with values > 40.20/>126.58 and > 41.27/> 59.06, respectively. In the IC 50 speed and stage-specific assays, Compounds 31 and 32 showed slow action, along with distinct effects on the ring and trophozoite stages. Microscopy observations further revealed that both compounds impact the development and delay the progression of the trophozoite and schizont stages in P. falciparum 3D7, especially at concentrations 100 times their IC 50 values. In a 72-h in vitro exposure experiment at their respective IC 80 in P. falciparum 3D7, significant alterations in parasitemia levels were observed compared to the untreated group. In Compound 31-treated cultures, parasites shrank and were unable to reinvade red blood cells (RBCs) during an extended 144-h incubation period, even after compound removal from the culture. In vivo assessments were conducted on P. yoelii 17XNL-infected mice treated with Compounds 31 and 32 at 20 mg/kg administered once daily for ten days. The treated groups showed statistically significant lower peaks of parasitemia (Compound 31-treated: trial 1 12.7%, trial 2 15.8%; Compound 32-treated: trial 1 12.7%, trial 2 14.0%) compared to the untreated group (trial 1 21.7%, trial 2 28.3%). These results emphasize the potential of further developing 2,5-diphenyloxazoles as promising antimalarial agents., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Nasal congestion in allergic rhinitis (AR) is caused by vascular hyperpermeability and vascular relaxation of the nasal mucosa. We previously detected high levels of a lipoxygenation metabolite of dihomogammalinolenic acid, 15-hydroxy-8Z,11Z,13E-eicosatrienoic acid (15-HETrE) in the nasal lavage fluid of AR model mice. Here, we investigated the effects of 15-HETrE on vascular functions associated with nasal congestion., Methods: We measured 15-HETrE levels in the nasal lavage fluid of ovalbumin-induced AR model mice and nasal discharge of patients with AR. We also assessed nasal congestion and vascular relaxation in mice. Vascular contractility was investigated using isolated mouse aortas., Results: Five ovalbumin challenges increased 15-HETrE levels in AR model mice. 15-HETrE was also detected in patients who exhibiting AR-related symptoms. Intranasal administration of 15-HETrE elicited dyspnea-related behavior and decreased the nasal cavity volume in mice. Miles assay and whole-mount immunostaining revealed that 15-HETrE administration caused vascular hyperpermeability and relaxation of the nasal mucosa. Intravital imaging demonstrated that 15-HETrE relaxed the ear vessels that were precontracted via thromboxane receptor stimulation. Moreover, 15-HETrE dilated the isolated mouse aortas, and this effect was attenuated by K + channel inhibitors and prostaglandin D 2 (DP) and prostacyclin (IP) receptor antagonists. Additionally, vasodilatory effects of 15-HETrE were accompanied by an increase in intracellular cAMP levels., Conclusions: Our results indicate that 15-HETrE, whose levels are elevated in the nasal cavity upon AR, can be a novel lipid mediator that exacerbates nasal congestion. Moreover, it can stimulate DP and IP receptors and downstream K + channels to dilate the nasal mucosal vasculature., (Copyright © 2024 Japanese Society of Allergology. Published by Elsevier B.V. All rights reserved.)

Purpose: To evaluate the 2-year efficacy, durability, and safety of dual angiopoietin-2 and vascular endothelial growth factor (VEGF) A pathway inhibition with intravitreal faricimab according to a personalized treat-and-extend (T&E)-based regimen with up to every-16-week dosing in the YOSEMITE and RHINE (ClinicalTrials.gov identifiers, NCT03622580 and NCT03622593, respectively) phase 3 trials of diabetic macular edema (DME)., Design: Randomized, double-masked, noninferiority phase 3 trials., Participants: Adults with visual acuity loss (best-corrected visual acuity [BCVA] of 25-73 letters) due to center-involving DME., Methods: Patients were randomized 1:1:1 to faricimab 6.0 mg every 8 weeks, faricimab 6.0 mg T&E (previously referred to as personalized treatment interval), or aflibercept 2.0 mg every 8 weeks. The T&E up to every-16-week dosing regimen was based on central subfield thickness (CST) and BCVA change., Main Outcome Measures: Included changes from baseline in BCVA and CST, number of injections, durability, absence of fluid, and safety through week 100., Results: In YOSEMITE and RHINE (n = 940 and 951, respectively), noninferior year 1 visual acuity gains were maintained through year 2; mean BCVA change from baseline at 2 years (weeks 92, 96, and 100 average) with faricimab every 8 weeks (YOSEMITE and RHINE, +10.7 letters and +10.9 letters, respectively) or T&E (+10.7 letters and +10.1 letters, respectively) were comparable with aflibercept every 8 weeks (+11.4 letters and +9.4 letters, respectively). The median number of study drug injections was lower with faricimab T&E (YOSEMITE and RHINE, 10 and 11 injections, respectively) versus faricimab every 8 weeks (15 injections) and aflibercept every 8 weeks (14 injections) across both trials during the entire study. In the faricimab T&E arms, durability was improved further during year 2, with > 60% of patients receiving every-16-week dosing and approximately 80% receiving every-12-week or longer dosing at week 96. Almost 80% of patients who achieved every-16-week dosing at week 52 maintained every-16-week dosing without an interval reduction through week 96. Mean CST reductions were greater (YOSEMITE/RHINE weeks 92/96/100 average: faricimab every 8 weeks -216.0/-202.6 µm, faricimab T&E -204.5/-197.1 µm, aflibercept every 8 weeks -196.3/-185.6 µm), and more patients achieved absence of DME (CST < 325 μm; YOSEMITE/RHINE weeks 92-100: faricimab every 8 weeks 87%-92%/88%-93%, faricimab T&E 78%-86%/85%-88%, aflibercept every 8 weeks 77%-81%/80%-84%) and absence of intraretinal fluid (YOSEMITE/RHINE weeks 92-100: faricimab every 8 weeks 59%-63%/56%-62%, faricimab T&E 43%-48%/45%-52%, aflibercept every 8 weeks 33%-38%/39%-45%) with faricimab every 8 weeks or T&E versus aflibercept every 8 weeks through year 2. Overall, faricimab was well tolerated, with a safety profile comparable with that of aflibercept., Conclusions: Clinically meaningful visual acuity gains from baseline, anatomic improvements, and extended durability with intravitreal faricimab up to every 16 weeks were maintained through year 2. Faricimab given as a personalized T&E-based dosing regimen supports the role of dual angiopoietin-2 and VEGF-A inhibition to promote vascular stability and to provide durable efficacy for patients with DME., Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (Copyright © 2024 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

P-glycoprotein (P-gp) is an ATP-binding cassette transporter known for its roles in expelling xenobiotic compounds from cells and contributing to cellular drug resistance through multidrug efflux. This mechanism is particularly problematic in cancer cells, where it diminishes the therapeutic efficacy of anticancer drugs. P-gp inhibitors, such as elacridar, have been developed to circumvent the decrease in drug efficacy due to P-gp efflux. An earlier study reported the cryo-EM structure of human P-gp-Fab (MRK-16) complex bound by two elacridar molecules, at a resolution of 3.6 Å. In this study, we have obtained a higher resolution (2.5 Å) structure of the P-gp- Fab (UIC2) complex bound by three elacridar molecules. This finding, which exposes a larger space for compound-binding sites than previously acknowledged, has significant implications for the development of more selective inhibitors and enhances our understanding of the compound recognition mechanism of P-gp., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Takeshi Murata reports financial support was provided by Collaboration of Structure Analysis for ADMETox Related Proteins. Takeshi Murata reports financial support was provided by Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS) from AMED. Takeshi Murata reports financial support was provided by Japan Society for the Promotion of Science (JSPS). If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: The efficacy of radiotherapy for symptomatic relief of malignant psoas syndrome (MPS) remains unknown because there are limited publications with high level evidence, including analyses with sufficient number of cases, clinical trials, and systematic reviews about radiotherapy for MPS. We aimed to investigate the characteristics of and symptom relief rates in patients treated with radiotherapy for MPS in palliative intent., Methods: In this single-center retrospective study, we analyzed data of 22 consecutive patients treated with radiotherapy for MPS at our institution in Japan between 2012 and 2022. We recorded patient characteristics, including primary site, invasion pattern, recognition of MPS by the attending physician, radiation regimen, biological effective dose with α/β = 10 Gy (BED 10 ), and adverse events. Since no objective evaluation index for palliative radiotherapy for non-bone metastases has been established, we modified and used an International Consensus on Palliative Radiotherapy Endpoint, which was originally used for bone metastases, to evaluate symptom relief in the present retrospective study. "Response" was defined as symptom relief described in medical records or the use of analgesic medications reduced by ≥25% within 3 months post-initiation of radiotherapy., Results: Genitourinary organs (41%) were the most common primary-tumor sites. MPS was caused by metastasis in the iliopsoas muscle in 14 patients (64%) and by direct invasion of the primary tumor in eight patients (36%). Since the optimal radiation dose for MPS has not been established, the radiation dose varied from low dose, which are used in palliative radiotherapy for painful bone metastases, to high dose with conventional fraction using 1.8 to 2 Gy per fraction, with a median BED 10 of 48 Gy (range, 10.6-79.2 Gy). Fifteen patients (68%) achieved a response. No acute nor late adverse events of grade 2 or higher, according to Common Terminology Criteria for Adverse Events version 5.0, were reported during the observation period., Conclusion: Radiotherapy for symptomatic MPS might be an effective treatment option with a high response rate (68%) and minimal adverse events. Since the present study is a retrospective study with small number of cases, a prospective study with a larger sample size is required., (Copyright © 2023. Published by Elsevier Inc.)

The fern plant Woodsia ilvensis (L.) R. Br. belongs to the Woodsiaceae family and its leaves are used to treat diarrhea, soft-tissue injuries, and external injuries. Investigations of the compounds obtained from the plasmin-inhibitory-active extracts of W. ilvensis led to the isolation of two undescribed maleimide N-glycosides, an undescribed stilbenoid glycoside, and five undescribed acetylated flavonol bisdesmosides, together with 19 known compounds. The chemical structures of the isolated compounds were determined using spectroscopy. The absolute configurations of the sugar moieties were determined via HPLC after acid hydrolysis. Among the isolated compounds, some flavonoids and stilbenoid glycosides exhibited plasmin-inhibitory activity., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Normal angiogenesis is essential for retinal development and maintenance of visual function in the eye, and its abnormality can cause retinopathy and other eye diseases. Prostaglandin D 2 is an anti-angiogenic lipid mediator produced by lipocalin-type PGD synthase (L-PGDS) or hematopoietic PGD synthase (H-PGDS). However, the exact role of these PGD synthases remains unclear. Therefore, we compared the roles of these synthases in murine retinal angiogenesis under physiological and pathological conditions. On postnatal day (P) 8, the WT murine retina was covered with an elongated vessel. L-PGDS deficiency, but not H-PGDS, reduced the physiological vessel elongation with sprouts increase. L-PGDS expression was observed in endothelial cells and neural cells. In vitro, L-PGDS inhibition increased the hypoxia-induced vascular endothelial growth factor expression in isolated endothelial cells, inhibited by a prostaglandin D 2 metabolite, 15-deoxy-Δ 12,14 -PGJ 2 (15d-PGJ 2 ) treatment. Pericyte depletion, using antiplatelet-derived growth factor receptor-β antibody, caused retinal hemorrhage with vessel elongation impairment and macrophage infiltration in the WT P8 retina. H-PGDS deficiency promoted hemorrhage but inhibited the impairment of vessel elongation, while L-PGDS did not. In the pericyte-depleted WT retina, H-PGDS was expressed in the infiltrated macrophages. Deficiency of the D prostanoid receptor also inhibited the vessel elongation impairment. These results suggest the endogenous role of L-PGDS signaling in physiological angiogenesis and that of H-PGDS/D prostanoid 1 signaling in pathological angiogenesis., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background/objective: The occurrence of iatrogenic tumor cell seeding (seeding) in needle tract scars formed by core needle biopsy (CNB) or vacuum-assisted biopsy (VAB) is well known. Some risk factors for seeding have been reported, but the clinicopathological risk factors and its prognosis have not been fully investigated. We evaluated the clinical features and prognosis of seeding., Methods: We included 4405 patients who had undergone surgery (lumpectomy or mastectomy) with a diagnosis of breast cancer by preoperative CNB or VAB at our hospital between January 2012 and February 2021. Data of patients with confirmed presence of seeding in resected specimens were collected from pathological records. We analyzed the risk factors of seeding using logistic regression analysis and compared the ipsilateral breast tumor recurrence (IBTR) rate between cases based on the presence or absence of seeding in the lumpectomy group., Results: Of the 4405 patients, 133 (3.0%) had confirmed seeding. Univariate analysis revealed the association of clinicopathological features of seeding with lower nuclear grade (NG1 vs NG2-3; p = 0.043), lower Ki-67 (<30 vs. ≥30; p = 0.049), estrogen receptor (ER) positivity (positive vs negative; p<0.01), and human epidermal growth factor receptor 2 (HER2) negativity (negative vs positive; p = 0.016). Multivariate analysis showed ER positivity (odds ratio, 5.23; p<0.05) as an independent risk factor of seeding. The IBTR rate was not significantly different between the seeding and non-seeding groups., Conclusions: Seeding was more likely to occur in ER positive, HER2 negative carcinomas with less aggressive features, and may remain subclinical if adequate adjuvant treatments are administered., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Asian Surgical Association and Taiwan Robotic Surgery Association. Published by Elsevier B.V. All rights reserved.)

In transplantation using allogeneic induced pluripotent stem cells (iPSCs), strategies focused on major histocompatibility complexes were adopted to avoid immune rejection. We showed that minor antigen mismatches are a risk factor for graft rejection, indicating that immune regulation remains one of the most important issues. In organ transplantation, it has been known that mixed chimerism using donor-derived hematopoietic stem/progenitor cells (HSPCs) can induce donor-specific tolerance. However, it is unclear whether iPSC-derived HSPCs (iHSPCs) can induce allograft tolerance. We showed that 2 hematopoietic transcription factors, Hoxb4 and Lhx2, can efficiently expand iHSPCs with a c-Kit + Sca-1 + Lineage - phenotype, which possesses long-term hematopoietic repopulating potential. We also demonstrated that these iHSPCs can form hematopoietic chimeras in allogeneic recipients and induce allograft tolerance in murine skin and iPSC transplantation. With mechanistic analyses, both central and peripheral mechanisms were suggested. We demonstrated the basic concept of tolerance induction using iHSPCs in allogeneic iPSC-based transplantation., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Ken-ichiro Seino reports financial support was provided by MEXT. Ken-ichiro Seino has patent pending to Licensee. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation., (Copyright © 2023 American Society of Transplantation & American Society of Transplant Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Several studies have reported the cost-effectiveness of sodium-glucose co-transporter 2 inhibitors in heart failure patients; however, their economic implications have not been sufficiently elucidated in Japan., Methods: A Markov cohort model was developed to evaluate the cost-effectiveness of empagliflozin plus standard of care (SoC) vs. SoC for patients with heart failure with reduced ejection fraction (HFrEF) in Japan. Model inputs, including risk of clinical events, costs, and utilities based on Kansas City Cardiomyopathy Questionnaire Clinical Summary Scores were derived from EMPEROR-Reduced trial data, published literature, and a claims database., Results: The model predicted lower lifetime hospitalizations for heart failure (HHFs) and additional quality-adjusted life-years (QALYs; 0.21) for empagliflozin plus SoC vs. SoC in the overall population. Increased costs of ¥100,495/patient ($772/patient), primarily driven by higher drug costs of ¥239,558/patient ($1,840/patient), were largely offset by reduced HHF management costs of -¥166,160/patient (-$1,276/patient), yielding an incremental cost-effectiveness ratio (ICER) of ¥469,672/QALY ($3,608/QALY). Results were consistent among subgroups and sensitivity analyses. In probabilistic sensitivity analysis, 82.5 % of runs were below the Japanese ICER reference value of ¥5,000,000/QALY ($38,408/QALY)., Conclusions: Empagliflozin was demonstrated to be cost-effective for HFrEF patients in Japan based on the EMPEROR-Reduced trial data., Competing Interests: Declaration of competing interest Hiroyuki Tsutsui received remuneration for attending meetings from Kowa Company, Limited, TEIJIN PHARMA, Nippon Boehringer Ingelheim Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Pfizer Japan Inc., Ono Pharmaceutical CO., LTD, Daiichi Sankyo Company, Novartis Pharma K.K, Bayer Yakuhin, Ltd., Otsuka Pharmaceutical, AstraZeneca K.K, received manuscript fee from Nippon Rinsho, received research funding from Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co., Ltd., IQVIA Services Japan K.K, medinet,inc, Medical Innovation Kyushu, Co., Ltd., Kowa Company, Daiichi Sankyo Company, Johnson & Johnson, NEC Corporation, received scholarship funds from Nippon Boehringer Ingelheim Co., Ltd., St.Mary's Hospital, TEIJIN PHARMA, Daiichi Sankyo Company, Mitsubishi Tanabe Pharma Corporation. Hiroyuki, Sakamaki received research funding from TOWA PHARMACEUTICAL CO., LTD. Shin-ichi Momomura received remuneration for attending meeting from Nippon Boehringer Ingelheim Co., Ltd. Yasushi Sakata received remuneration for attending meeting from Otsuka Pharmaceutical, Daiichi Sankyo Company, Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co., Ltd., AstraZeneca K.K, Ono Pharmaceutical, CO., LTD, Novartis Pharma K.K, received research funding from Nippon Boehringer Ingelheim, received scholarship funds from Ono Pharmaceutical, CO., LTD, Otsuka Pharmaceutical, Daiichi Sankyo Company, Mitsubishi Tanabe Pharma Corporation, Nippon Boehringer Ingelheim Co., Ltd. Yutaro Kotobuki and Daisuke Nitta are employees of Nippon Boehringer Ingelheim Co., Ltd., while Stephan Linden is employed by Boehringer Ingelheim International GmbH. Tatsunori Murata is an employee of CRECON Medical Assessment Inc. Tetsuaki Hirase is an employee of Eli Lilly Japan K. K. and has stock from Eli Lilly and Company. Odette Reifsnider, Pal Rakonczai, and Matthew Stargardter are employees of Evidera, a biopharmaceutical research and consulting firm. In these salaried positions, they work with a variety of companies and are explicitly precluded from accepting any payment or honoraria directly from those companies for services rendered. Evidera received payment from Nippon Boehringer Ingelheim Co., Ltd. for collaboration on this project and article., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Scutellaria scordiifolia Fisch. ex Schrank is used to treat various inflammatory diseases and other ailments in traditional and contemporary medicine. In this study, 10 undescribed compounds, including a flavanone (1), four chrysin C-glycosides (2-5), a phenanthrene glucoside (6), four iridoid glucosides (7-10) and 31 known compounds were identified from an extract of the aerial parts of S. scordiifolia. The absolute configurations of sugars in C-glycosides were determined by comparing electric circular dichroism spectra with calculated data. The flavanones (1 and 17), flavonols (11-13), flavone (14), and some of the flavone glucuronides (15, 16) exhibited trypanocidal activities against Trypanosoma congolense. The activity data and quantitative HPLC analysis of flavonoids from the aerial parts of S. scordiifolia suggest that they may effectively treat diseases caused by the aforementioned trypanosomes. Other compounds such as novel iridoids and phenanthrene glycosides, which may be useful for chemophenetic and chemoecological discussions, were also identified., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Although maternal triglyceride (TG) is important for fetal growth, there are few large cohort studies investigating the relationships between maternal TG during pregnancy and neonatal outcomes., Objectives: The objective of this study was to investigate the associations between maternal TG during the second and third trimesters and neonatal outcomes including preterm birth (PTB), low birth weight (LBW), small for gestational age (SGA) and large for gestational age (LGA)., Methods: This was a prospective birth cohort study using data of the Japan Environment and Children's Study included data of births from 2011-2014 in Japan including 79,519 pairs. Participants were divided into tertiles according to maternal TG in the second or third trimesters. Multiple logistic regression modeling was used to examine the risks of LBW, SGA, LGA and PTB in association with maternal TG levels in the second or third trimesters RESULTS: In the second trimester, compared with reference TG group (T2), women in higher TG group (T3) and lower TG group (T1) were also at increased risk of LGA (aOR 1.20, 95% CI 1.11-1.29) and SGA (aOR 1.25, 95% CI 1.10-1.41), respectively. In the third trimester, women in T3 and T1 were at increased risk of LGA (aOR 1.27, 95% CI 1.17-1.38) and SGA (aOR 1.17, 95% CI 1.02-1.34), respectively., Conclusion: In this study, higher maternal TG levels in the second or third trimesters were associated with risks of LGA, however, lower maternal TG levels in the second or third trimesters were conversely associated with risks of SGA., (Copyright © 2023. Published by Elsevier Inc.)

Tau, a microtubule-binding protein, is a major component of neurofibrillary tangles in the brains of Alzheimer's disease patients. Tau aggregation following fibril formation induces Alzheimer's disease pathogenesis. The accumulation of D-isomerized amino acids in proteins that occurs in several tissues with aging is thought to be implicated in age-related diseases. D-isomerized Asp accumulation has also been found in Tau in neurofibrillary tangles. We previously demonstrated the effects of D-isomerization of Asp within microtubule-binding repeat peptides of Tau, Tau R2, and R3 on the rates of structural transition and fibril formation. Here, we investigated the potency of Tau aggregation inhibitors on fibril formation of wild-type Tau R2 and R3 peptides and D-isomerized Asp-containing Tau R2 and R3 peptides. D-isomerization of Asp within Tau R2 and R3 peptides attenuated the potency of inhibitors. We next investigated the fibril morphology of D-isomerized Asp-containing Tau R2 and R3 peptides by electron microscopy. D-isomerized Asp-containing Tau R2 and R3 fibrils showed significantly different fibril morphology from that of wild-type peptides. Our results indicate that D-isomerization of Asp within Tau R2 and R3 peptides affects fibril morphology, resulting in attenuation of the potency of Tau aggregation inhibitors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Transradial mechanical thrombectomy (MT) is increasingly used because it is associated with a low incidence of vascular access site complications. However, transradial carotid cannulation can be technically challenging to perform in patients with an unfavorable supra-aortic takeoff. In this study, the feasibility and safety of a new transradial MT system with a radial-specific neurointerventional guiding sheath-6F Simmons guiding sheath was evaluated-in patients with anterior circulation large-vessel occlusions. Additionally, a literature review was performed., Methods: We retrospectively analyzed data from our institutional database about consecutive patients who underwent transradial MT for anterior circulation large-vessel occlusion. After the 6F Simmons guiding sheath was engaged into the target common carotid artery, a triaxial system (Simmons guiding sheath/aspiration catheter/microcatheter), was established. MT using the continuous aspiration prior to intracranial vascular embolectomy technique was performed. Then, procedural success rate, successful revascularization, and procedure-related complications were assessed., Results: A total of 13 patients who had transradial MT were included in the analysis. All 13 patients underwent successful thrombectomy without catheter kinking or system instability, and 12 of them achieved successful revascularization (modified Thrombolysis in Cerebral Infarction score of ≥2b). No complications occurred., Conclusions: To the best of our knowledge, this is the first case series on transradial MT using a radial-specific neurointerventional system for anterior circulation large-vessel occlusions. This method may increase the success rate of transradial MT. Based on our initial experience, transradial MT, using this system, was feasible and safe for anterior circulation large-vessel occlusions., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Aims: Regucalcin, which plays a multifunctional role in cell regulation, contributes as a suppressor in carcinogenesis. Survival of cancer patients is prolonged with high expression of regucalcin in tumor tissues. Ovarian cancer is the most lethal in gynecologic malignancies. This study elucidates the repressive role of regucalcin on the growth of human ovarian cancer SK-OV-3 cells that are resistant to cytotoxic cancer drugs., Materials and Methods: SK-OV-3 wild type-cells and regucalcin-overexpressing cells (transfectants) were cultured in Dulbecco's Modification of Eagle's Medium containing 10 % fetal bovine serum., Key Findings: Colony formation and proliferation of SK-OV-3 cells were repressed by regucalcin overexpression. The suppressive effects of regucalcin on proliferation were independent of cell death. The proliferation of SK-OV-3 wild-type cells was repressed by various inhibitors, including cell cycle, signaling processes, and transcriptional activity. The effects of all inhibitors were not revealed in transfectants, suggesting the involvement of multiple signaling pathways in regucalcin effects. Of note, the overexpressed regucalcin declined the levels of Ras, Akt, mitogen-activating protein kinase, NF-κB p65, β-catenin, and STAT3, while it raised the levels of tumor suppressors p53 and Rb, and cell cycle inhibitor p21. Interestingly, the stimulatory effects of epidermal growth factor (EGF) on cell proliferation were blocked in regucalcin-overexpressing cells. Extracellular regucalcin repressed the proliferation independent of the death of SK-OV-3 cells and blocked EGF-enhanced cell proliferation., Significances: The overexpressed regucalcin may repress cell proliferation by targeting diverse signal pathways, including EGF signaling. This study offers a novel approach to the treatment of ovarian cancer with regucalcin., Competing Interests: Declaration of competing interest All 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 Elsevier Inc. All rights reserved.)

Background: /Objective: To evaluate the usefulness of combining radioisotopes (RI) and indocyanine green (ICG) and investigate discordances in sentinel lymph node (SN) reactivity using each tracer in cN0 breast cancer patients., Methods: In total, 338 cN0 primary breast cancer patients who underwent SN biopsy with RI and ICG and axillary lymph node (ALN) dissection were included. SN positivity with RI, ICG, and a combination of RI and ICG was denoted as SN(RI), SN(ICG), and SN(RI+ICG), respectively. We retrospectively estimated metastatic SN detection rates, each method's discordance rate, and the correlation of discordances in SN reactivity with postoperative N staging., Results: The combination of RI and ICG had higher metastatic SN detection rates (99.7%) than RI or ICG alone (91.7% and 96.4%, respectively; p < 0.01). The discordance rate between SN(RI) and SN(ICG) in detecting metastatic SNs was 11.3% (38/337 cases). The absence of SN(RI), cT stage (cT2-3), higher histological grade (G3), and histological type (special type) were identified as risk factors of pN2-3 disease (odds ratios: 8.64, 2.56, 1.92, and 3.28, respectively; p < 0.01)., Conclusion: Discordances in SN reactivity between RI and ICG helps in identifying SN metastasis. Although the absence of SN(RI) is rare, it is a significant sign of advanced ALN metastases. The findings of our study indicate that ALN dissection should be considered for accurate nodal staging in such cases., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2022 Asian Surgical Association and Taiwan Robotic Surgery Association. Published by Elsevier B.V. All rights reserved.)

Objectives: Almost all preference-based measures (PBMs) have been developed in Western countries, with none having been formulated in Asian countries. In this study, we construct a new generic PBM based on concept elicitation using interview surveys in East and Southeast Asian countries and qualitative analysis., Methods: This cross-sectional study included 225 adults recruited from 9 East and Southeast Asian countries or regions (Indonesia, Japan, Korea, mainland China, Malaysia, the Philippines, Singapore, Taiwan, and Thailand). Trained interviewers conducted semistructured interviews with 25 participants from the general population of each country/region. Qualitative data were analyzed using a content analysis approach. The selection of items was determined based on interview surveys and team member discussions. The description of items was considered based on a detailed qualitative analysis of the interview survey., Results: A new region-specific PBM-the Asia PBM 7 dimensions instrument-was designed. It reflects East and Southeast Asian values and comprises 7 items: pain, mental health, energy, mobility, work/school, interpersonal interactions, and burden to others., Conclusions: The new region-specific instrument is one of the first PBMs developed in the context of non-Western countries. The Asia PBM 7 dimensions contains 7 items that address the core concepts of health-related quality of life that are deemed important based on East and Southeast Asian health concepts., (Copyright © 2022 International Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Aims: RGPR-p117 was originally discovered as a novel transcription factor, which specifically binds to a nuclear factor I (NFI) consensus motif TTGGC(N) 6 CC in the promoter region of the regucalcin gene. RGPR-p117 is also called as Lztr2 and SEC16B. The role of RGPR-p117 in cell regulation is poorly understood. This study was undertaken to determine whether the overexpression of RGPR-p117 impacts the proliferation of normal rat kidney proximal tubular epithelial NRK-52E cells in vitro., Main Methods: The NRK-52E wild-type cells and RGPR-p117-overexpressing NRK-52E cells were cultured in DMEM containing fetal bovine serum., Key Findings: The overexpression of RGPR-p117 repressed colony formation and proliferation of NRK-52E cells. Interestingly, RGPR-p117 overexpression blocked cell proliferation promoted by culturing with Bay K 8644, a calcium-entry agonist, and phorbol 12-myristate 13-acetate, an activator of protein kinase C. The depressive effects of RGPR-p117 overexpression on cell proliferation were not occurred by culturing with various inhibitors of cell cycle and intracellular signaling processes. RGPR-p117 overexpression increased the translocation of RGPR-p117 into the nucleus of NRK-52E cells. Mechanistically, RGPR-p117 overexpression diminished the levels of Ras, PI3 kinase, Akt, mitogen-activated protein kinase, and mTOR, while it raised the levels of p53, Rb, p21, and regucalcin. Furthermore, RGPR-p117 overexpression protected cell death caused by apoptosis-inducing factors, suggesting that the suppressive effects of RGPR-p117 on cell growth are independent of cell death., Significance: The present study demonstrates that the overexpressed transcription factor RGPR-p117 suppresses cell proliferation via targeting diverse signaling processes, suggesting a role of RGPR-p117 in cell regulation., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: We aimed to examine the impact of preconception pro-inflammatory diet on hypertensive disorders of pregnancy., Study Design: Data from the Japan Environmental Children's Study (JECS), a nation-wide birth cohort study, were used., Main Outcome Measures: Information on meal patterns before pregnancy, derived through food frequency questionnaires, was used to calculate the dietary inflammatory index. Based on the dietary inflammatory index, participants were categorized into quartiles (Q1 and Q4 representing the diet with the highest anti-inflammatory and pro-inflammatory effects, respectively), and a multiple logistic regression model was used to estimate the effect of pro-inflammatory diet on hypertensive disorders of pregnancy, early-onset-hypertensive disorders of pregnancy, late-onset-hypertensive disorders of pregnancy, and hypertensive disorders of pregnancy with/without small for gestational age birth., Results: After applying our inclusion criteria, 93,265 participants were eligible. The mean white blood cell count during the first trimester and urine 8-hydroxy-2'-deoxyguanosine levels during pregnancy were highest in the Q4 group (both p < 0.01). Multiple regression analysis showed that pro-inflammatory diet consumption increased the risk of both early-onset-hypertensive disorders of pregnancy (adjusted odds ratio: 1.53, 95% confidence interval: 1.06-2.20) and hypertensive disorders of pregnancy without small for gestational age birth (adjusted odds ratio: 1.26, 95% confidence interval: 1.03-1.54) among multiparous women., Conclusion: Consumption of diet with a high dietary inflammatory index score before pregnancy increases maternal inflammation and oxidative stress during pregnancy. Preconception lifestyle influences the risk of hypertensive disorders of pregnancy, especially among multiparous women., (Copyright © 2022 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Surfactant-induced cumulative irritant contact dermatitis (ICD) is a common and clinically important skin disorder. CCL2 is known to mediate inflammation after tissue damage in various organs. Thus, we investigated whether and how CCL2 contributes to the development of murine cumulative ICD induced by a common surfactant, SDS. Wild-type mice treated topically with SDS for 6 consecutive days developed skin inflammation that recapitulated the features of human cumulative ICD, including barrier disruption, epidermal thickening, and neutrophil accumulation. CCL2 was upregulated in SDS-treated skin, and local CCL2 blockade attenuated SDS-induced ICD. SDS-induced ICD and neutrophil accumulation were also attenuated in mice deficient in CCR2, the receptor for CCL2. Neutrophil depletion alleviated SDS-induced ICD, suggesting that impaired neutrophil accumulation was responsible for the amelioration of ICD in CCR2-deficient mice. In RNA-sequencing analyses of SDS-treated skin, the expression levels of Il1b in Ccr2-deficient mice were highly downregulated compared with those in wild-type mice. Furthermore, the intradermal administration of IL-1β in the SDS-treated skin of CCR2-deficient mice restored the local accumulation of neutrophils and the development of ICD. Collectively, our results suggest that CCL2‒CCR2 signaling in the skin critically promotes the development of SDS-induced ICD by inducing IL-1β expression for neutrophil accumulation., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To use Markov modeling to estimate the cost-effectiveness of treatment with etanercept 25 mg once weekly plus methotrexate (MTX) in Japanese patients with rheumatoid arthritis who had achieved remission or low disease activity with etanercept 50 mg once weekly plus MTX., Methods: Effectiveness data were estimated based on results from a clinical trial (PRESERVE) in patients with rheumatoid arthritis who had achieved remission or low disease activity and who were then randomized to receive etanercept 25 mg plus MTX or placebo plus MTX. A Markov model was established and included flare rates of 21% and 62% in the etanercept 25 mg and placebo groups, respectively. EQ-5D was calculated using an ordinary least-squares model that included the health assessment questionnaire disability index and pain visual analog scale. Worsening of the health assessment questionnaire score over 1 year was estimated to be 0.047 for patients with flare, and when associated with radiographic progression it was estimated to increase by 0.006 and 0.025 in the etanercept 25 mg and placebo groups, respectively. A cycle length of 1 year was applied to calculate the cumulative cost and effectiveness for a 10-year time span., Results: Compared with the placebo group, the quality-adjusted life-years for the etanercept 25 mg group was increased by 0.841. The incremental cost-effectiveness ratio was ¥6 173 772., Conclusion: These results suggest that maintenance treatment with etanercept 25 mg is cost-effective., (Copyright © 2021 ISPOR--The professional society for health economics and outcomes research. Published by Elsevier Inc. All rights reserved.)

179 compounds in a Mongolian compound library were investigated for their inhibitory effect on the in vitro growth of Plasmodium falciparum and Toxoplasma gondii. Among these compounds, brachangobinan A at a half-maximal inhibition concentration (IC 50 ) of 2.62 μM and a selectivity index (SI) of 27.91; 2-(2'-hydroxy-5'-O-methylphenyl)-5-(2″,5″-dihydroxyphenyl)oxazole (IC 50 3.58 μM and SI 24.66); chrysosplenetin (IC 50 3.78 μM and SI 15.26); 4,11-di-O-galloylbergenin (IC 50 3.87 μM and SI 13.38); and 2-(2',5'-dihydroxyphenyl)-5-(2″-hydroxyphenyl)oxazole (IC 50 6.94 μM and SI 11.48) were identified as potential inhibitors of P. falciparum multiplication. Additionally, tricin (IC 50 12.94 μM and SI > 23.40) was identified as a potential inhibitor of T. gondii multiplication. Our findings represent a good starting point for developing novel antimalarial and anti-Toxoplasma therapeutics from Mongolian compounds., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Feline calicivirus is one of the surrogate viruses of human norovirus. This study aimed to identify virucidal compounds, chemical constituents of plants from the genus Dracocephalum, which are rich in flavonoids and phenylpropanoid oligomers. Four undescribed compounds, including a flavanone glucoside, two stilbenoid glycosides, and a phenylpropanoid amide glycoside, as well as 17 known compounds, were isolated from the Mongolian plants Dracocephalum fruticulosum Stephan ex Willd., and D. nutans L. belonging to the family Lamiaceae. The structures of the compounds were determined based on NMR, MS, and electronic CD spectroscopic data. In addition to these 21 compounds, 15 previously reported compounds from D. foetidum Bunge in C.F. von Ledebour were included, and a total of 36 compounds were evaluated for their virucidal activities against feline calicivirus. Some of the flavanone glycosides and phenylpropanoid oligomers showed virucidal activities, and their structural features are discussed. The findings suggest that isosakuranetin glycosides and phenylpropanoid oligomers may have the potential for norovirus inactivation., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Clozapine is commonly prescribed in dopamine supersensitivity psychosis (DSP) cases in Japan. However, limited knowledge on treatment post-clozapine discontinuation use exists. We investigated antipsychotic medications, patient status, and DSP episodes before, during, and after clozapine treatment using medical records of 30 schizophrenia patients (mean age, 51 years; mean illness duration before clozapine treatment, 24 years; mean clozapine treatment duration, 1.6 years), who discontinued clozapine between 2009 and 2019. In our region, long-acting injectable antipsychotic monotherapy and polypharmacy (half with aripiprazole) accounted for 17% and 50% post-clozapine use, respectively. Furthermore, patient status rarely improved with subsequent DSP treatment, including clozapine re-initiation., (Copyright © 2021. Published by Elsevier B.V.)

We developed a methodology for rapid quantification of extracellular neurotransmitters in mouse brain by PESI/MS/MS and longitudinal data analysis using the R and Stan-based Bayesian state-space model. We performed a rapid analysis for quantifying extracellular l-glutamic acid (L-Glu) and gamma-aminobutyric acid (GABA) in the mouse striatum by combined use of probe electrospray ionization/tandem mass spectrometry (PESI/MS/MS) and in vivo brain microdialysis. We optimized the PESI/MS/MS parameters with the authentic L-Glu, GABA, L-Glu- 13 C 5 , 15 N 1 , and GABA-D 6 standards. We constructed calibration curves of L-Glu and GABA with the stable isotope internal standard correction method (L-Glu- 13 C 5 , 15 N 1 , and GABA-D 6 ), demonstrating sufficient linearity (R > 0.999). Additionally, the quantitative method for L-Glu and GABA was validated with low-, middle-, and high-quality control samples. The intra- and inter-day accuracy and precision were 0.4%-7.5% and 1.7%-5.4% for L-Glu, respectively, and 0.1%-4.8% and 2.1%-5.7% for GABA, respectively, demonstrating high reproducibility of the method. To evaluate the feasibility of this method, microdialyses were performed on free-moving mice that were stimulated by high-K + -induced depolarization under different sampling conditions: 1) every 5 min for 150 min (n = 2) and 2) every 1 min for 30 min (n = 3). We applied the R and Stan-based Bayesian state-space model to each mouse's time-series data considering autocorrelation, and the model successfully detected abnormal changes in the L-Glu and GABA levels in each mouse. Thus, the L-Glu and GABA levels in all microdialysates approximately increased up to two- and seven-fold levels through high-K + -induced depolarization. Additionally, a 1-min temporal resolution was achieved using this method, thereby successfully monitoring microenvironmental changes in the extracellular L-Glu and GABA of the mouse striatum. In conclusion, this methodology using PESI/MS/MS and Bayesian state-space model allowed easy monitoring of neurotransmitters at high temporal resolutions and appropriate data interpretation considering autocorrelation of time-series data, which will reveal hidden pathological mechanisms of brain diseases, such as Parkinson's disease and Huntington's disease in the future., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: Several clinical studies have reported the efficacy of favipiravir in reducing viral load and shortening the duration of symptoms. However, the viability of SARS-CoV-2 in the context of favipiravir therapy and the potential for resistance development is unclear., Methods: We sequenced SARS-CoV-2 in nasopharyngeal specimens collected from patients who participated in a randomized clinical trial of favipiravir at hospitals across Japan between March and May 2020. Paired genomes were sequenced from those who remained RT-PCR-positive 5-8 days into favipiravir therapy. Daily nasopharyngeal specimens from 69 patients who were RT-PCR-positive at randomization were examined for a cytopathic effect (CPE)., Results: Some strains early in the trial belonged to clade 19 B, whereas the majority belonged to clade 20 B. The median time from the disease onset to negative CPE was 9 days. CPE was strongly correlated with the time from disease onset, viral load, age, and male sex. Among 23 patients for whom paired genomes were available, all except one had identical genomes. Two mutations were observed in one patient who received favipiravir, neither in the RdRp gene., Conclusions: The SARS-CoV-2 genome distribution in this clinical trial conducted in Japan reflected the early influx of strains from China followed by replacement by strains from Europe. CPE was significantly associated with age, male sex, and viral loads but not with favipiravir therapy. There was no evidence of resistance development during favipiravir therapy., (Copyright © 2021 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Objectives: To evaluate the ability of different imaging modalities to accurately detect bone invasion in oral squamous cell carcinomas., Patients and Methods: Patients with oral squamous cell carcinoma, who were scheduled for mandibulectomy or maxillectomy, underwent clinical evaluation using five preoperative imaging diagnosis methods-contrast-enhanced MRI, CT, 99m Tc scintigraphy (Tc scan), FDG-PET CT (PET/CT), and panoramic radiography. The sensitivity and specificity of each modality in detecting bone invasion were calculated by comparing the findings on the images with postoperative histopathological findings. In a subgroup of patients, we further assessed the ability of MRI and CT to detect the accurate extent of bone invasion, including the height, width, and depth in patients with pathological mandibular invasion., Results: Overall, 50 patients were enrolled in this study, and nine patients with pathological mandibular invasion were included in our subgroup analysis. MRI was found to be the most useful method in detecting bone invasion, showing the highest sensitivity (88.9%) and negative predictive values (92.3%). CT (87.5% specificity and 77.8% sensitivity) was more specific than MRI, though less sensitive. Combined PET/CT was more sensitive (83.3%) and less specific (71.9%) than CT. Tc scan had high sensitivity (88.9%); however, the specificity was relatively low (71.9%)., Conclusion: MRI was the most useful method in detecting bone invasion. A negative MRI result definitively excludes bone marrow invasion. In patients with positive MRI findings, a negative CT may be useful in ruling out bone marrow invasion., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: It has been determined that axillary lymph node dissection after the detection of limited axillary lymph node metastasis does not improve the prognosis of patients with breast cancer. Thus, a need exists for less-invasive axillary surgery. However, it remains unclear whether a predictive model based on preoperative data would be sufficient to accurately predict the probability of pN2-N3 (> 3 lymph node metastases). We sought to develop an easy-to-use scoring system to distinguish between pN0-N1 (0-3 lymph node metastases) and pN2-N3 using only preoperative data and validate its predictive performance., Patients and Methods: We retrospectively identified 2687 patients diagnosed with cT1-3cN0-N1 who had undergone surgery in our hospital from 2013 to 2019. We evaluated the risk factors associated with pN2-N3 by logistic regression analysis and developed a scoring system. Predictive performance was assessed by calculating the receiver operating characteristic area under the curve (AUC) and was validated using K-fold cross-validation., Results: We identified 1987 patients with stage pN0, 522 with pN1, and 178 with pN2-N3. Multivariate analysis revealed tumor size, number of suspicious lymph nodes on axillary ultrasound examination, histologic type, histologic grade, and receptor status were significant risk factors for pN2-N3. The AUC value was 0.87, and the mean AUC of the 10-fold cross-validation was 0.88. When the cutoff score was set at 6, the negative predictive value for excluding patients with pN2-N3 was 98.4%., Conclusion: Our easy-to-use scoring system could be useful to preoperatively identify patients at lower risk of pN2-N3 and avoid unnecessary axillary lymph node dissection., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Age-related macular degeneration (AMD) is a leading cause of visual impairment. Anti-vascular endothelial growth factor drugs used to treat AMD carry the risk of inducing subretinal fibrosis. We investigated the use of adrenomedullin (AM), a vasoactive peptide, and its receptor activity-modifying protein 2, RAMP2, which regulate vascular homeostasis and suppress fibrosis. The therapeutic potential of the AM-RAMP2 system was evaluated after laser-induced choroidal neovascularization (LI-CNV), a mouse model of AMD. Neovascular formation, subretinal fibrosis, and macrophage invasion were all enhanced in both AM and RAMP2 knockout mice compared with those in wild-type mice. These pathologic changes were suppressed by intravitreal injection of AM. Comprehensive gene expression analysis of the choroid after LI-CNV with or without AM administration revealed that fibrosis-related molecules, including Tgfb, Cxcr4, Ccn2, and Thbs1, were all down-regulated by AM. In retinal pigment epithelial cells, co-administration of transforming growth factor-β and tumor necrosis factor-α induced epithelial-mesenchymal transition, which was also prevented by AM. Finally, transforming growth factor-β and C-X-C chemokine receptor type 4 (CXCR4) inhibitors eliminated the difference in subretinal fibrosis between RAMP2 knockout and wild-type mice. These findings suggest the AM-RAMP2 system suppresses subretinal fibrosis in LI-CNV by suppressing epithelial-mesenchymal transition., (Copyright © 2021 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objectives: Determining the appropriate preconception care to reduce the occurrence of hypertensive disorders of pregnancy (HDP) remains a challenge in modern obstetrics. We aimed to examine the association between pre-pregnancy sodium (Na) intake and the development of HDP in normotensive women., Study Design: From the Japan Environment and Children's study (JECS) database, we identified 85,152 normotensive Japanese women who were recruited to the JECS between January 2011 and March 2014. Participants were categorized into five groups according to pre-pregnancy Na intake quintiles (Q1 and Q5 were the lowest and highest Na intake groups, respectively)., Main Outcome Measures: Multiple logistic regressions were performed to identify the effect of pre-pregnancy Na intake on HDP, early-onset (<34 weeks) HDP, late-onset (34 ≥ weeks) HDP, and HDP with/without small for gestational age (SGA)., Results: Using Q3 (the middle Na intake group) as the reference, multiple logistic regression showed that both the lowest (Q1) and highest (Q5) Na intake groups had an increased risk of HDP with SGA [adjusted odds ratio (aOR): 1.50, 95% confidence interval (CI): 1.02-2.21 and aOR: 1.52, 95% CI: 1.03-2.24, respectively]., Conclusions: Both lower and higher Na intake before pregnancy increases the risk of HDP with SGA in normotensive Japanese women. This finding may indicate new recommendations for Na intake before pregnancy to prevent HDP., (Copyright © 2020 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

V-ATPases are ubiquitous proton-transporting ATPases of eukaryotic and prokaryotic membranes that utilize energy from ATP hydrolysis. The hydrophilic catalytic part called V 1 -ATPase is composed of a ring-shaped hexametric A 3 B 3 complex and a central DF shaft. We previously proposed a rotation mechanism of the Enterococcus hirae V 1 -ATPase based on the crystal structures of the V 1 and A 3 B 3 complexes. However, the driving force that induces the conformational changes of A 3 B 3 and rotation of the DF shaft remains unclear. In this study, we investigated the binding affinity changes between subunits of V 1 -ATPase by surface plasmon resonance analysis. The binding of ATP to subunit A was found to considerably increase the affinity between the A and B subunits, and thereby ATP binding contributes to forming the A 1 B 1 tight conformation. Furthermore, the DF shaft bound to the reconstituted A 1 B 1 complex with high affinity, suggesting that the tight A 1 B 1 complex is a major binding unit of the shaft in the A 3 B 3 ring complex. Based on these results, we propose that rotation of the V 1 -ATPase is driven by affinity changes between each subunit via thermal fluctuations., Competing Interests: Declaration of competing interests 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 © 2020 Elsevier Inc. All rights reserved.)

Understanding the proximate factors and mechanisms driving primary production in manmade reservoirs is crucial because such production can translate into added fish yields that provide people with food and livelihoods. Furthermore, reservoir fish production could potentially compensate for the loss of fish yields due to habitat fragmentation and alterations caused by damming and impoundment. We monitored primary production, identified environmental factors responsible for its variability, and examined the relationship between primary production and fish production in nine large water bodies of the Lower Mekong Basin for 2 years. The estimated primary production ranged from 40 to 302 g C/m 2 /y and was generally greater in the wet season than in the dry season. Linear mixed-effects modelling identified the concentration of dissolved inorganic carbon as a significant fixed-effect variable regulating primary production, after variability due to random and fixed effects of water body and seasonality, respectively, were taken into account. Fish yields marginally increased with increasing primary production across the water bodies, with the estimated energy transfer efficiency ranging from 0.004 to 0.009. Dissolved inorganic carbon was partly determined by the lithological composition of the water body catchment, suggesting that the geographic locations of proposed dams determine the magnitude of primary production and hence future fish production., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Podoplanin (PDPN) is a highly O-glycosylated glycoprotein that is utilized as a specific lymphatic endothelial marker under pathophysiological conditions. We previously developed an anti-human PDPN (hPDPN) monoclonal antibody (mAb), clone LpMab-3, which recognizes the epitope, including both the peptides and the attached disialy-core-l (NeuAcα2-3Galβl-3 [NeuAcα2-6]GalNAcαl-O-Thr) structure at the Thr76 residue in hPDPN. However, it is unclear if the mAb binds directly to both the peptides and glycans. In this study, we synthesized the binding epitope region of LpMab-3 that includes the peptide (- 67 LVATSVNSV-T-GIRIEDLP 84 -) possessing a disialyl-core-1 O-glycan at Thr76, and we determined the crystal structure of the LpMab-3 Fab fragment that was bound to the synthesized glycopeptide at a 2.8 Å resolution. The six amino acid residues and two sialic acid residues are directly associated with four complementarity-determining regions (CDRs; H1, H2, H3, and L3) and four CDRs (H2, H3, L1, and L3), respectively. These results suggest that IgG is advantageous for generating binders against spacious epitopes such as glycoconjugates., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

A chemical examination of an extract from the aerial part of Oxytropis lanata led to the isolation and identification of 36 compounds, including saponins, isoflavonoids, oxazoles, and glycosides. The three among them were previously unreported oleanane-type saponins. In trypanocidal screening, 5,7,4'-trihydroxyisoflavone showed inhibitory activity against Trypanosoma congolense (IC 50  = 10.5 μM), the causative agent of African trypanosomosis in animals; this activity was similar to that of active compounds from the roots of this plant. O. lanata is known to be a traditional medicinal plant in Mongolia for the treatment of inflammatory diseases. The anti-hyaluronidase effect of saponins 3, 5, 8, and 9, (IC 50  = 0.15-0.22 mM) was stronger than that of sodium cromoglicate, which was used as a reference drug (IC 50  = 0.37 mM). The chemical structures of the new saponins were determined based on HRFABMS, 1 H and 13 C NMR, 1 H- 1 H COSY, HMQC, HMBC, and ROESY spectroscopic data along with chemical procedures., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2020. Published by Elsevier B.V.)

Objective: We investigated the quantification of the response shift-adjusted treatment effect on quality-of-life (QOL) data in a randomized controlled trial of taxane versus S-1 for patients with metastatic breast cancer (SELECT-BC)., Methods: This study was a secondary data analysis of a previously published trial. The response shift-adjusted treatment effect on health-related QOL (HRQOL) data measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) was estimated using structural equation modeling techniques in addition to quantifying the "true" treatment effect. Measurement invariances in the values of the common factor loadings, intercepts, and residual variances between before treatment and at the 3-, 6-, and 12-month visits were considered the response shift effects., Results: In the taxane group, we observed positive recalibration effects for role functioning and positive reprioritization and negative recalibration effects for emotional functioning. The observed change of -4.56 for role functioning comprised +2.26 response shifts and -6.82 "true" change. The observed change of +9.41 for emotional functioning comprised +12.43 response shifts and -1.17 "true" change. In the S-1 group, we observed positive reprioritization and negative recalibration effects for emotional functioning and positive reprioritization effects for social functioning. The observed change of +10.54 for emotional functioning comprised +10.07 response shifts and +0.47 "true" change. The observed change of +2.43 for social functioning comprised +3.50 response shifts and -1.07 "true" change., Conclusion: Detailed analysis of the response shift effects will improve the evaluation reliability of observed HRQOL data during clinical trials., (Copyright © 2020 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Background: ALN dissection (ALND) is the only way to obtain information on ALN metastasis status accurately when sentinel lymph node (SLN) metastasis is present. In this study, we established a model for intraoperatively predicting non-SLN metastasis and the presence of four or more ALNs (pN2), based on the combined use of one-step nucleic acid amplification (OSNA) and histological examination following SLN biopsy., Materials and Methods: Subjects comprised 318 consecutive breast cancer patients (cTis-3, N0) who underwent SLN biopsy with a combination of OSNA and histological examination, and who were found to have SLN metastasis and were treated by ALND. We allotted points to each patient according to their SLN metastasis status as defined by both OSNA and histology, then defined the "National Cancer Center sentinel lymph node metastatic score" (NCS score) based on the total points. Correlations between the NCS score and both non-SLN metastasis and pN2 status were analyzed by logistic regression analysis. The accuracy of this score was evaluated using receiver operating characteristic (ROC) analysis., Results: The NCS score was significantly correlated with both non-SLN metastasis and pN2 status (adjusted odds ratio: 1.26 for non-SLN metastasis, 1.56 for pN2 status). The area under the ROC curve (AUC) of the NCS score demonstrated 0.74 for non-SLN metastasis, 0.91 for pN2 status., Conclusions: The NCS score was a strong independent predictor of non-SLN metastasis and pN2 status. Use of this score will facilitate the selection of optimal adjuvant therapies without requiring unnecessary ALND., Competing Interests: Declaration of competing interest None declared., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Dissolution dynamic nuclear polarization (DNP) has wide variety of important applications such as real-time monitoring of chemical reactions and metabolic imaging. We construct DNP using photoexcited triplet electron spins (Triplet-DNP) apparatus combined with dissolution apparatus for solution NMR in a high magnetic field. Triplet-DNP enables us to obtain high nuclear polarization at room temperature. Solid-state samples polarized by Triplet-DNP are transferred to a superconducting magnet and dissolved by injecting aqueous solvents. The 13 C polarization of 0.22% has been obtained for [caryboxy- 13 C]benzoic acid-d in the liquid state. Our results show that Triplet-DNP can be applied to real-time monitoring with solution NMR., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Ankle-foot orthosis (AFO) can improve gait in stroke patients. Addition of plantar flexion resistance (PFR) can improve the first foot rocker function. However, the effect of changing the PFR on the ankle muscle force during gait training is unclear. This study aimed to determine the effect of changing the PFR of an AFO on spatiotemporal parameters (speed, bilateral step length, and cadence), peak angle of ankle plantar flexion and knee flexion, and muscle force (tibialis anterior [TA], medial head of the gastrocnemius [MGAS], and soleus) during early stance using a musculoskeletal model. Ten healthy adult men walked under five conditions: a no-AFO condition and PFR conditions 1-4. Spatiotemporal parameters and peak joint angles during the early stance phase were measured from experimental data, with muscle force estimated from simulations of a musculoskeletal model. Increasing the PFR of the AFO decreased TA muscle force and increased MGAS muscle force but had no influence on spatiotemporal parameters and joint angles. Adjustment of the PFR modifies the muscle force around the ankle, which can maximize the effect of AFO during gait training., (Copyright © 2019 Elsevier Ltd. All rights reserved.)