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A woman in her 70s who was taking warfarin 3.75 mg/day had a prothrombin time-international normalized ratio (PT-INR) within the therapeutic range. Her medication for pulmonary hypertension was changed from bosentan to macitentan. After 40 days, she developed respiratory distress, anorexia, and vomiting caused by common cold. When she visited the pharmaceutical outpatient clinic without reservation, the pharmacist suspected that bosentan discontinuation, which cancelled cytochrome P450 (CYP) 2C9 and CYP3A4 enzyme induction, and decreased vitamin K intake due to appetite loss had enhanced warfarin effect, causing PT-INR prolongation. The pharmacist requested the physician to examine the patient's PT-INR. Results showed that her PT-INR was >7. Hence, she was urgently hospitalized. Warfarin and macitentan were discontinued, and the patient's PT-INR decreased to 1.77 after the intravenous administration of vitamin K. Her appetite improved, and warfarin 2 mg/day was resumed. Additionally, when she had been administered macitentan, her hemoglobin levels decreased from 10.8 to 6.6 mg/dL. Therefore, the pharmacist and the physician during hospitalization planned to resume treatment with bosentan, but not with macitentan. The pharmacist proposed to increase the warfarin dose to 3.75 mg since the bosentan and warfarin interaction could lower PT-INR. Thereafter, the patient's PT-INR was controlled within the therapeutic range, and her hemoglobin level was 8-9 mg/dL. The patient was discharged on day 17 of admission. Thus, pharmacist intervention plays a significant role in warfarin control with consideration of drug-drug interaction in patients receiving pulmonary hypertension treatment.

Aim: Sentinel lymph node (SLN) mapping using indocyanine green (ICG) is an alternative for reducing comprehensive lymph node dissection and its associated morbidity. This trial aimed to assess the efficacy and safety of ICG for SLN detection in patients with cervical and endometrial cancers at a single academic teaching hospital., Methods: This single-arm, open-label trial conducted at Chiba University Hospital included patients with endometrial or cervical cancer, aged 20-70 years, with an Eastern Cooperative Oncology Group performance status of 0 or 1. ICG was injected into the uterine cervix after anesthesia induction. For patients with endometrial cancer, ICG was additionally injected into the uterine myometrium after laparotomy. Imaging-assisted surgery was then performed to locate and remove the SLNs. Systematic pelvic lymph node dissection was performed as the standard procedure, with additional para-aortic lymph node dissection in selected cases., Results: The overall and bilateral SLN detection rates were 80.4% (37/46) and 50.0% (23/46), respectively. SLN identification was successful in 37 patients. Of these, 34 had pathologically negative SLNs, and all of them showed no lymph node metastasis in the backup dissection (negative predictive value: 100%). The remaining three cases had pathologically positive SLNs. No adverse events were observed in a total of 49 enrolled patients., Conclusions: ICG injection was found to be safe. SLN mapping using ICG has demonstrated significant potential in reducing surgical interventions and associated complications in the treatment of early-stage gynecological cancers., (© 2025 Japan Society of Obstetrics and Gynecology.)

Objective: Therapy-related myeloid neoplasms (t-MNs) are often fatal and arise as late complications of previous anticancer drug treatment. No single-center case series has examined t-MNs in epithelial ovarian cancer (EOC)., Methods: All patients with EOC treated at Chiba University Hospital between 2000 and 2021 were included. We retrospectively analyzed the characteristics, clinical course, and outcomes of patients who developed t-MNs., Results: Among 895 cases with EOC, 814 cases were treated with anticancer drugs. The median follow-up period was 45 months (interquartile range, 27-81) months. Ten patients (1.2%) developed t-MNs (FIGO IIIA in one case, IIIC in three, IVA in one, and IVB in five). Nine patients were diagnosed with myelodysplastic syndrome and one with acute leukemia. One patient with myelodysplastic syndrome developed acute leukemia. The median time from the first chemotherapy administration to t-MN onset was 42 months (range, 21-94 months), with t-MN diagnoses resulting from pancytopenia in four cases, thrombocytopenia in three, and blast or abnormal cell morphology in four. The median number of previous treatment regimens was four (range, 1-7). Paclitaxel + carboplatin therapy was administered to all patients, gemcitabine and irinotecan combination therapy to nine, bevacizumab to eight, and olaparib to four. Six patients received chemotherapy for t-MN. All patients died (eight cancer-related deaths and two t-MN-related deaths). None of the patients was able to restart cancer treatment. The median survival time from t-MN onset was 4 months., Conclusions: Patients with EOC who developed t-MN were unable to restart cancer treatment and had a significantly worse prognosis., (© 2024 Japan Society of Obstetrics and Gynecology.)

Background: Optimised antithrombotic therapy requires clinical experience and an understanding of the current guidelines. This retrospective study aimed to evaluate whether pharmacist interviews and interventions with patients taking oral antithrombotic drugs in the pharmaceutical outpatient cardiology clinic had favourable clinical outcomes including decreased bleeding., Methods: The participants included patients visiting the outpatient clinic of cardiovascular internal medicine at the Kobe University Hospital from January-December 2017, and were taking oral antithrombotic medication. The observation period was from the first visit to the outpatient clinic to October 2021 or death. Patients who received pharmacist intervention more than twice were defined as the pharmacist intervention group. Two control patients per one pharmacist intervention group individual were selected from the non-intervention pool matched for age, gender and antithrombotic medication type., Results: Of the 895 eligible patients, 132 were in the pharmacist intervention group and 264 were selected for the matched non-intervention group. Bleeding events according to the Bleeding Academic Research Consortium criteria over type 2 were significantly lower in the pharmacist intervention group compared with the non-intervention group (17.4% versus 28.4%, P = 0.019). There were no significant differences in mortality and heart failure hospitalisation frequency, stroke, or cardiovascular events between the groups. Multivariate analysis identified age (≥ 65 years) and pharmacist intervention as factors associated with bleeding (odds ratio = 2.29 and 0.51, respectively)., Conclusion: Pharmacist intervention in the outpatient clinic of cardiovascular internal medicine was effective in reducing the risk of bleeding in patients undergoing antithrombotic therapy., (© 2023. The Author(s).)

No therapeutic drugs are currently available for nonalcoholic steatohepatitis (NASH) that progresses from nonalcoholic fatty liver via oxidative stress-involved pathways. Three cognate peroxisome proliferator-activated receptor (PPAR) subtypes (PPARα/δ/γ) are considered as attractive targets. Although lanifibranor (PPARα/δ/γ pan agonist) and saroglitazar (PPARα/γ dual agonist) are currently under investigation in clinical trials for NASH, the development of seladelpar (PPARδ-selective agonist), elafibranor (PPARα/δ dual agonist), and many other dual/pan agonists has been discontinued due to serious side effects or little/no efficacies. This study aimed to obtain functional and structural insights into the potency, efficacy, and selectivity against PPARα/δ/γ of three current and past anti-NASH investigational drugs: lanifibranor, seladelpar, and elafibranor. Ligand activities were evaluated by three assays to detect different facets of the PPAR activation: transactivation assay, coactivator recruitment assay, and thermal stability assay. Seven high-resolution cocrystal structures (namely, those of the PPARα/δ/γ-ligand-binding domain (LBD)-lanifibranor, PPARα/δ/γ-LBD-seladelpar, and PPARα-LBD-elafibranor) were obtained through X-ray diffraction analyses, six of which represent the first deposit in the Protein Data Bank. Lanifibranor and seladelpar were found to bind to different regions of the PPARα/δ/γ-ligand-binding pockets and activated all PPAR subtypes with different potencies and efficacies in the three assays. In contrast, elafibranor induced transactivation and coactivator recruitment (not thermal stability) of all PPAR subtypes, but the PPARδ/γ-LBD-elafibranor cocrystals were not obtained. These results illustrate the highly variable PPARα/δ/γ activation profiles and binding modes of these PPAR ligands that define their pharmacological actions.

Beige adipocytes are transiently induced during early postnatal period in mice. Previous studies have suggested that, unlike in adults, the induction is independent of the sympathetic nerve activity; however, the mechanism is yet unknown. Here, we showed that beige adipocytes are induced during the preweaning period in association with the formation of microbiota in mice. Alteration of gut microbiota composition in preweaning mice by maternal treatment with antibiotics or high-fat diet feeding substantially suppressed WAT browning. The suppression was also found in pups transplanted cecal microbiota from pups of high-fat diet-fed dams. These treatments reduced the hepatic expression of genes involved in bile acid synthesis and the serum bile acids level. The abundance of Porphyromonadaceae and Ruminococcaceae in microbiota showed a positive and negative correlation with the induction of beige adipocytes, respectively. This finding may provide comprehensive understanding of the association between gut microbiota and adipose tissue development in the neonatal period., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

We conducted a phase Ib study to examine the safety of a combination of carbon-ion RT (CIRT) with durvalumab (MEDI4736; AstraZeneca) in patients with locally advanced cervical cancer. This was an open-label, single-arm study with a modified 3 + 3 design. Patients with newly diagnosed histologically proven locally advanced cervical cancer were enrolled. All patients received 74.4 Gy of CIRT in 20 fractions and concurrent weekly cisplatin (chemo-CIRT) at a dose of 40 mg/m 2 . Durvalumab was administered (1500 mg/body) at weeks two and six. The primary endpoint was the incidence of adverse events (AEs) and serious AEs (SAEs), including dose-limiting toxicity (DLT). All three enrolled patients completed the treatment without interruption. One patient developed hypothyroidism after treatment and was determined to be an SAE. No other SAEs were observed. The patient recovered after levothyroxine sodium hydrate treatment. None of the AEs, including hypothyroidism, were associated with DLT in the present study. All three patients achieved complete responses within the CIRT region concerning treatment efficacy. This phase 1b trial demonstrates the safety of combining chemo-CIRT and durvalumab for locally advanced cervical cancer in the early phase. Further research is required as only three patients were included in this study.

Objectives: We investigated prospectively whether, in cervical cancer (CC) treated with concurrent chemoradiotherapy (CCRT), the Apparent diffusion coefficient (ADC) histogram and texture parameters and their change rates during treatment could predict prognosis., Methods: Fifty-seven CC patients treated with CCRT at our institution were included. They underwent MRI scans up to four times during the treatment course (1st, before treatment [n = 41], 2nd, at the start of image-guided brachytherapy (IGBT) [n = 41], 3rd, in the middle of IGBT [n = 27], 4th, after treatment [n = 53]). The entire tumor was manually set as the volume of interest (VOI) manually in the axial images of the ADC map by two radiologists. A total of 107 image features (morphology features 14, histogram features 18, texture features 75) were extracted from the VOI. The recurrence prediction values of the features and their change rates were evaluated by Receiver operating characteristics (ROC) analysis. The presence or absence of local and distant recurrence within two years was set as an outcome. The intraclass correlation coefficient (ICC) was also calculated., Results: The change rates in kurtosis between the 1st and 3rd, and 1st and 2nd MRIs, and the change rate in grey level co-occurrence matrix_cluster shade between the 2nd and 3rd MRIs showed particularly high predictive powers (area under the ROC curve = 0.785, 0.759, and 0.750, respectively), which exceeded the predictive abilities of the parameters obtained from pre- or post-treatment MRI only. The change rate in kurtosis between the 1st and 2nd MRIs had good reliability (ICC = 0.765)., Conclusions: The change rate in ADC kurtosis between the 1st and 2nd MRIs was the most reliable parameter, enabling us to predict prognosis early in the treatment course., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Takada et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Water scarcity is a serious agricultural problem causing significant losses to crop yield and product quality. The development of technologies to mitigate the damage caused by drought stress is essential for ensuring a sustainable food supply for the increasing global population. We herein report that the exogenous application of ethanol, an inexpensive and environmentally friendly chemical, significantly enhances drought tolerance in Arabidopsis thaliana, rice and wheat. The transcriptomic analyses of ethanol-treated plants revealed the upregulation of genes related to sucrose and starch metabolism, phenylpropanoids and glucosinolate biosynthesis, while metabolomic analysis showed an increased accumulation of sugars, glucosinolates and drought-tolerance-related amino acids. The phenotyping analysis indicated that drought-induced water loss was delayed in the ethanol-treated plants. Furthermore, ethanol treatment induced stomatal closure, resulting in decreased transpiration rate and increased leaf water contents under drought stress conditions. The ethanol treatment did not enhance drought tolerance in the mutant of ABI1, a negative regulator of abscisic acid (ABA) signaling in Arabidopsis, indicating that ABA signaling contributes to ethanol-mediated drought tolerance. The nuclear magnetic resonance analysis using 13C-labeled ethanol indicated that gluconeogenesis is involved in the accumulation of sugars. The ethanol treatment did not enhance the drought tolerance in the aldehyde dehydrogenase (aldh) triple mutant (aldh2b4/aldh2b7/aldh2c4). These results show that ABA signaling and acetic acid biosynthesis are involved in ethanol-mediated drought tolerance and that chemical priming through ethanol application regulates sugar accumulation and gluconeogenesis, leading to enhanced drought tolerance and sustained plant growth. These findings highlight a new survival strategy for increasing crop production under water-limited conditions., (© The Author(s) 2022. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists.)

We describe a 46-year-old woman who developed multiple cerebral infarctions in the left middle cerebral artery territory and deep vein thrombosis, presumably related to uterine adenomyosis. Uterine adenomyosis can cause coagulation abnormalities, as observed in Trousseau's syndrome. Along with previous reports, our case experienced a stroke during menstruation and presented with increased cancer antigen 125 (CA125) levels. A hysterectomy was performed to prevent the recurrence of cerebral infarction. Our case also had complicated deep vein thrombosis, which is also known as a complication of uterine adenomyosis. We consider cerebral infarction and deep vein thrombosis with uterine adenomyosis might be caused by a common mechanism, hypercoagulation. Hysterectomy requires careful discussion before undergoing it because of fertility problems, but it might be the most effective approach for preventing the recurrence of brain infarction derived from adenomyosis and may be effective for both cerebral infarction and deep vein thrombosis., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Tamura et al.)

Objective: To evaluate the effect of head-down tilt on airway pressure in gynecologic patients with obesity during robot-assisted hysterectomy., Methods: We retrospectively reviewed the records of 27 patients with body mass index (BMI) ≥ 25 kg/m 2 who underwent robot-assisted hysterectomy for endometrial cancer and endometrial atypical hyperplasia using the da Vinci Xi system. Mechanical ventilation was performed using pressure-controlled ventilation (PCV). Surgery was performed at 20° (group A, n = 17) or 25° head-down tilt (group B, n = 10). Respiratory parameters, including positive end-expiratory pressure (PEEP), tidal volume (TV), mean airway pressure (P mean), and peak airway pressure (P peak), were measured before (T1) and after the head-down tilt at 1 h (T2) and 2 h (T3) during anesthesia., Results: The median BMI was 37.5 (range 28-51) kg/m 2 , with no between-group variation. Oxygenation was maintained intraoperatively for all patients. The expiratory carbon dioxide partial pressure was 43.6 (95% confidence interval (CI) 42.2-45.0) mmHg. The P mean peak at T2 in group B was significantly higher than in group A (P < 0.011); however, other parameters at T2 and T3 did not differ significantly between the groups. Patients with BMI ≥ 40 kg/m 2 had significantly higher respiratory parameters than those with BMI < 40 kg/m 2 . In patients with BMI ≥ 40 kg/m 2 , the mean P means and P peaks at T3 were 17.3 cmH 2 O (95% CI 16.3-18.3) and 29.4 cmH 2 O (95% CI 27.1-31.7), respectively., Discussion: With careful anesthetic management during PCV, robot-assisted surgery with a head-down tilt of 25° or below may be safe, even in patients with class III obesity., 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., (© 2022 The Authors.)

Among the agonists against three peroxisome proliferator-activated receptor (PPAR) subtypes, those against PPARα (fibrates) and PPARγ (glitazones) are currently used to treat dyslipidemia and type 2 diabetes, respectively, whereas PPARδ agonists are expected to be the next-generation metabolic disease drug. In addition, some dual/pan PPAR agonists are currently being investigated via clinical trials as one of the first curative drugs against nonalcoholic fatty liver disease (NAFLD). Because PPARα/δ/γ share considerable amino acid identity and three-dimensional structures, especially in ligand-binding domains (LBDs), clinically approved fibrates, such as bezafibrate, fenofibric acid, and pemafibrate, could also act on PPARδ/γ when used as anti-NAFLD drugs. Therefore, this study examined their PPARα/δ/γ selectivity using three independent assays-a dual luciferase-based GAL4 transactivation assay for COS-7 cells, time-resolved fluorescence resonance energy transfer-based coactivator recruitment assay, and circular dichroism spectroscopy-based thermostability assay. Although the efficacy and efficiency highly varied between agonists, assay types, and PPAR subtypes, the three fibrates, except fenofibric acid that did not affect PPARδ-mediated transactivation and coactivator recruitment, activated all PPAR subtypes in those assays. Furthermore, we aimed to obtain cocrystal structures of PPARδ/γ-LBD and the three fibrates via X-ray diffraction and versatile crystallization methods, which we recently used to obtain 34 structures of PPARα-LBD cocrystallized with 17 ligands, including the fibrates. We herein reveal five novel high-resolution structures of PPARδ/γ-bezafibrate, PPARγ-fenofibric acid, and PPARδ/γ-pemafibrate, thereby providing the molecular basis for their application beyond dyslipidemia treatment.

We fabricated nanostructured Ge and GeSn films using He radio-frequency magnetron plasma sputtering deposition. Monodisperse amorphous Ge and GeSn nanoparticles of 30-40 nm size were arranged without aggregation by off-axis sputtering deposition in the high He-gas-pressure range of 0.1 Torr. The Ge film porosity was over 30%. We tested the charge/discharge cycle performance of Li-ion batteries with nanostructured Ge and GeSn anodes. The Ge anode with a dispersed arrangement of nanoparticles showed a Li-storage capacity of 565 mAh/g after the 60th cycle. The capacity retention was markedly improved by the addition of 3 at% Sn in Ge anode. The GeSn anode (3 at% Sn) achieved a higher capacity of 1128 mAh/g after 60 cycles with 92% capacity retention. Precise control of the nano-morphology and electrical characteristics by a single step procedure using low temperature plasma is effective for stable cycling of high-capacity Ge anodes., (© 2022. The Author(s).)

Objective: We aimed to evaluate the prevalence of pulmonary embolism (PE) before cancer therapies in patients with ovarian and endometrial cancers with enhanced computed tomography (CT) using D-dimer (DD), and determine the optimal cut-off level of DD., Methods: Since 2009, we have performed preoperative venous thromboembolism (VTE) screening of patients with ovarian and endometrial cancer. For patients with DD levels of more than 1.0 μg/ml, enhanced CT images were obtained from the pulmonary apex to the foot to detect PE and deep venous thrombosis (DVT) simultaneously., Results: Among patients with ovarian cancer, 84 of 413 (20.3%) had VTEs (DVT alone, n = 31 [7.5%]; PE with or without DVT, n = 53 [12.8%]; PE alone, n = 12 [2.9%]). Among patients with endometrial cancer, 50 of 455 (11.0%) had VTEs (DVT alone, n = 19 [4.2%]; PE with or without DVT, n = 31 [6.8%], PE alone, n = 14 [3.1%]). The optimal cut-off level of DD was estimated to be ≥1.5 and ≥1.2 μg/ml in ovarian and endometrial cancers, respectively., Conclusion: Our study revealed a high prevalence of PE before cancer therapies in patients with ovarian and endometrial cancers by enhanced CT using DD., (© 2021 Wiley Periodicals LLC.)

Conferring drought resistant traits to crops is one of the major aims of current breeding programs in response to global climate changes. We previously showed that exogenous application of acetic acid to roots of various plants could induce increased survivability under subsequent drought stress conditions, but details of the metabolism of exogenously applied acetic acid, and the nature of signals induced by its application, have not been unveiled. In this study, we show that rice rapidly induces jasmonate signaling upon application of acetic acid, resulting in physiological changes similar to those seen under drought. The major metabolite of the exogenously applied acetic acid in xylem sap was determined as glutamine-a common and abundant component of xylem sap-indicating that acetic acid is not the direct agent inducing the observed physiological responses in shoots. Expression of drought-responsive genes in shoot under subsequent drought conditions was attenuated by acetic acid treatment. These data suggest that acetic acid activates root-to-shoot jasmonate signals that partially overlap with those induced by drought, thereby conferring an acclimated state on shoots prior to subsequent drought.