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Background and Aims: The common genetic variant rs641738 C>T is a risk factor for metabolic dysfunction-associated steatotic liver disease and metabolic dysfunction-associated steatohepatitis (MASH), including liver fibrosis, and is associated with decreased expression of the phospholipid-remodeling enzyme MBOAT7 (LPIAT1). However, whether restoring MBOAT7 expression in established metabolic dysfunction-associated steatotic liver disease dampens the progression to liver fibrosis and, importantly, the mechanism through which decreased MBOAT7 expression exacerbates MASH fibrosis remain unclear., Approach and Results: We first showed that hepatocyte MBOAT7 restoration in mice with diet-induced steatohepatitis slows the progression to liver fibrosis. Conversely, when hepatocyte-MBOAT7 was silenced in mice with established hepatosteatosis, liver fibrosis but not hepatosteatosis was exacerbated. Mechanistic studies revealed that hepatocyte-MBOAT7 restoration in MASH mice lowered hepatocyte-TAZ (WWTR1), which is known to promote MASH fibrosis. Conversely, hepatocyte-MBOAT7 silencing enhanced TAZ upregulation in MASH. Finally, we discovered that changes in hepatocyte phospholipids due to MBOAT7 loss-of-function promote a cholesterol trafficking pathway that upregulates TAZ and the TAZ-induced profibrotic factor Indian hedgehog (IHH). As evidence for relevance in humans, we found that the livers of individuals with MASH carrying the rs641738-T allele had higher hepatocyte nuclear TAZ, indicating higher TAZ activity and increased IHH mRNA., Conclusions: This study provides evidence for a novel mechanism linking MBOAT7-LoF to MASH fibrosis, adds new insight into an established genetic locus for MASH, and, given the druggability of hepatocyte TAZ for MASH fibrosis, suggests a personalized medicine approach for subjects at increased risk for MASH fibrosis due to inheritance of variants that lower MBOAT7., (Copyright © 2024 American Association for the Study of Liver Diseases.)

The concomitant use of IMPELLA and veno-arterial extracorporeal membrane oxygenation (V-A ECMO) (ECPELLA) has been increasingly used to treat severe cardiogenic shock. However, the relationship between severity of heart failure on admission and prognosis based on differences in the mechanical circulatory support (MCS) is not fully understood. This study evaluated the association between lactate levels on admission and clinical outcomes based on differences in MCS. We identified 852 patients (median age 71 years; 78% male) with cardiogenic shock due to ST-elevation myocardial infarction (STEMI) from the Japanese Registry for Percutaneous Ventricular Assist Devices. The primary endpoint was the in-hospital mortality rate. Additionally, patients were classified into three groups based on lactate levels according to the SCAI SHOCK classification for the assessment of in-hospital mortality: group 1 (lactate level < 2 mmol/L), group 2 (lactate level 2-8 mmol/L), and group 3 (lactate level ≥ 8 mmol/L). The in-hospital mortality rate was 41.8%. The rate of V-A ECMO combined with IMPELLA use was 37.6%. The in-hospital mortality rates of the IMPELLA alone and ECPELLA group were 30.1% and 61.3%, respectively. The median lactate level was significantly higher in non-survivors than in survivors (5.7 mmol/L vs. 3.5 mmol/L, p < 0.0001). The in-hospital mortality rate with IMPELLA alone was significantly higher in group 3 compared to groups 1 and 2; however, there was no difference in in-hospital mortality with ECPELLA among the three groups. A lactate cut-off value of 6.9 mmol/L showed the best discrimination for in-hospital mortality. Patients classified as the SCAI SHOCK stage E have a higher mortality rate with IMPELLA support alone. Further research is needed to optimize management strategies for this high-risk group., Competing Interests: Declarations. Conflict of interest: Drs. Yahagi and Tanabe have received lecture fee from Abiomed Japan. All other authors have no relationships relevant to the contents of this article to disclose., (© 2025. Springer Nature Japan KK, part of Springer Nature.)

The therapeutic time window for endovascular therapy in acute stroke patients with large-vessel occlusion was extended to 24 hours from onset. Although a retrospective study showed the efficacy of endovascular therapy beyond 24 hours from the last known well, it remains unclear whether endovascular therapy is effective. Extending the time window of Endovascular therapy in the Triage of Late Presenting Strokes beyond 24 h (SKIP-EXTEND trial) aimed to clarify the efficacy of endovascular therapy compared to the best medical management. This is an investigator-initiated, multicenter, prospective, randomized, open-label, blinded end-point clinical trial. Eligibility criteria included adults and pre-stroke modified Rankin scale score ≤2 with internal carotid artery or M1 (horizontal or sphenoidal segment) occlusion beyond 24 to 72 hours of the last known well. The target enrollment is 260 patients, with 130 reeiving endovascular therapy and 130 receiving the best medical treatment. The primary outcome is the rate of favorable outcome defined as a modified Rankin scale score ≤2 at 90 days. The secondary outcomes are the ordinal logistic regression analysis of the modified Rankin scale score and the rate of recanalization at 48 hours. As safety outcomes, the rate of any and symptomatic intracranial hemorrhage at 24 hours and the rate of mortality at 90 days are assessed. This is the first randomized controlled trial to focus on the efficacy of endovascular therapy beyond 24 hours. Our results will not only benefit patients but also reduce healthcare costs. We believe that this novel study will be useful in clinical practice.

Background: Infarct volume on diffusion-weighted imaging (DWI) is a promising imaging marker for clinical outcomes in patients with acute stroke treated with mechanical thrombectomy (MT), but its predictive value has not been well evaluated, especially in consecutive patients. The present study aimed to elucidate the relationship between infarct volume and its change and favorable functional outcomes in consecutive patients with acute stroke who underwent MT., Method: Of patients with consecutive acute stroke who underwent MT from September 2014 through December 2019, those who were pre-morbidly independent were enrolled. Infarct volume on DWI was measured at admission (DWI initial ) and 24 h after admission (DWI 24h ) with semi-automated imaging software. Infarct growth (IG) was calculated as the difference between DWI 24h and DWI initial . Factors associated with a favorable outcome (mRS score 0-2) 3 months after stroke onset were assessed by multivariable analyses. Model performance was evaluated with the C-statistic., Results: A total of 251 patients (165 male [66 %], median age 75 [IQR 67-81] years, median NIHSS score 15 [7-21]) were enrolled in the present study. Multivariable logistic regression analysis showed that DWI 24h (OR 0.74, 95 % CI 0.62-0.87 for every 10-mL increment) and IG (0.74, 0.62-0.88 for every 10-mL increment) were independently and negatively associated with a favorable outcome. These associations were observed in patients with diverse vessel occlusions. Adding DWI 24h or IG to the conventional predictors of favorable outcomes improved predictive accuracy (p < 0.05)., Conclusion: DWI infarct volume 24 h after admission and IG can be strong imaging predictors of favorable outcomes after MT., Competing Interests: Declaration of competing interest This work was partly supported by JSPS KAKENHI Grant Number JP23K19574, Research fund of Mitsukoshi Health and Welfare Foundation 2024, and Grants-in-aid for medical research from Kitsuokai., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: The effectiveness of glucagon-like peptide-1 receptor agonists (GLP1Ras) for prevention of heart failure (HF) in patients with type 2 diabetes (T2DM) without HF and for risk of death in patients with T2DM with HF has not been fully elucidated in routine clinical practice., Methods: Using the real-world global electronic medical record TriNetX database, individuals with T2DM and with or without HF who initiated either GLP1Ras or sitagliptin from 2017 to 2020 were retrospectively analyzed. In individuals with T2DM without HF, the primary outcome was a composite of all-cause mortality and a new diagnosis of HF within three years. In individuals with T2DM with HF, the primary outcome was all-cause mortality within three years. Propensity-score (PS) matching was used to adjust for over 100 baseline characteristics., Results: A total of 65,598 individuals with T2DM without HF starting a GLP1Ras were PS matched with 65,598 starting sitagliptin. GLP1Ras were associated with a lower incidence of the composite endpoint (10.5 % versus 11.8 %, hazard ratio [HR] 0.82, [0.80-0.85], p < 0.001), mortality (HR 0.66 [0.63-0.69]) and new diagnosis of HF (HR 0.92 [0.88-0.96]). There were 6002 individuals in each group matched for T2DM and HF. Mortality was lower in the GLP1Ras group (17.6 % versus 22.8 %, HR 0.70 [0.65-0.76], p < 0.001). Results were consistent across subgroups., Conclusions: In this global real-world data analysis, GLP1Ra use was associated with a lower risk of death and HF in individuals with T2DM without HF, and lower risk of death in those with HF., Competing Interests: Declaration of competing interest Yu Horiuchi received honoraria from TriNetX, Nippon Boehringer Ingelheim, Ono Pharmaceutical Company, AstraZeneca, Kyowa Kirin, Sanofi and Eli Lilly Japan. Nicholas Wettersten received grants from Department of Veterans Affairs National Institutes of Health, consulting fees from Guidepoint and honoraria from San Diego Heart Failure Symposium. Masahiko Asami received honoraria from Astellas, Daiichi Sankyo, AstraZeneca and Kyowa Kirin. Kazuyuki Yahagi received honoraria from Daiichi Sankyo and Nippon Boehringer Ingelheim. Hitomi Yuzawa received honoraria from Daiichi Sankyo. Kota Komiyama received honoraria from Astellas, Daiichi Sankyo, Ono Pharmaceutical and Kowa. Jun Tanaka received honoraria from Eli Lilly Japan, Novo Nordisk and Daiichi Sankyo. Jiro Aoki received honoraria from Daiichi Sankyo, Ono Pharmaceutical and Kowa, and has stock of Eli Lilly and Novo Nordisk. Kengo Tanabe received honoraria from Eli Lilly Japan, Novo Nordisk, Daiichi Sankyo, Ono Pharmaceutical, Industry, AstraZeneca and Kowa., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Anatomical representation of site-specific clustering of biomolecules is a powerful way of predicting a potential interaction among signaling cascades and orchestrating molecular functions in cells and organs. The greater the number of molecules visualized simultaneously, the deeper we can understand each molecule's role in cellular metabolism and function. In the present study, we investigated site-specific localization of small biomolecules in the slug using Space and Time Coherent Mapping (STCM), a key technology in matrix-assisted laser desorption ionization time-of-flight imaging mass spectrometry. We acquired mass measurements and mass-based molecular images simultaneously under the microscope-mode instrumentation developed specifically in our laboratory. Mass images were generated in the increment of 0.2 in the mass-to-charge ratio ( m / z ) with spatial resolution of 2 μm. Resultant images were unique in each mass increment and allowed us to predict anatomical site-specific clustering of bioactive signaling molecules. We suggest that STCM is a useful tool to promote the compilation of comprehensive molecular maps and understand the role of individual molecules and their interactive mechanisms in situ.

Scrub typhus (tsutsugamushi disease) is an acute febrile illness caused by Orientia tsutsugamushi , often found in Asia and Oceania. The presence of an eschar, characterized by a crust, is a key diagnostic finding. Many symptoms of this disease are already known, however reactive arthritis following scrub typhus is very rare. Here, we present a case of 79-year-old man who was referred to our hospital because of continuous fever and left shoulder pain. We found 4-fold rise in Orientia tsutugamushi -specific IgG titer using paired serum samples and Orientia sp. genes by real-time PCR from a crust of right thigh. And the left shoulder joint image was consistent with aseptic arthritis; thus we diagnosed as scrub typhus with reactive arthritis. This case highlights the importance of recognizing reactive arthritis as a symptom of scrub typhus. In this report, we also review published cases of reactive arthritis associated with scrub typhus, and we suppose that this arthritis related to this infection may recover after antibiotic use and have a good prognosis. Physicians' awareness of newly appeared arthritis may contribute to facilitate early diagnosis, and may improve the course of such patients., 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., (© 2025 The Authors. Published by Elsevier Ltd.)

As current methods of production of phycocyanobilin, a photosynthetic blue pigment derived from phycocyanin of filamentous cyanobacteria, Pseudanabaena sp. ABRG5-3, Limnothrix sp. SK1-2-1, and Spirulina sp., exhibit a low extraction efficiency, a new extraction method using ethanol extraction as a type of solvolysis with an autoclave (130 ℃, 5.7 bar, 10 min) was developed in this study. This method exhibited high efficiency and enabled easy recovery of the three types of phycocyanobilins. The identity of the three types of phycocyanobilins was confirmed by high-performance liquid chromatography and electrospray ionization-tandem mass spectrometry. Phycocyanobilins were stable at high temperatures (80 ℃) and acidic (pH 3) conditions. Phycocyanobilins also possessed a remarkable antioxidant property. This is the first time that a simple phycocyanobilin extraction method with a recovery rate of more than 60 % and approximately 1 % per dry cell weight of filamentous cyanobacteria has been demonstrated. This novel production method is thus convenient and effective for obtaining high-purity phycocyanobilins., 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 Elsevier B.V. All rights reserved.)

Objectives: Heart failure may result in reduced brain perfusion, limiting the blood flow needed to achieve clinical recovery. We investigated whether plasma levels of brain natriuretic peptide (BNP), a biological marker of heart failure, were related to clinical outcomes after mechanical thrombectomy (MT)., Materials and Methods: Data were analyzed from stroke patients with internal carotid or middle cerebral artery occlusion enrolled in the SKIP trial for whom plasma level of BNP was evaluated on admission. Favorable outcome was defined as a modified Rankin scale score of 0-2 at 3 months., Results: Among 169 patients (median age, 74 years; 62% men, median National Institutes of Health Stroke Scale score, 18), 104 (62%) achieved favorable outcomes. Median plasma BNP level was lower in the favorable outcome group (124.1 pg/mL; interquartile range [IQR], 62.1-215.5 pg/mL) than in the unfavorable outcome group (198.0 pg/mL; IQR, 74.8-334.0 pg/mL; p=0.005). In multivariate regression analysis, the adjusted odds ratio for BNP for favorable outcomes was 0.971 (95% confidence interval, 0.993-0.999; p=0.048). At 3 months after onset, the favorable outcome rate was lower in the ≥186 pg/mL group (45%) than in the <186 pg/mL group (72%; p=0.001). This significant difference remained regardless of the presence of atrial fibrillation (AF), with rates of 47% and 76%, respectively, in AF patients (p=0.003) and 33% and 68%, respectively, in patients without AF (p=0.046)., Conclusion: High plasma BNP concentration appears associated with unfavorable outcomes after MT., Competing Interests: Declaration of competing interest Kazumi Kimura received lecture fees from Bristol-Myers Squibb Co. Ltd., Nippon Boehringer Ingelheim Co. Ltd., Bayer Healthcare Co. Ltd., and Daiichi Sankyo Co.; research funding from Nippon Boehringer Ingelheim Co. Ltd., Daiichi Sankyo Co., Pfizer Japan Inc., Medtronic Co. Ltd., and Teijin Pharma Ltd.; and personal funding from the 38th Mihara Cerebrovascular Disorder Research Promotion Fund Ltd. Masataka Takeuchi received lecture fees from Stryker Co. Ltd. Shigeru Fujimoto received lecture fees from Nippon Boehringer Ingelheim Co. Ltd., Daiichi Sankyo Co. Ltd., Pfizer Japan Inc., Bristol-Myers Squibb Co. Ltd., Bayer Healthcare Co. Ltd., and Takeda Pharmaceutical Co. Ltd. Teruyuki Hirano received lecture fees from Bayer Healthcare Co. Ltd., Daiichi Sankyo Co. Ltd., Nippon Boehringer Ingelheim Co. Ltd., Bristol-Myers Squibb Co. Ltd., Medtronic Co. Ltd, Sanofi Co. Ltd. Otsuka Pharmaceutical Co. Ltd., Mitsubishi Tanabe Pharma Co., CSL Behring K.K., Astellas Pharma Inc., and Pfizer Japan Inc. Yasuhiro Nishiyama received lecture fees from Daiichi Sankyo Co. Ltd. Yasuyuki Iguchi received lecture fees from Bayer Healthcare Co. Ltd., Pfizer Japan Inc., Nippon Boehringer Ingelheim Co. Ltd., Takeda Pharmaceutical Co. Ltd., Otsuka Pharmaceutical Co. Ltd., and Daiichi Sankyo Co. Ltd.; and research funding from Sanofi Co. Ltd. Yuki Kamiya received lecture fees from Daiichi Sankyo Co. Ltd.; and research funding from Bristol-Myers Squibb Co. Ltd. Yuji Matsumaru received lecture fees from Medtronic Co. Ltd, Stryker Co. Ltd, Sanofi Co. Ltd., Daiichi Sankyo Co. Ltd., Otsuka Pharmaceutical Co. Ltd., and Biomedical solutions., (Copyright © 2024. Published by Elsevier Inc.)

Background: The global use of angiotensin receptor neprilysin inhibitor (ARNI) in clinical practice, especially in patients with heart failure and below-normal ejection fraction (HFbnEF), has not been thoroughly evaluated. We aimed to investigate the characteristics, outcomes, and adverse events in patients treated with ARNI for HF with reduced (HFrEF), below-normal (HFbnEF), and supranormal left ventricular EF (HFsnEF)., Methods: This observational study analyzed data from the electronic healthcare records (EHR) of patients with HF treated with ARNI between 2015 and 2022 in North and South America, Europe, the Middle East, Africa, and Asia-Pacific. Based on the left ventricular EF, patients were categorized as HFrEF (< 40%), HFbnEF (40-60%), and HFsnEF (> 60%). Mortality and the incidence of adverse events were investigated., Results: Of the 11,141 patients analyzed, HFrEF, HFbnEF and HFsnEF accounted for 74%, 22%, and 4%, respectively. Patients with a higher EF were more likely to be older, female, and obese. Hypertension and atrial fibrillation were the most common in HFsnEF. Systolic blood pressure was lower and natriuretic peptide levels were higher in the lower EF groups. Mortality was lowest in HFbnEF (7.7 per 100 patient-years follow-up in HFrEF, 5.8 in HFmrEF, and 6.0 in HFsnEF). Similarly, hypotension and acute kidney injury were the least frequent in HFbnEF. Incidence of elevated serum potassium levels was similar between the groups., Conclusions: In this analysis of large-scale EHR, ARNI was mainly used in HFrEF and HFbnEF, consistent with previous randomized trials and pooled analyses. Adverse events were less common in HFbnEF., (© 2024. Springer Nature Japan KK, part of Springer Nature.)

This is the first consensus statement of the Joint Committee on Renal Denervation of the Japanese Society of Hypertension (JSH)/Japanese Association of Cardiovascular Intervention and Therapeutics (CVIT)/Japanese Circulation Society (JCS). The consensus is that the indication for renal denervation (RDN) is resistant hypertension or "conditioned" uncontrolled hypertension, with high office and out-of-office blood pressure (BP) readings despite appropriate lifestyle modification and antihypertensive drug therapy. "Conditioned" uncontrolled hypertension is defined as having one of the following: (1) inability to up-titrate antihypertensive medication due to side effects, the presence of complications, or reduced quality of life. This includes patients who are intolerant of antihypertensive drugs; or (2) comorbidity at high cardiovascular risk due to increased sympathetic nerve activity, such as orthostatic hypertension, morning hypertension, nocturnal hypertension, or sleep apnea (unable to use continuous positive airway pressure), atrial fibrillation, ventricular arrythmia, or heart failure. RDN should be performed by the multidisciplinary Hypertension Renal Denervation Treatment (HRT) team, led by specialists in hypertension, cardiovascular intervention and cardiology, in specialized centers validated by JSH, CVIT, and JCS. The HRT team reviews lifestyle modifications and medication, and the patient profile, then determines the presence of an indication of RDN based on shared decision making with each patient. Once approval for real-world clinical use in Japan, however, the joint RDN committee will update the indication and treatment implementation guidance as appropriate (annually if necessary) based on future real-world evidence., (© 2024. The Author(s).)

Objective: To date, there are no widely implemented machine learning (ML) models that predict progression from prediabetes to diabetes. Addressing this knowledge gap would aid in identifying at-risk patients within this heterogeneous population who may benefit from targeted treatment and management in order to preserve glucose metabolism and prevent adverse outcomes. The objective of this study was to utilize readily available laboratory data to train and test the performance of ML-based predictive risk models for progression from prediabetes to diabetes. Methods: The study population was composed of laboratory information services data procured from a large U.S. outpatient laboratory network. The retrospective dataset was composed of 15,029 adults over a 5-year period with initial hemoglobin A1C (A1C) values between 5.0% and 6.4%. ML models were developed using random forest survival methods. The ground truth outcome was progression to A1C values indicative of diabetes (i.e., ≥6.5%) within 5 years. Results: The prediabetes risk classifier model accurately predicted A1C ≥6.5% within 5 years and achieved an area under the receiver-operator characteristic curve of 0.87. The most important predictors of progression from prediabetes to diabetes were initial A1C, initial serum glucose, A1C slope, serum glucose slope, initial HDL, HDL slope, age, and sex. Conclusions: Leveraging readily obtainable laboratory data, our ML risk classifier accurately predicts elevation in A1C associated with progression from prediabetes to diabetes. Although prospective studies are warranted, the results support the clinical utility of the model to improve timely recognition, risk stratification, and optimal management for patients with prediabetes.

Objective Although the body mass index (BMI) is considered a meaningful parameter for evaluating obesity, the association between the BMI and acute non-cardioembolic stroke remains unclear. We investigated how the BMI was related to patients' background, type of infarction, and infarction location in patients with non-cardioembolic stroke using an acute dual study (ADS) cohort. Methods The ADS trial was conducted between May 2011 and June 2017 in Japan. The BMI classifications were those proposed by the World Health Organization classification: underweight, <18.5 kg/m 2 ; normal weight, 18.5-24.9 kg/m 2 ; overweight, 25-29.9 kg/m 2 ; and obese, ≥30 kg/m 2 . Results Data from 1,136 patients were analyzed. The median BMI was 23.6 kg/m 2 (interquartile range: 21.6-25.8 kg/m 2 ), with a BMI ≥30 kg/m 2 in 63 patients (6%), 25-29.9 kg/m 2 in 321 (28%), 18.5-24.9 kg/m 2 in 692 (61%), and <18.5 kg/m 2 in 60 (5%). The group with a BMI ≥30 kg/m 2 was the youngest, and the group with a BMI <18.5 kg/m 2 was the oldest (p<0.001). The proportion of patients with a history of hypertension (p<0.001), diabetes (p<0.001), dyslipidemia (p<0.001), and statin therapy (p=0.005) increased with increasing BMI. Pontine infarcts were frequent in the following order: obese, overweight, normal weight, and underweight (24%, 18%, 14%, and 13%, respectively; p=0.034). In contrast, cortical infarct were frequent in the order of underweight, normal weight, overweight, and obese at 20%, 19%, 14%, and 3%, respectively (p=0.007). Conclusion Acute stroke patients with a high BMI have more atherosclerosis-related factors in their backgrounds than those with lower BMIs. In addition, the BMI may be a determinant of infarct location in patients with acute stroke.

Bitter taste receptors (TAS2Rs) are not only expressed in the oral cavity but also in skin. Extraoral TAS2Rs are thought to be involved in non-taste perception and tissue-specific functions. Keratinocytes that express TAS2Rs in the skin provide a first-line defense against external threats. However, the functional roles of these receptors in host defense remain unclear. Here, we demonstrated the sensory role of intracellularly located TAS2Rs against toxic substances in keratinocytes. Although many G protein-coupled receptors elicit signals from the surface, TAS2Rs were found to localize intracellularly, possibly to the ER, in human keratinocytes and HaCaT cells. TAS2R38, one of the TAS2R members, activated the G α12/13 /RhoA/ROCK/p38 MAP kinase/NF-κB pathway upon stimulation by phenylthiocarbamide (PTC), an agonist for this receptor, leading to the production of ABC transporters, such as ABCB1, in these cells. Notably, treatment with bitter compounds, such as PTC and saccharin, induced the upregulation of ABCB1 in HaCaT cells. Mechanistically, intracellular TAS2R38 and its downstream signaling G α12/13 /RhoA/ROCK/p38 MAP kinase/NF-κB pathway were identified to be responsible for the above effect. Pretreatment with PTC prevented the accumulation of rhodamine 123 because of its excretion via ABCB1. Furthermore, pretreatment with PTC or saccharin counteracted the effect of the toxic compound, diphenhydramine, and pretreated HaCaT cells were found to proliferate faster than untreated cells. This anti-toxic effect was suppressed by treatment with verapamil, an ABCB1 inhibitor, indicating that enhanced ABCB1 helps clear toxic substances. Altogether, harmless activators of TAS2Rs may be promising drugs that enhance the excretion of toxic substances from the human skin., (©2024 The Authors FASEB BioAdvances published by The Federation of American Societies for Experimental Biology.)

Interaction of mast cells (MCs) with fibroblasts is essential for MC maturation within tissue microenvironments, although the underlying mechanism is incompletely understood. Through a phenotypic screening of >30 mouse lines deficient in lipid-related genes, we found that deletion of the lysophosphatidic acid (LPA) receptor LPA 1 , like that of the phospholipase PLA2G3, the prostaglandin D 2 (PGD 2 ) synthase L-PGDS, or the PGD 2 receptor DP1, impairs MC maturation and thereby anaphylaxis. Mechanistically, MC-secreted PLA2G3 acts on extracellular vesicles (EVs) to supply lysophospholipids, which are converted by fibroblast-derived autotaxin (ATX) to LPA. Fibroblast LPA 1 then integrates multiple pathways required for MC maturation by facilitating integrin-mediated MC-fibroblast adhesion, IL-33-ST2 signaling, L-PGDS-driven PGD 2 generation, and feedforward ATX-LPA 1 amplification. Defective MC maturation resulting from PLA2G3 deficiency is restored by supplementation with LPA 1 agonists or PLA2G3-modified EVs. Thus, the lipid-orchestrated paracrine circuit involving PLA2G3-driven lysophospholipid, eicosanoid, integrin, and cytokine signaling fine-tunes MC-fibroblast communication, ensuring MC maturation., Competing Interests: Declaration of interests J.C. has an employment relationship with Neurocrine Biosciences, Inc. as a Distinguished Scholar, unrelated to the current manuscript., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

We investigated suitable culture conditions for the production of the blue pigment phycocyanin (PC) from the unique filamentous cyanobacteria Pseudanabaena sp. ABRG5-3 and Limnothrix sp. SK1-2-1. White, green, or red LED irradiation at 30 μmol photons/m 2 /s was effective for phycocyanin production when compared with Arthrospira platensis (Spirulina) sp. NIES-39, which is generally grown under high light irradiation. To investigate the safety of the cyanobacteria, ABRG5-3 cells were subjected to Ames (reverse mutation) tests and single oral-dose rat studies, which revealed non-mutagenic and non-toxic properties. When three purified phycocyanins (abPC, skPC, and spPC) were subjected to agarose gel electrophoresis, they showed different mobility, indicating that each phycocyanin has unique properties. abPC exhibited strong antiglycation activities as novel function., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Various biomarkers have been developed and evaluated to predict the prognosis and complications of allogeneic hematopoietic cell transplantation (HCT). Most previous studies conducted on different biomarkers evaluated single effects such as those associated with inflammation, immunology, iron metabolism, and nutrition, and only a few studies have comprehensively analyzed markers., Objective: The study aimed to survey comprehensive multiple markers prior to HCT and extract those that significantly predict the outcomes., Study Design: A prospective multicenter observational study was performed. (UMIN000013506) Patients undergoing HCT for hematologic diseases were consecutively enrolled. Besides the usual clinical biomarkers, serum samples for extra-clinical biomarkers were collected and cryopreserved before starting the conditioning regimen. A total of 32 candidate biomarkers were selected, 23 from hematology, biochemistry, immunology, nutrition, and iron metabolism, and 9 from composite markers. Based on the area under the curve (AUC) values for survival, promising biomarkers was extracted. Internal validation for these markers was applied based on bootstrap methods. Setting the cut-off values for them, log-rank test was applied and outcomes including overall survival (OS), relapse, and non-relapse mortality (NRM) were evaluated using multivariate analyses. Furthermore, detailed analysis including transplant-related complications and external validation were conducted focusing on C-reactive protein (CRP) to platelet (Plt) ratio., Results: A total of 152 patients with hematologic malignancies were enrolled from April 2014 to March 2017. CRP, soluble interleukin-2 receptor (IL2R), CRP to albumin (Alb) ratio, CRP to Plt ratio, Plt to IL2R ratio, and IL2R to Alb ratio were identified as promising markers. Internal validation successfully confirmed their reliability of AUC and multivariate analysis demonstrated the statistical significance between the higher and the lower markers. Above all, a higher CRP to Plt ratio was significantly associated with a lower OS (hazard ratio [HR] 2.77; 95% confidence interval [CI] 1.30-5.91; P = 0.008) and higher non-relapse mortality rates (HR 2.79; 95%CI 1.14-6.80; P = 0.024) at 180 days. Furthermore, univariate analysis showed that a higher CRP to Plt ratio was significantly associated with a higher incidence of sinusoidal obstructive syndrome (P < 0.001) and bloodstream infection (P = 0.027). An external validation test confirmed the significance of the CRP to Plt ratio for these outcomes., Conclusion: The multicenter prospective observational study successfully identified significant biomarkers in patients with hematologic malignancies who received HCT. In particular, CRP to Plt ratio was identified as a novel and useful biomarker for predicting transplant outcomes. Further investigations are needed to validate the novel markers, analysis of the pathophysiology, and application to treatment settings other than HCT., Competing Interests: Declaration of Competing Interest TT reports honoraria from Pfizer, Otsuka, MSD, Chugai, bbi, Astellas, outside the submitted work. SF has received honoraria from Bristol-Myers-Squibb, Astellas, Nipppon Shinyaku, Otsuka, Pfizer, Novartis, MSD, Sanofi, Janssen, SymBio, Kyowa Hakko Kirin, AstraZeneca, CSL Behring, Meiji Seika Pharma, AbbVie, Takeda, and Chugai Pharma, and received research funding from Shionogi, Kyowa Hakko Kirin, Chugai Pharma, Otsuka, Asahi-Kasei, and Daiichi Sankyo, outside the submitted work. HN reports honoraria from Novartis and Daiichi-Sankyo, scholarship from Daiichi-Sankyo, Cellgene, Chugai, Nihon-Shinyaku, Astellas, Asahikasei-pharma, Chugai, Takeda, Pfizer, and Eisai, outside the submitted work. The other authors have no conflict of interest., (Copyright © 2024 International Society for Cell & Gene Therapy. Published by Elsevier Inc. All rights reserved.)

Poor prognostic factors, such as transfusion dependency and chromosomal risk, need to be considered in the indication of allogeneic hematopoietic cell transplantation (allo-HCT) for patients harboring myelodysplastic syndromes with less than 5% marrow blasts (MDS-Lo). We analyzed the post-transplant outcomes of 1229 MDS-Lo patients who received myeloablative (MAC)(n = 651), reduced-intensity (RIC)(n = 397), and non-myeloablative conditioning (NMAC) regimens (n = 181). The multivariate analysis revealed that the RIC group had better chronic graft-versus-host disease (GVHD)- and relapse-free survival (CRFS) (P = 0.021), and GVHD- and relapse-free survival (GRFS) than the MAC group (P = 0.001), while no significant differences were observed between the NMAC and MAC groups. In the subgroup analysis, the MAC group has better overall survival (P = 0.008) than the RIC group among patients with an HCT-comorbidity index (HCT-CI) score of 0, while the RIC group had better overall survival (P = 0.029) than the MAC group among those with an HCT-CI score ≥3. According to the type of conditioning regimen, total body irradiation 12 Gy-based MAC regimen showed better OS and CRFS than the other MAC regimen, and comparable outcomes to the RIC regimen. In conclusion, the RIC and NMAC regimens are promising options for MDS-Lo patients in addition to the MAC regimen., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Functional mass spectrometry imaging (fMSI) is a potent tool for elucidating the spatial distribution of enzyme activities in tissues at high resolution. In this study, we applied fMSI to probe the intricate biosynthesis of phospholipids, which exist as thousands of molecular species in tissues and exhibit a unique distribution specific to cell type. By using deuterium- and 13 C-labeled substrates, we visualized the activities of key enzymes involved in phospholipid synthesis, including glycerol 3-phosphate acyltransferase (GPAT), lysophosphatidic acid acyltransferases (LPAAT), lysophospholipid acyltransferases (LPLAT), and long-chain acyl-CoA synthetase (ACSL). Additionally, we were able to visualize a two-step sequential enzyme reaction involving ACSL and LPLAT. This novel approach unveiled significant variations in enzyme activity distribution depending on the type of fatty acids used as substrates. It will also help to reveal the mechanisms underlying the formation of numerous phospholipid species.

Activated microglia contribute to many neuroinflammatory diseases in the central nervous system. In this study, we attempted to identify an anti-inflammatory compound that could suppress microglial activation. We performed high-throughput screening with a chemical library developed at our institute. We performed a luciferase assay of nuclear factor-kappa B (NF-κB) reporter stable HT22 cells and identified a compound that was confirmed to inhibit the anti-inflammatory response in BV2 microglial cells. The selected dihydropyridine derivative can suppress the expression response of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor (TNF), as well as NF-κB phosphorylation and nuclear translocation, and reduce the intracellular calcium level. Thus, our identified compound has a potential role in suppressing microglial activation and may contribute to the development of a new therapeutic molecule against neuroinflammatory diseases.

Libman-Sacks endocarditis is an important cause of embolic stroke in systemic lupus erythematosus, although the detailed pathogenesis of stroke remains unclear. We herein report two cases of stroke with Libman-Sacks endocarditis in which the emboli were retrieved by mechanical thrombectomy. The embolus consisted of eosinophilic homogeneous acellular structures, whereas fibrin-platelet thrombi were hardly observed in the embolus. Immunohistochemistry showed immunoglobulin deposits in the embolus, suggesting that immunological mechanisms were involved in the growth of the embolus. A pathological analysis of the embolus retrieved by mechanical thrombectomy provided useful information on the etiology, leading to optimal treatment.

We report primordial aqueous alteration signatures in water-soluble organic molecules from the carbonaceous asteroid (162173) Ryugu by the Hayabusa2 spacecraft of JAXA. Newly identified low-molecular-weight hydroxy acids (HO-R-COOH) and dicarboxylic acids (HOOC-R-COOH), such as glycolic acid, lactic acid, glyceric acid, oxalic acid, and succinic acid, are predominant in samples from the two touchdown locations at Ryugu. The quantitative and qualitative profiles for the hydrophilic molecules between the two sampling locations shows similar trends within the order of ppb (parts per billion) to ppm (parts per million). A wide variety of structural isomers, including α- and β-hydroxy acids, are observed among the hydrophilic molecules. We also identify pyruvic acid and dihydroxy and tricarboxylic acids, which are biochemically important intermediates relevant to molecular evolution, such as the primordial TCA (tricarboxylic acid) cycle. Here, we find evidence that the asteroid Ryugu samples underwent substantial aqueous alteration, as revealed by the presence of malonic acid during keto-enol tautomerism in the dicarboxylic acid profile. The comprehensive data suggest the presence of a series for water-soluble organic molecules in the regolith of Ryugu and evidence of signatures in coevolutionary aqueous alteration between water and organics in this carbonaceous asteroid., (© 2024. The Author(s).)

Background: Recently, we developed the machine learning (ML)-based Progressive CKD Risk Classifier (PCRC), which accurately predicts CKD progression within 5 years. While its performance is robust, it is unknown whether PCRC categorization is associated with CKD-mineral bone disorder (CKD-MBD), a critical, yet under-recognized, downstream consequence. Therefore, we aimed to 1) survey real-world testing utilization data for CKD-MBD and 2) evaluate ML-based PCRC categorization with CKD-MBD., Methods: The cohort study utilized deidentified data from a US laboratory outpatient network, composed of 330,238 outpatients, over 5 years. The main outcomes were: 1) Laboratory testing utilization of eGFR, urine albumin creatinine ratio (UACR), parathyroid hormone (PTH), calcium, phosphate; and 2) PCRC categorization and biochemical abnormalities associated with CKD-MBD over 5 years., Results: We identified significant under-utilization of laboratory testing for UACR, phosphate and PTH, which ranged from -40 % to -100 % against the minimum standard-of-care. At five years, the CKD progression group, as predicted by the PCRC, was associated with 15.5 % increase in phosphate ( P value <<0.01) and 94.9 % increase in PTH (P value <<0.01), consistent with CKD-MBD., Conclusions: We identified significant under-utilization of laboratory testing for CKD-MBD. Moreover, we demonstrated that CKD progression, as predicted by the PCRC, is associated with CKD-MBD, several years in advance of disease. To our knowledge, this investigation is the first to examine the role of predictive analytics for CKD progression on mineral bone disorder. While further studies are required, these findings have the potential to advance AI/ML-based risk stratification and treatment of CKD and CKD-MBD., Competing Interests: The authors declare they have no conflicts of interest to disclose., (© 2024 Sonic Healthcare USA. Published by Elsevier Inc.)

The endocannabinoid system (ECS) is a widely recognized lipid messenger system involved in many aspects of our health and diseases [...].

Background and Objective: Whether intracranial hemorrhage (ICH) detected using magnetic resonance imaging (MRI) affects the clinical outcomes of patients with large-vessel occlusion (LVO) treated with mechanical thrombectomy (MT) remains unclear. This study investigated the clinical features of ICH after MT detected solely by MRI., Methods: This was a retrospective analysis of patients with acute ischemic stroke and occlusion of the internal carotid artery or middle cerebral artery treated with MT between April 2011 and March 2021. Among 632 patients, patients diagnosed with no ICH using CT, with a pre-morbid modified Rankin Scale (mRS) score ≤ 2, and those who underwent MRI including T2* and computed tomography (CT) within 72 h from MT were enrolled. The main outcomes were the association between ICH detected solely by MRI and clinical outcomes at 90 days. Poor clinical outcomes were defined as mRS score > 2 at 90 days after onset., Results: Of the 246 patients, 29 (12%) had ICH on MRI (MRI-ICH(+)), and 217 (88%) were MRI-ICH(-). There was no significant difference between number of patients with MRI-ICH(+) experiencing poor (10 [12%]) and favorable (19 [12%]) outcomes. The mRS score at 90 days between patients with MRI-ICH (+) and MRI-ICH(-) was not significantly different (2 [1-4] vs. 2 [1-4], respectively). Higher age and lower ASPECTS were independent risk factors for poor outcomes, as shown by multivariate regression analysis. MRI-ICH(+) status was not associated with poor outcomes., Conclusions: ICH detected by MRI alone did not influence clinical outcomes in patients with LVO treated with MT., Competing Interests: Declaration of competing interest Kazumi Kimura received lecture fees from Bristol-Myers Squibb Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., Bayer Healthcare Co., Ltd., and Daiichi Sankyo Co.; research funding from Nippon Boehringer Ingelheim Co., Ltd., Daiichi Sankyo Co., Pfizer Japan Inc., Medtronic Co., Ltd., and Teijin Pharma Ltd.; and personal funding from the 38th Mihara Cerebrovascular Disorder Research Promotion Fund, Ltd., (Copyright © 2023. Published by Elsevier B.V.)

Background The fractional flow reserve (FFR) derived from coronary computed tomography (CT) angiography (FFRCT) is a variable tool for coronary disease diagnosis that non-invasively provides the value of FFR. It can add physiological information to coronary CT angiography (CCTA) and reduce unnecessary invasive coronary angiography (CAG). However, it cannot be analyzed in some cases, which is also called "non-measurability." While FFRCT has become globally widespread, the current data on non-measurability are lacking. This study aimed to determine the rate of non-measurability and identify predictors thereof in routine clinical settings to explore potential approaches to reduce the non-measurability rate. Methods and results This retrospective observational single-center study included consecutive patients who underwent FFRCTanalysis in Japan. The mean age of the overall population was 71.3 ± 10.6, and an FFRCTof ≤0.8 was seen in 47.6% of patients with a measurable FFRCT. Of the 307 enrolled patients, FFRCT analysis was not feasible in 21 cases (6.8%). Heart rate (HR) at a CT scan and coronary calcium scores (CCS) were significantly higher in patients with non-measurability than those in patients whose FFRCT was appropriately analyzed (HR: 69.6±8.9 bpm vs. 61.0±11.1 bpm; p < 0.01; CCS; 931.2 (290.8, 1451.3) vs. 322.9 (100.7, 850.0); p < 0.01). Multiple logistic regression showed that HR was an independent predictor for non-measurability (odds ratio: 1.05; 95% confidential interval: 1.02, 1.09; p < 0.01)). Based on the receiver operating characteristic curve analysis, the optimal cut-off value of HR and CCS was 63 bpm (specificity: 67.1%; sensitivity: 76.2%) and 729.2 (specificity: 71.3%; sensitivity: 66.7%). In addition, the combination of two features (HR > 63 bpm and CCS > 729.2) showed a high negative predictive value (99.3%) for FFRCT non-measurability. Conclusions In this study, the rate of FFRCTnon-measurability was 6.8%. Higher HR at a CT scan and CCS were significantly associated with non-measurability, and in cases with both HR and CCS below a specified threshold, the likelihood of ruling out non-measurability could be significantly high. Our findings suggest that reducing the HR to ideally under 63 bpm at the time of the CT scan significantly ensures feasibility. Further study on large-scale cohorts is warranted., Competing Interests: The authors have declared financial relationships, which are detailed in the next section., (Copyright © 2024, Nonaka et al.)

Despite the emergence of monoclonal antibodies, the prognosis of patients with multiple myeloma (MM) with extramedullary disease remains poor. The present report describes a rare case of daratumumab-refractory MM that was successfully treated with elotuzumab, pomalidomide and dexamethasone. A 66-year-old male patient diagnosed with MM was treated with bortezomib, lenalidomide and dexamethasone, followed by high-dose chemotherapy and autologous stem cell transplantation. Thereafter, the patient was treated with lenalidomide and dexamethasone as maintenance therapy. This was changed to daratumumab, bortezomib and dexamethasone when new paraskeletal lesions were identified, resulting in marked tumor shrinkage. After 15 months, an increase in serum monoclonal protein levels, development of a skeletal lesion in the right second rib and extramedullary disease of the right thoracic mediastinal lymph nodes were noted. Treatment with elotuzumab, pomalidomide and dexamethasone (EPd) resulted in expeditious symptomatic improvement and regression of the lesions. Notably, during daratumumab, bortezomib and dexamethasone treatment, lymphocyte counts gradually increased to a level at which elotuzumab was sufficiently effective. EPd might be a promising strategy for the treatment of patients with relapsed extramedullary MM while on daratumumab treatment., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2024, Spandidos Publications.)

Mast cell stabilizers, including disodium cromoglycate (DSCG), were found to have potential as the agonists of an orphan G protein-coupled receptor, GPR35, although it remains to be determined whether GPR35 is expressed in mast cells and involved in suppression of mast cell degranulation. Our purpose in this study is to verify the expression of GPR35 in mast cells and to clarify how GPR35 modulates the degranulation. We explored the roles of GPR35 using an expression system, a mast cell line constitutively expressing rat GPR35, peritoneal mast cells, and bone marrow-derived cultured mast cells. Immediate allergic responses were assessed using the IgE-mediated passive cutaneous anaphylaxis (PCA) model. Various known GPR35 agonists, including DSCG and newly designed compounds, suppressed IgE-mediated degranulation. GPR35 was expressed in mature mast cells but not in immature bone marrow-derived cultured mast cells and the rat mast cell line. Degranulation induced by antigens was significantly downmodulated in the mast cell line stably expressing GPR35. A GPR35 agonist, zaprinast, induced a transient activation of RhoA and a transient decrease in the amount of filamentous actin. GPR35 agonists suppressed the PCA responses in the wild-type mice but not in the GPR35 -/- mice. These findings suggest that GPR35 should prevent mast cells from undergoing degranulation induced by IgE-mediated antigen stimulation and be the primary target of mast cell stabilizers. SIGNIFICANCE STATEMENT: The agonists of an orphan G protein-coupled receptor, GPR35, including disodium cromoglycate, were found to suppress degranulation of rat and mouse mature mast cells, and their antiallergic effects were abrogated in the GPR35 -/- mice, indicating that the primary target of mast cell stabilizers should be GPR35., (Copyright © 2024 by The Author(s).)

(1) Background : In patients with heart failure (HF) and impaired nutritional status or decreased muscle mass, sodium-glucose cotransporter-2 inhibitors (SGLT2is) may worsen these conditions and result in poor prognosis, especially worsening of frailty. We aimed to investigate the relationship between SGLT2is and clinical outcomes, including frailty-related events, in patients with HF and malnutrition, frailty, sarcopenia, or cachexia. (2) Methods : In this retrospective observational cohort study, a global federated health research network provided data on patients with HF and malnutrition, frailty, sarcopenia, or cachexia from January 2016 to December 2021. We investigated the incidence of the composite endpoint of death or frailty-related events within one year. (3) Results : Among 214,778 patients included in the analysis, 4715 were treated with SGLT2is. After propensity score matching, 4697 patients in the SGLT2is group were matched with 4697 patients in the non-SGLT2is groups. The incidence of the composite endpoint, mortality, and frailty-related events was lower in the SGLT2is group than in the non-SGLT2is group (composite endpoint, 65.6% versus 77.6%, p < 0.001; mortality, 17.4% vs. 35.5%, p < 0.001; frailty-related events, 59.4% vs. 64.3%, p < 0.001). (4) Conclusions : Patients with HF and malnutrition, frailty, sarcopenia, or cachexia had a high incidence of death and frailty-related events. SGLT2is were associated with a lower incidence of these events.

Background: We investigated the clinical effect of intravenous thrombolysis using a magnetic resonance imaging (MRI)-guided approach in cardioembolic stroke (CE) patients with unknown time of onset., Methods and results: This subanalysis of the THAWS trial assessed the efficacy and safety of alteplase 0.6 mg/kg in CE patients with unknown time of onset and showing diffusion-weighted imaging-fluid-attenuated inversion recovery mismatch. Patients were classified as CE and non-CE using the SSS-TOAST classification system during the acute period. The efficacy outcome was a modified Rankin Scale score of 0-1 at 90 days. In all, 126 patients from the THAWS trial were included in this study, of whom 45 (35.7%) were diagnosed with CE. In the CE group, a favorable outcome was numerically more frequent in the alteplase than control group (52% vs. 35%; adjusted odds ratio [aOR] 2.25; 95% confidence interval [CI] 0.50-9.99). However, in the non-CE group, favorable outcomes were comparable between the alteplase and control groups (44% vs. 55%, respectively; aOR 0.39; 95% CI 0.12-1.21). Treatment-by-cohort interaction for a favorable outcome was modestly significant between the CE and non-CE groups (P=0.069). In the CE group, no patients experienced symptomatic intracranial hemorrhage (ICH) or parenchymal hematoma Type II following thrombolysis., Conclusions: When an MRI-guided approach is used, CE patients with unknown time of onset appear to be suitable candidates for thrombolysis.

Background and Objective: Whether asymptomatic intracranial hemorrhage (ICH) affects the clinical outcomes in patients with acute large vessel occlusion treated with mechanical thrombectomy (MT) remains unclear. This study aimed to address this uncertainty., Methods: We retrospectively analyzed patients with acute ischemic stroke and internal carotid or middle cerebral (M1 segment) artery occlusion treated with MT between April 2011 and March 2021 at a single center. All patients had a premorbid modified Rankin scale (mRS) score ≤ 2 and an anterior circulation occlusion and underwent magnetic resonance imaging at admission. Asymptomatic ICH was defined as ICH without symptomatic ICH defined by the SITS-MOST criteria. A favorable outcome was defined as an mRS score ≤ 2 at 90 days after stroke onset., Results: Our study included 349 patients; 62% were men, the median age was 76 [67-83] years, and the median National Institutes of Health Stroke Scale (NIHSS) score was 15 [8-21]. As determined via computed tomography, 103 (30%) patients had ICH (20 symptomatic and 83 asymptomatic). The favorable outcome rate was significantly lower for asymptomatic vs. no ICH (30% vs. 67%, p < 0.01). In a multivariate regression analysis, a high NIHSS score (odds ratio [OR], 1.06; 95% confidence interval [CI], 1.02-1.10; p < 0.01) and low Alberta Stroke Program Early CT Score (OR, 0.78; 95% CI, 0.65-0.92; p < 0.01) were independent risk factors for ICH., Conclusions: Asymptomatic ICH is associated with poor clinical outcome at 90 days after stroke onset., Competing Interests: Declaration of competing interest Kazumi Kimura received lecture fees from Bristol-Myers Squibb Co. Ltd., Nippon Boehringer Ingelheim Co. Ltd., Bayer Healthcare Co. Ltd., and Daiichi Sankyo Co.; research funding from Nippon Boehringer Ingelheim Co. Ltd., Daiichi Sankyo Co., Pfizer Japan Inc., Medtronic Co. Ltd., and Teijin Pharma Ltd., (Copyright © 2024 Elsevier B.V. All rights reserved.)

GPR34 is a recently identified G-protein coupled receptor, which has an immunomodulatory role and recognizes lysophosphatidylserine (LysoPS) as a putative ligand. Here, we report cryo-electron microscopy structures of human GPR34-G i complex bound with one of two ligands bound: either the LysoPS analogue S3E-LysoPS, or M1, a derivative of S3E-LysoPS in which oleic acid is substituted with a metabolically stable aromatic fatty acid surrogate. The ligand-binding pocket is laterally open toward the membrane, allowing lateral entry of lipidic agonists into the cavity. The amine and carboxylate groups of the serine moiety are recognized by the charged residue cluster. The acyl chain of S3E-LysoPS is bent and fits into the L-shaped hydrophobic pocket in TM4-5 gap, and the aromatic fatty acid surrogate of M1 fits more appropriately. Molecular dynamics simulations further account for the LysoPS-regioselectivity of GPR34. Thus, using a series of structural and physiological experiments, we provide evidence that chemically unstable 2-acyl LysoPS is the physiological ligand for GPR34. Overall, we anticipate the present structures will pave the way for development of novel anticancer drugs that specifically target GPR34., (© 2024. The Author(s).)

Cancer cells harness lipid metabolism to promote their own survival. We screened 47 cancer cell lines for survival dependency on phosphatidylserine (PS) synthesis using a PS synthase 1 (PTDSS1) inhibitor and found that B cell lymphoma is highly dependent on PS. Inhibition of PTDSS1 in B cell lymphoma cells caused a reduction of PS and phosphatidylethanolamine levels and an increase of phosphoinositide levels. The resulting imbalance of the membrane phospholipidome lowered the activation threshold for B cell receptor (BCR), a B cell-specific survival mechanism. BCR hyperactivation led to aberrant elevation of downstream Ca2+ signaling and subsequent apoptotic cell death. In a mouse xenograft model, PTDSS1 inhibition efficiently suppressed tumor growth and prolonged survival. Our findings suggest that PS synthesis may be a critical vulnerability of malignant B cell lymphomas that can be targeted pharmacologically., (© 2023 Omi et al.)

Background: Recent advances in omics techniques have allowed detailed genetic characterization of aldosterone-producing adenoma (APA). The pathogenesis of APA is characterized by tumorigenesis-associated aldosterone synthesis. The pathophysiological intricacies of APAs have not yet been elucidated at the level of individual cells. Therefore, a single-cell level analysis is speculated to be valuable in studying the differentiation process of APA., Methods: We conducted single-nucleus RNA sequencing of APAs with KCNJ5 mutation and nonfunctional adenomas obtained from 3 and 2 patients, respectively., Results: The single-nucleus RNA sequencing revealed the intratumoral heterogeneity of APA and identified cell populations consisting of a shared cluster of nonfunctional adenoma and APA. In addition, we extracted 2 cell fates in APA and obtained a cell population specialized in aldosterone synthesis. Genes related to ribosomes and neurodegenerative diseases were upregulated in 1 of these fates, whereas those related to the regulation of glycolysis were upregulated in the other fate. Furthermore, the total RNA reads in the nucleus were higher in hormonally activated clusters, indicating a marked activation of transcription per cell., Conclusions: The single-nucleus RNA sequencing revealed intratumoral heterogeneity of APA with KCNJ5 mutation. The observation of 2 cell fates in KCNJ5 -mutated APAs provides the postulation that a heterogeneous process of cellular differentiation was implicated in the pathophysiological mechanisms underlying APA tumors., Competing Interests: Disclosures None.

Prototypic antidepressants, such as tricyclic/tetracyclic antidepressants (TCAs), have multiple pharmacological properties and have been considered to be more effective than newer antidepressants, such as selective serotonin reuptake inhibitors, in treating severe depression. However, the clinical contribution of non-monoaminergic effects of TCAs remains elusive. In this study, we discovered that amitriptyline, a typical TCA, directly binds to the lysophosphatidic acid receptor 1 (LPAR1), a G protein-coupled receptor, and activates downstream G protein signaling, while exerting a little effect on β-arrestin recruitment. This suggests that amitriptyline acts as a G protein-biased agonist of LPAR1. This biased agonism was specific to TCAs and was not observed with other antidepressants. LPAR1 was found to be involved in the behavioral effects of amitriptyline. Notably, long-term infusion of mouse hippocampus with the potent G protein-biased LPAR agonist OMPT, but not the non-biased agonist LPA, induced antidepressant-like behavior, indicating that G protein-biased agonism might be necessary for the antidepressant-like effects. Furthermore, RNA-seq analysis revealed that LPA and OMPT have opposite patterns of gene expression changes in the hippocampus. Pathway analysis indicated that long-term treatment with OMPT activated LPAR1 downstream signaling (Rho and MAPK), whereas LPA suppressed LPAR1 signaling. Our findings provide insights into the mechanisms underlying the non-monoaminergic antidepressant effects of TCAs and identify the G protein-biased agonism of LPAR1 as a promising target for the development of novel antidepressants., (© 2023. The Author(s).)

Asthma is a chronic inflammatory disease of the airways characterized by recurrent episodes of airway obstruction, hyperresponsiveness, remodeling, and eosinophilia. Phospholipase A 2 s (PLA 2 s), which release fatty acids and lysophospholipids from membrane phospholipids, have been implicated in exacerbating asthma by generating pro-asthmatic lipid mediators, but an understanding of the association between individual PLA 2 subtypes and asthma is still incomplete. Here, we show that group III-secreted PLA 2 (sPLA 2 -III) plays an ameliorating, rather than aggravating, role in asthma pathology. In both mouse and human lungs, sPLA 2 -III was expressed in bronchial epithelial cells and decreased during the asthmatic response. In an ovalbumin (OVA)-induced asthma model, Pla2g3 -/- mice exhibited enhanced airway hyperresponsiveness, eosinophilia, OVA-specific IgE production, and type 2 cytokine expression as compared to Pla2g3 +/+ mice. Lipidomics analysis showed that the pulmonary levels of several lysophospholipids, including lysophosphatidylcholine, lysophosphatidylethanolamine, and lysophosphatidic acid (LPA), were decreased in OVA-challenged Pla2g3 -/- mice relative to Pla2g3 +/+ mice. LPA receptor 2 (LPA 2 ) agonists suppressed thymic stromal lymphopoietin (TSLP) expression in bronchial epithelial cells and reversed airway hyperresponsiveness and eosinophilia in Pla2g3 -/- mice, suggesting that sPLA 2 -III negatively regulates allergen-induced asthma at least by producing LPA. Thus, the activation of the sPLA 2 -III-LPA pathway may be a new therapeutic target for allergic asthma., (© 2024 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)

Objective Whether or not the initial dip in the glomerular filtration rate (GFR) after the initiation of sodium-glucose co-transporter 2 inhibitors (SGLT2is) is associated with renal tubular injury in patients with heart failure with a reduced ejection fraction (HFrEF) is unclear. We therefore investigated the relationship between changes in the estimated GFR (eGFR) and urine N-acetyl-β-D-glucosaminidase (uNAG) after the initiation of dapagliflozin in patients with HFrEF. Methods We prospectively investigated 89 patients with HFrEF who were newly started on dapagliflozin 10 mg/day. Changes in the eGFR and uNAG-to-creatinine ratio (uNAG/Cre) were evaluated at 2 weeks and 2 months after the initiation of dapagliflozin. Results The eGFR was decreased at 2 weeks but had not declined further by 2 months. The uNAG/Cre was increased at 2 weeks but had not increased further by 2 months. There was no correlation between the changes in the eGFR and uNAG/Cre (r=-0.022, p=0.853 at 2 weeks and r=0.078, p=0.538 at 2 months). The relative change in the systolic blood pressure, hematocrit, plasma volume, and N-terminal pro-brain natriuretic peptide (NT-proBNP) were correlated with the relative change in the eGFR. In a multiple linear regression analysis, the relative change in the eGFR at 2 weeks was significantly associated with NT-proBNP, and the relative change in the uNAG/Cre was significantly associated with the use of loop diuretics and the relative change in urine osmolality at 2 weeks. Conclusion A transient decrease in the eGFR after the initiation of dapagliflozin in patients with HFrEF was not generally associated with renal tubular injury and might have been the result of hemodynamic alteration.

Background: Our previous acute dual study (ADS) reported that dual antiplatelet therapy (DAPT) using cilostazol and aspirin did not reduce the rate of neurological deterioration in non-cardioembolic stroke patients. In this post-hoc analysis, we investigated whether the impact of dual antiplatelet therapy (DAPT) may depend on neurological severity, as represented by large artery disease., Methods: Neurological deterioration was defined as neurological progression with an increment of the National Institutes of Health Stroke Scale (NIHSS) score of ≥2. NIHSS score subgroups were divided into that of 0-1, 2-4, 5-10, and >10., Results: Among 1014 patients, 203 (20%) had the large artery disease, and 811 (80%) did not. In the total cohort, the rate of neurological deterioration was 10.8% in the DAPT group and 8.3% in the aspirin group (P = 0.197). When we focused on the large artery disease group, DAPT group had a higher rate of neurological deterioration as 18.3% compared to 8.2% in the aspirin group (P = 0.036). Among patients with NIHSS score of 0-1 and 2-4, the rates of neurological deterioration were not different between the two group (both, P = 1.000). However, when NIHSS score elevated to 5-10, 45% in the DAPT group and 9.1% in the aspirin group deteriorated (P = 0.013). Among the patients with NIHSS score of >10, 60% in the DAPT group and none (0%) in the aspirin group had the neurological deterioration (P = 0.045)., Conclusion: DAPT with aspirin and cilostazol was associated with higher rate of neurological deterioration when patients have large artery disease and not mild neurological deficits., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest or funding sources to disclose., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Psychological stress can cause various mental and physical health problems. The previous results on stress and oral health are inconsistent, possibly because of the narrow stress measurements. We aimed to examine the association between a broader range of stressful life events and oral health among workers., Methods: This cross-sectional study analyzed anonymous individual data from a national survey in Japan. Data on stressful life events, oral health problems which are one or more of tooth pain, gum swelling/bleeding, and difficulty chewing, and covariates were obtained using a self-reported questionnaire. Covariates used included gender, age group, and disease under treatment. Logistic regression analysis was used to estimate the association between stressful life events and oral health problems. We then estimated the causal treatment effects of stress using the augmented inverse-probability weighting (AIPW) method., Results: Among the 274,881 subjects, 152,850 men (55.6%) and 122,031 women (44.4%) with a mean age of 47.0 (standard deviation, 14.4) years, 4.0% reported oral health problems, with a prevalence of 2.1% among those without any stress. The prevalence increased with stress score, reaching 15.4% for those with the maximum stress score. The adjusted odds ratio of this group compared to those without any stress was 9.2 (95% confidence interval [CI], 8.2-10.3). The estimated prevalence of oral health problems by the AIPW analysis was 2.2% (95% CI, 2.1-2.3%) for those without any stress and 14.4% (95% CI, 12.1-16.7%) for those with the maximum stress scores., Conclusion: There was a clear dose-response association between stressful life events and oral health problems.

Introduction: The aim of this study was to determine the safety and efficacy of intravenous (IV) alteplase at 0.6 mg/kg for patients with acute wake-up or unclear-onset strokes in clinical practice., Methods: This multicenter observational study enrolled acute ischemic stroke patients with last-known-well time &gt;4.5 h who had mismatch between DWI and FLAIR and were treated with IV alteplase. The safety outcomes were symptomatic intracranial hemorrhage (sICH) after thrombolysis, all-cause deaths, and all adverse events. The efficacy outcomes were favorable outcome defined as an mRS score of 0-1 or recovery to the same mRS score as the premorbid score, complete independence defined as an mRS score of 0-1 at 90 days, and change in NIHSS at 24 h from baseline., Results: Sixty-six patients (35 females; mean age, 74 ± 11 years; premorbid complete independence, 54 [82%]; median NIHSS on admission, 11) were enrolled at 15 hospitals. Two patients (3%) had sICH. Median NIHSS changed from 11 (IQR, 6.75-16.25) at baseline to 5 (3-12.25) at 24 h after alteplase initiation (change, -4.8 ± 8.1). At discharge, 31 patients (47%) had favorable outcome and 29 (44%) had complete independence. None died within 90 days. Twenty-three (35%) also underwent mechanical thrombectomy (no sICH, NIHSS change of -8.5 ± 7.3), of whom 11 (48%) were completely independent at discharge., Conclusions: In real-world clinical practice, IV alteplase for unclear-onset stroke patients with DWI-FLAIR mismatch provided safe and efficacious outcomes comparable to those in previous trials. Additional mechanical thrombectomy was performed safely in them., (© 2023 S. Karger AG, Basel.)

Background: Antithrombotic therapy (AT) should generally be avoided within 24 hours after recombinant tissue-plasminogen activator (rt-PA) treatment but should be considered in patients with large-artery atherosclerosis (LAA) who undergo concomitant emergent endovascular treatment (EVT). The aim of the present study was to assess the safety of AT within 24 hours after rt-PA treatment in patients with hyperacute ischemic stroke due to LAA who received concomitant EVT., Methods: From January 2013 through July 2019, consecutive patients with acute ischemic cerebrovascular disease due to LAA who were admitted within 6 hours from symptom onset were recruited. The patients were classified into six groups based on the reperfusion treatment and early (within 24 hours) AT from rt-PA treatment. Safety outcomes were compared among the groups., Results: A total of 155 patients (35 women [23%], median age 74 [IQR 66-79] years; NIHSS score 3 [1-10]) were included in the present study. Of these, 73 (47%) received no reperfusion therapy, 24 (15%) received rt-PA treatment and early AT, seven (6%) received rt-PA without early AT, 26 (17%) received EVT only, six (4%) received both rt-PA and EVT without early AT, and 19 (12%) received rt-PA and EVT with early AT. AT was administered a median of 3.9 (1.6-8.0) hours after rt-PA in patients with rt-PA+EVT with early AT. AT within 24 hours after rt-PA and EVT treatment did not increase hemorrhagic complications (p > 0.05 for all)., Conclusion: In this retrospective analyses, early AT administration for patients with hyperacute stroke due to LAA treated with rt-PA plus EVT did not increase hemorrhagic events.

Late gadolinium enhancement (LGE) in cardiovascular magnetic resonance imaging (CMR) prevents left ventricular reverse remodeling (LVRR), resulting in a poor prognosis. However, the prognosis of patients who have LGE and achieve LVRR and patients who do not have LGE and do not achieve LVRR remains unknown. This study aimed to answer this question by sorting patients with heart failure based on the presence of LGE and LVRR and comparing their prognoses. Another aim was to identify useful factors for predicting LVRR.All patients were followed-up for 24 months. LVRR was defined as a ≥ 10% increase at the last follow-up at 12 ± 6 months from baseline, on echocardiography. The primary endpoint was a composite of cardiovascular death and hospitalization due to worsening heart failure within 18 ± 6 months. Baseline data and data from each outpatient visit were collected and analyzed. We enrolled 80 consecutive patients with heart failure and reduced left ventricular ejection fraction (< 50%) who underwent CMR.LGE was positive in 40 patients (50.0%) and LVRR was observed in 50 patients (63%). The incidence of the primary endpoint was significantly lower in the group that achieved LVRR, regardless of LGE status (LGE-positive group, P = 0.01; LGE-negative group, P = 0.02). In the multivariate analysis, the percentage change in NT-pro BNP levels at 3 months, NT-pro BNP levels at 6 months, and age were independent predictors of LVRR.LGE-positive patients may have a better prognosis if they achieve LVRR. Serial NT-pro BNP testing may be a valuable predictor of LVRR.

Polycyclic aromatic hydrocarbons (PAHs) contain ≲20% of the carbon in the interstellar medium. They are potentially produced in circumstellar environments (at temperatures ≳1000 kelvin), by reactions within cold (~10 kelvin) interstellar clouds, or by processing of carbon-rich dust grains. We report isotopic properties of PAHs extracted from samples of the asteroid Ryugu and the meteorite Murchison. The doubly- 13 C substituted compositions (Δ2× 13 C values) of the PAHs naphthalene, fluoranthene, and pyrene are 9 to 51‰ higher than values expected for a stochastic distribution of isotopes. The Δ2× 13 C values are higher than expected if the PAHs formed in a circumstellar environment, but consistent with formation in the interstellar medium. By contrast, the PAHs phenanthrene and anthracene in Ryugu samples have Δ2× 13 C values consistent with formation by higher-temperature reactions.

Lysophosphatidic acid (LPA) is a key player in many physiological and pathophysiological processes. The biological activities of LPA are mediated through interactions with-at least-six subtypes of G-protein-coupled receptors (GPCRs) named LPA 1-6 . Developing a pharmacological tool molecule that activates LPA subtype receptors selectively will allow a better understanding of their specific physiological roles. Here, we designed and synthesized conformationally restricted 25 1-oleoyl LPA analogues MZN-001 to MZN-025 by incorporating its glycerol linker into dihydropyran, tetrahydropyran, and pyrrolidine rings and variating the lipophilic chain. The agonistic activities of these compounds were evaluated using the TGFα shedding assay. Overall, the synthesized analogues exhibited significantly reduced agonistic activities toward LPA 1 , LPA 2 , and LPA 6 , while demonstrating potent activities toward LPA 3 , LPA 4 , and LPA 5 compared to the parent LPA. Specifically, MZN-010 showed more than 10 times greater potency (EC 50 = 4.9 nM) than the standard 1-oleoyl LPA (EC 50 = 78 nM) toward LPA 5 while exhibiting significantly lower activity on LPA 1 , LPA 2 , and LPA 6 and comparable potency toward LPA 3 and LPA 4 . Based on the MZN-010 scaffold, we synthesized additional analogues with improved selectivity and potency toward LPA 5 . Compound MZN-021 , which contains a saturated lipophilic chain, exhibited 50 times more potent activity (EC 50 = 1.2 nM) than the natural LPA against LPA 5 with over a 45-fold higher selectivity when compared to those of other LPA receptors. Thus, MZN-021 was found to be a potent and selective LPA 5 agonist. The findings of this study could contribute to broadening the current knowledge about the stereochemical and three-dimensional arrangement of LPA pharmacophore components inside LPA receptors and paving the way toward synthesizing other subtype-selective pharmacological probes., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)