Search

Xu Jiang,1 Sungyeun Bae,1 Deok Yong Yoon,2 Shin Jung Park,3 Jaeseong Oh,1 Joo-Youn Cho,1,4 Kyung-Sang Yu1,4 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea; 2Department of Pharmaceutics, Center for Pharmacometrics and Systems Pharmacology, College of Pharmacy, University of Florida, Orlando, FL, USA; 3Department of Pharmaceutical Research Laboratory, Chong Kun Dang Research Institute, Chong Kun Dang Pharmaceutical Corporation, Yongin, Republic of Korea; 4Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of KoreaCorrespondence: Kyung-Sang Yu, Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, 101, Dae-hak ro, Jong-ro gu, Seoul, 03080, Republic of Korea, Tel/Fax +82-2072-1666, Email ksyu@snu.ac.krPurpose: Empagliflozin is a sodium-glucose cotransporter 2 inhibitor that is commonly used for the treatment of type 2 diabetes mellitus. As cocrystal formulation can improve the chemical properties of drugs, CKD-370 was newly developed as a cocrystal formulation of empagliflozin with solvate L-proline. This study aimed to compare the pharmacokinetics, safety, and tolerability of these two empagliflozin formulations in healthy Korean subjects.Methods: A randomized, open-label, two-sequence, two-period crossover study was conducted on healthy Korean participants. The subjects received a single oral 25 mg dose of either test (CKD-370) or reference treatment (Jardiance®) tablet at each period. Plasma empagliflozin concentrations were determined using liquid chromatography with tandem mass spectrometry. Pharmacokinetic (PK) parameters were analyzed using non-compartmental methods. The primary PK parameters included the maximum concentration (Cmax) and the area under the concentration-time curve from 0 to last (AUClast). The safety of both formulations was monitored and evaluated.Results: A total of 28 healthy Korean adult subjects were randomized, and 27 subjects were included in the PK analysis. The mean ± standard deviation values of the primary PK parameters, Cmax and AUClast after administration of the test treatment, were 442.02 ± 103.37 μg/L and 3131.08 ± 529.30 μg·h/L, respectively, and those after administration of the reference treatment were 436.29 ± 118.74 μg/L and 3006.88 ± 514.21 μg·h/L, respectively. The geometric mean ratio and its 90% confidence interval of test to reference treatment for Cmax and AUClast were 1.0221 (0.9527– 1.0967) and 1.0411 (1.0153– 1.0677), respectively, which were within the commonly accepted bioequivalence criteria of 0.80 to 1.25. Both treatments were well-tolerated.Conclusion: The two formulations of empagliflozin showed similar PK characteristics and were generally well tolerated in healthy subjects.Keywords: T2DM, cocrystal, L-proline, biosimilar, CKD-370

Deok Yong Yoon,1 Sang-In Park,2 Jin-A Jung,3 Yong-Il Kim,3 In-Jin Jang,1 Jae-Yong Chung4 1Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Hospital, Seoul, Republic of Korea; 2Department of Clinical Pharmacology and Therapeutics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; 3Hanmi Pharm. Co., Ltd., Seoul, Republic of Korea; 4Department of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, Seongnam, Republic of KoreaCorrespondence: Jae-Yong ChungDepartment of Clinical Pharmacology and Therapeutics, Seoul National University College of Medicine and Bundang Hospital, 82, Gumi-ro, 173 Beon-gil, Bundang-gu, Seongnam-si, Gyeonggi-do 13620, Republic of KoreaTel +82-31-787-3955Fax +82-31-787-4045Email jychung@snubh.orgBackground: A fixed-dose combination (FDC) tablet formulation of amlodipine/losartan/rosuvastatin 5/100/20 mg was developed to improve medication compliance in patients with both hypertension and dyslipidemia. The comparative pharmacokinetic study was performed to compare the profile of an FDC tablet formulation of amlodipine/losartan/rosuvastatin with that of concomitant administration of a currently marketed FDC tablet of amlodipine/losartan with a rosuvastatin tablet.Subjects and Methods: A randomized, open-label, single oral dose, two-way crossover study was conducted in 60 healthy subjects. Subjects were orally administered the FDC tablet of amlodipine/losartan/rosuvastatin and a loose combination (LC) of two tablets comprising an FDC of amlodipine/losartan and rosuvastatin. Blood samples were collected for up to 144 h post dose for pharmacokinetic evaluations. Plasma concentrations of amlodipine, losartan, EXP3174 (an active metabolite of losartan), and rosuvastatin were measured by using liquid chromatography-tandem mass spectrometry. The geometric mean ratio (GMR) and its 90% confidence interval (90% CI) in the FDC treatment to LC treatment for the area under the concentration-time curve from zero to the last quantifiable time point (AUClast) and the maximum plasma concentration (Cmax) were calculated. Safety was monitored throughout the study.Results: The GMR (90% CI) values of AUClast and Cmax were 0.9946 (0.9663– 1.0238) and 0.9690 (0.9379– 1.0011) for amlodipine, 0.9855 (0.9422– 1.0308) and 0.9178 (0.8349– 1.0089) for losartan, 0.9814 (0.9501– 1.0136) and 0.9756 (0.9313– 1.0219) for EXP3174, and 0.9448 (0.8995– 0.9923) and 0.9609 (0.8799– 1.0494) for rosuvastatin, respectively. No clinically significant changes were observed in any of the safety parameters, including clinical laboratory tests, vital signs, electrocardiograms, and physical examinations, between the FDC treatment and the LC treatment.Conclusion: We confirmed the pharmacokinetic equivalence of the FDC and LC treatments. This triple combination FDC formulation could be a clinically useful replacement for LC therapy.Keywords: fixed-dose combination, loose combination, bioequivalence, pharmacokinetics, hypertension, dyslipidemia

Rationale and Objectives: The aim of this study was to determine the accuracy and reproducibility of low-dose computed tomography (CT) and magnetic resonance (MR) for abdominal adipose tissue quantification on phantom and human studies. Materials and Methods: An adiposity phantom (with known internal/external oil volumes) was scanned at three different tube voltages (140, 120, and 90 kVp) using a 16-detector row CT scanner and was imaged using a T1-weighted spin echo MR sequence. For human studies, whole-volume coverage of the abdomen was obtained using CT (at 140 and 90 kVp) and T1-weighted spin echo MR imaging from five obese male volunteers (mean age, 40.6 years; mean body mass index, 30.2). The volumes of total, visceral, and subcutaneous adipose tissues (TAT, VAT, and SAT, respectively) were calculated independently by two radiologists for each CT scan and MR imaging using a computer-aided semiautomatic program. Results: The estimated radiation dose could be reduced by approximately 75% with a 90-kVp protocol as compared with the 140-kVp protocol. Phantom studies showed that there was no statistically significant difference between the four methods in estimating the percentage predicted of the true volumes (measurement errors <4% for all methods, P > .05). In human studies, we found no statistically significant difference between the three methods in TAT, VAT, and SAT volumes (P > .05). Inter- and intraobserver reproducibilities of the CT volume estimates using the 90-kVp protocol were better than those obtained from MR imaging (κ > 0.9 versus 0.4–0.5; coefficient of variation < 1% versus 15–22%). Conclusion: Low-dose CT provides accurate and reproducible measurement of abdominal adipose tissue volumes with a relevant dose reduction. [Copyright &y& Elsevier]

OBJECTIVE: To investigate the molecular mechanisms of the antiarthritic effects of bee venom (BV) and melittin (a major component of BV) in a murine macrophage cell line (Raw 264.7) and in synoviocytes obtained from patients with rheumatoid arthritis. METHODS: We evaluated the antiarthritic effects of BV in a rat model of carrageenan-induced acute edema in the paw and in a rat model of chronic adjuvant-induced arthritis. The inhibitory effects of BV and melittin on inflammatory gene expression were measured by Western blotting, and the generation of prostaglandin E(2) (PGE(2)) and nitric oxide (NO) and the intracellular calcium level were assayed. NF-kappaB DNA binding and transcriptional activity were determined by gel mobility shift assay or by luciferase assay. Direct binding of BV and melittin to the p50 subunit of NF-kappaB was determined with a surface plasmon resonance analyzer. RESULTS: BV (0.8 and 1.6 mug/kg) reduced the effects of carrageenan- and adjuvant-induced arthritis. This reducing effect was consistent with the inhibitory effects of BV (0.5, 1, and 5 mug/ml) and melittin (5 and 10 mug/ml) on lipopolysaccharide (LPS; 1 mug/ml)-induced expression of cyclooxygenase 2, cytosolic phospholipase A(2), inducible NO synthase, generation of PGE(2) and NO, and the intracellular calcium level. BV and melittin prevented LPS-induced transcriptional and DNA binding activity of NF-kappaB via the inhibition of IkappaB release and p50 translocation. BV (affinity [K(d)] = 4.6 x 10(-6)M) and melittin (K(d) = 1.2 x 10(-8)M) bound directly to p50. CONCLUSION: Target inactivation of NF-kappaB by directly binding to the p50 subunit is an important mechanism of the antiarthritic effects of BV. [ABSTRACT FROM AUTHOR]

Inflammatory bowel disease, including Crohn's disease and ulcerative colitis, poses an emerging threat as it can lead to colorectal cancer, thrombosis, and other chronic conditions. The present study demonstrated the protective effects of peanut sprout extracts (PSEs) prepared from day 2 to day 7 of germination against lipopolysaccharide (LPS)-induced epithelial barrier breakdown. Although the peanut sprout length increased in a time-dependent manner from day 1 to day 7, the extraction yields remained relatively consistent from day 2 to day 7. With regard to antioxidant activities, the PSE from day 6 of germination exhibited the highest oxidative radical scavenging activity and total phenolic content. Similarly, it showed remarkable anti-permeability effects in LPS-stimulated Caco-2 cells and suppressed the degradation and dissociation of junctional markers (e.g., ZO-1 and E-cadherin) at cell-cell junctions. Collectively, these data demonstrate that PSE from day 6 of germination can be used as a functional food resource to reduce inflammatory barrier dysfunction., Competing Interests: AUTHOR DISCLOSURE STATEMENT The authors declare no conflict of interest., (© 2024 The Korean Society of Food Science and Nutrition.)

Aims: This study aims to evaluate the exposure-efficacy relationship of nilotinib and longitudinal BCR::ABL1 levels in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukaemia in chronic phase (CML-CP) and those who are imatinib-resistant or intolerant using a semimechanistic disease model., Methods: The analysis included 489 CML-CP patients from 3 nilotinib trials (NCT00109707; NCT00471497; NCT01043874) with duration of follow-up ranging from 2 to 9 years. The semimechanistic disease model of CML-CP consisted of quiescent leukaemic stem cells, proliferating drug-susceptible and -resistant bone marrow cells. Drug effect on the elimination of susceptible cells was characterized by a maximum response model based on the individual daily area under the concentration-time curve over the last 24 h simulated using their empirical Bayes estimates from a population pharmacokinetic model. The influence of line of therapy was evaluated on model parameters and its impact was investigated through simulations of the major molecular response (MMR) rate, defined as the proportion of the simulated profiles that achieved BCR::ABL1 level of ≤0.1% at 48 and 96 weeks of treatment., Results: The final disease model was based on a truncated 3-year data that characterized the biphasic pattern of BCR::ABL1 transcript profiles. Line of therapy was a significant covariate of the drug kill effect, susceptible and resistant cells. Simulations of BCR::ABL1 time course predicted MMR rates at 48 weeks and 96 weeks for both nilotinib 300 and 400 mg twice-daily of 66-71 and 77-82% in first-line, and 34-39 and 46-54% in second-line, respectively. Results are consistent with observed MMR rates in the respective trials., Conclusion: The ability to distinguish molecular response between lines of therapy is demonstrated using model-based analysis. These nilotinib information enable the extrapolation of novel tyrosine kinase inhibitors (e.g., asciminib) response to other lines of therapy in patients with CML-CP., (© 2024 British Pharmacological Society.)

Aims: This study evaluates how changes in intestinal bile acid composition, induced by cholestyramine, a bile acid sequestrant, affect metformin's pharmacodynamics (PD)., Methods: An open-label, 2-period 1-sequence crossover study was conducted with healthy male adults. Each period consisted of both before and after metformin treatments. Cholestyramine was administered during the second period to change the bile acid pool. For, PD assessment, an oral glucose tolerance test was conducted at each treatment in both periods. Metformin was administered 3 times during each period, and cholestyramine was administered 3 times per day for 7 days during the second period. Maximum serum glucose concentration, area under the glucose concentration curve and homeostatic model assessment of insulin resistance were calculated. Baseline-corrected PD parameters were derived by subtracting pre-metformin values from post-metformin values. Lipid and panels and bile acid profiles in stool were measured. Adverse events were monitored throughout the study., Results: Fourteen subjects completed the study. The mean values of 3 PD parameters were all decreased after metformin administration in both periods. Cholestyramine administration led to a further decrease in baseline-corrected PD parameters, significantly reducing the area under the glucose concentration curve by 44.7%. Diarrhoea, the most common adverse event, was reported in 10 subjects during the metformin alone treatment and in 1 subject during the cholestyramine combined treatment (P < .01)., Conclusion: Cholestyramine affected the glucose-lowering effect of metformin by the possible change in the bile acid pool in the gut, and metformin-associated diarrhoea was improved by cholestyramine., (© 2024 British Pharmacological Society.)

Introduction: A change from the supine to prone position causes hemodynamic alterations. We aimed to evaluate the effect of fluid preloading in the supine position, the subsequent hemodynamic changes in the prone position and postoperative outcomes., Patients and Methods: This prospective, assessor-blind, randomized controlled trial was conducted between March and June 2023. Adults scheduled for elective orthopaedic lumbar surgery under general anaesthesia were enrolled. In total, 80 participants were randomly assigned to fluid maintenance (M) or loading (L) groups. Both groups were administered intravenous fluid at a rate of 2 ml/kg/h until surgical incision; Group L was loaded with an additional 5 ml/kg intravenous fluid for 10 min after anaesthesia induction. The primary outcome was incidence of hypotension before surgical incision. Secondary outcomes included differences in the mean blood pressure (mBP), heart rate, pleth variability index (PVi), stroke volume variation (SVV), pulse pressure variation (PPV), stroke volume index and cardiac index before surgical incision between the two groups. Additionally, postoperative complications until postoperative day 2 and postoperative hospital length of stay were investigated., Results: Hypotension was prevalent in Group M before surgical incision and could be predicted by a baseline PVi >16. The mBP was significantly higher in Group L immediately after fluid loading. The PVi, SVV and PPV were lower in Group L after fluid loading, with continued differences at 2-3 time points for SVV and PPV. Other outcomes did not differ between the two groups., Conclusion: Fluid loading after inducing general anaesthesia could reduce the occurrence of hypotension until surgical incision in patients scheduled for surgery in the prone position. Additionally, hypotension could be predicted in patients with a baseline PVi >16. Therefore, intravenous fluid loading is strongly recommended in patients with high baseline PVi to prevent hypotension after anaesthesia induction and in the prone position., Trial Number: KCT0008294 (date of registration: 16 March 2023).

Duchenne muscular dystrophy (DMD), a rare pediatric disease, presents numerous challenges when designing clinical trials, mainly due to the scarcity of available trial participants and the heterogeneity of disease progression. A quantitative clinical trial simulator (CTS) has been developed based on previously published five disease progression models describing each of the longitudinal changes in the velocity at which individuals can complete specified timed functional tests, frequently used as clinical trial efficacy endpoints (supine-stand, 4-stair climb, and 10 m walk/run test or 30-foot walk/run test), as well as each of the longitudinal changes in forced vital capacity and North Star Ambulatory Assessment total score. The model-based CTS allows researchers to optimize the selection of numerous trial parameters for designing trials for the five functional measures commonly used as endpoints in DMD clinical trials. This case report serves as a demonstration of the tool's functionality while providing an easy-to-follow guide for users to reference when preparing simulations of their own design. Two case studies, using input selection based on previous DMD clinical trials, provide realistic examples of how the tool can help optimize clinical trial design without the risk of decreasing statistical significance. This optimization allows researchers to mitigate the risk of designing trials that may be longer, larger, or more inclusive/exclusive than necessary., (© 2024 The Author(s). CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

The impact of complete revascularization (CR), achieved through the recanalization of coronary chronic total occlusions (CTOs), on long-term patient outcomes remains uncertain. To evaluate this in patients who achieved CR after CTO-PCI with those who did not due to deferred CTO-PCI, the Asan Medical Center Registry was reviewed to identify coronary artery disease (CAD) patients with CTOs treated between January 2003 and December 2018. Patients were included with single-vessel disease with CTO and with multivessel disease who had undergone revascularization for non-CTO lesions. These subjects were divided into those who achieved CR with CTO-PCI and those who did not due to deferred CTO-PCI. Their outcomes were compared following 1:1 propensity score matching. Of the 2746 enrolled CAD patients with CTOs, 1837 achieved CR with CTO-PCI and 909 did not. Propensity score matching yielded 653 patient pairs. The CR-achieving group had a significantly lower 10-year risk of the primary composite outcome of death, myocardial infarction, stroke, or repeat revascularization (hazard ratio [HR]: 0.57; 95 % confidence interval [CI]: 0.46-0.72; P < 0.001), as well as significantly lower risks of death (HR: 0.66; 95 % CI: 0.51-0.87; P = 0.003) and repeat revascularization (HR: 0.67; 95 % CI: 0.48-0.95; P = 0.023). CR was beneficial in all subgroups, including patients with major cardiovascular risk factors such as older age, hypertension, diabetes, and advanced CAD. Compared with incomplete revascularization, CR may significantly reduce the 10-year incidence of major adverse cardiac events in patients with CTO., Competing Interests: This study was supported by a grant (2024IE0006) from the 10.13039/501100005006Asan Institute for Life Sciences, Asan Medical Center. The funding source had no involvement in the design of the study, the collection, analysis, and interpretation of data, the writing of the manuscript, or the decision to submit the paper for publication. The authors have no conflicts of interest to declare., (© 2024 The Authors.)

Background: This study aimed to investigate the hemodynamic and anatomic factors associated with sinus thrombosis following transcatheter aortic valve replacement (TAVR), integrating in vivo patient data analysis and in vitro experiments., Methods and Results: Postprocedural, 4-dimensional, multiphase computed tomography data from 211 patients enrolled in the ADAPT-TAVR (Anticoagulation Versus Dual Antiplatelet Therapy for Prevention of Leaflet Thrombosis and Cerebral Embolization After Transcatheter Aortic Valve Replacement) study were analyzed. The prevalence of native sinus thrombosis was examined in relation to valve type, implant depth, and anatomic features. In vitro experiments used particle image velocimetry to observe changes in sinus flow based on the transcatheter heart valves (23-mm SAPIEN3, Edwards Lifesciences; and 29-mm CoreValve, Medtronic) height and coronary artery flow. Native sinus thrombosis was more common in self-expanding valves (39.1% versus 14.9%, P =0.004). In per-cusp analysis of in vivo patient data, adjusted transcatheter heart valve implant depth (odds ratio, 1.2 [95% CI, 1.1-1.3]; P <0.001), noncoronary sinus of Valsalva (odds ratio, 4.0 [95% CI, 2.0-7.8]; P <0.001), sinus inflow diameter (odds ratio, 0.8 [95% CI, 0.6-0.9]; P =0.008), and implanted valve size (odds ratio, 0.8 [95% CI, 0.7-1.0]; P =0.025) were significant factors associated with native sinus thrombosis. In the in vitro experiments, CoreValve showed noticeable flow stasis compared with SAPIEN3. High-positioned SAPIEN3 was linked to reduced velocity within the native sinus of Valsalva. Coronary artery flow led to higher sinus velocity and improved particle washout, reducing sinus thrombosis risk., Conclusions: This study provides insights into the relationship between transcatheter heart valve deployment and native sinus thrombosis, emphasizing the role of anatomic factors in relation to the risk of sinus thrombosis.

Keratinocytes are susceptible to airborne particulate matter (PM) exposure, resulting in human skin barrier dysfunction. Therefore, it is important to find useful reagents to resolve skin damages caused by PM. Here, we explored the protective effect of 7S MaR1, a specialized pro-resolving mediator derived from docosahexaenoic acid, on skin inflammation and the oxidative stress induced by PM with a diameter 10 μm or less (PM10) in human keratinocyte HaCaT cells. Interestingly, PM10-induced ROS generation was modulated by 7S MaR1 via the recovery of ROS scavenger genes. 7S MaR1 reduced PM10-induced IL-6 expression via modulating the p38/ERK/NF-κB signaling pathways. These results demonstrate that PM 10 induces inflammatory cytokines, which can lead to skin diseases. In addition, 7S MaR1 can resolve inflammation caused by PM 10 -induced oxidative stress and inflammatory cytokines. [BMB Reports 2024; 57(11): 490-496].

Interleukin-32γ (IL-32γ) has diverse functions in various malignancies. In this study, we investigated the role of IL-32γ in autophagy induction in liver cancer cells and delineated the underlying mechanisms. We found that the increased IL-32γ expression inhibited the growth, cell cycle progression, and migration of HepG2 and Hep3B cell lines; it also decreased the expression of related proteins. Furthermore, the IL-32γ overexpression induced autophagy, as indicated by the number of puncta, the expression of LC3, and the expression of autophagy-related markers. The expression levels of LAMP1, a protein essential for autophagosome formation, and colocalization with LC3 also increased. Big data analysis revealed that the expression of MET, a well-known target of autophagy, and the expression of mTOR and mTOR-related proteins were decreased by the IL-32γ overexpression. The combination treatment of MET inhibitor, cabozantinib (2 µM), and IL-32γ overexpression further increased the number of puncta, the colocalization of LC3 and LAMP1, and the expression of autophagy-related proteins. In vivo, liver tumor growth was suppressed in the IL-32γ-overexpressing mouse model, and autophagy induction was confirmed by the increased expression of LC3 and LAMP1 and the decreased expression of autophagy pathway markers (MET and mTOR). Autophagy was also decreased in the liver tumor sample of human patients. ROC curve and spearman analysis revealed that the expression levels of LC3 and IL-32γ were significantly correlated in human tumor serum and tissues. Therefore, IL-32γ overexpression induced autophagy in liver tumors through the suppression of MET and mTOR pathways critical for tumor growth inhibition.

Background: There is a dearth of research on the factors linked with adverse events (AEs) associated with nirmatrelvir/ritonavir (NMVr) and molnupiravir (MOL), particularly in the elderly. Therefore, this study aimed to investigate self-reported AEs and identify factors associated with the occurrence of AEs following NMVr or MOL treatment among survey participants aged 60 years or older in South Korea., Methods: This nationwide survey was conducted through in-person interviews using structured questionnaires, from July 24 to August 31, 2023. Eligible participants included individuals aged 60 years or older who had been diagnosed with coronavirus disease 2019 (COVID-19) and received NMVr or MOL. The study outcomes included self-reported demographic, lifestyle, and health characteristics associated with the occurrence of AEs. Multivariate logistic regression analysis was used to estimate the adjusted odds ratio (aOR) and 95% confidence interval (CI) of each characteristic in participants with and without AEs., Results: Of the 520 participants, 123 (23.7%) experienced at least one AE with oral COVID-19 treatment: 21.0% (96/458) for NMVr and 43.5% (27/62) for MOL. None of the participants reported any serious AEs. Increased odds of AE occurrence were observed in participants treated with MOL compared to those treated with NMVr (aOR, 3.05; 95% CI, 1.67-5.57), a history of two or more compared to one COVID-19 diagnosis (1.93; 1.03-3.62), and self-reported health status as "Unhealthy" compared to "Healthy" (2.65; 1.31-5.36)., Conclusion: No AEs required further evaluation to change treatment strategies in elderly patients on NMVr or MOL. Several factors, including the use of MOL, history of COVID-19, and reported health status, were associated with an increased incidence of AEs. Both treatments may still be useful choices for patients with non-severe COVID-19 aged 60 years or older. However, close monitoring of unidentified potential harm and further investigation of the factors associated with the occurrence of AEs are needed., Competing Interests: Ju-Young Shin received grants from the Korea Institute of Drug Safety and Risk Management. Other authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

Competing Interests: The authors have no financial conflicts of interest.

Purpose: A "Smart Cancer Care" platform that integrates patient-reported outcomes (PROs) with management has been established in Korea. This study focused on improving health behaviors and connecting patients to welfare services by introducing and assessing the feasibility of "Smart Cancer Care 2.0," an enhanced version designed for monitoring complications post-cancer treatment., Materials and Methods: Smart Cancer Care 2.0 was developed by conducting a literature review and consulting with expert panels to identify symptoms or variables requiring monitoring and management guidelines based on the treatment type. Qualitative and quantitative surveys were conducted to assess the feasibility of the app and web system based on the experiences of patients with cancer and healthcare workers., Results: A total of 81 symptoms or variables (chemotherapy-, surgery-, radiotherapy-, rehabilitation-, and health management-related) were selected for management in Smart Cancer Care 2.0. PROs for these symptoms were basically categorized into three severity grades: preventive management, self-treatment, and consultation with a healthcare worker or visit to a healthcare institution. The overall mean scores in the feasibility evaluation by patients and healthcare workers were 3.83 and 3.90 points, respectively, indicating high usefulness., Conclusion: Smart Cancer Care 2.0 leverages the existing information and communication technologies-based platform, Smart Cancer Care, and further includes health behaviors and welfare services. Smart Cancer Care 2.0 may play a crucial role in establishing a comprehensive post-discharge management system for patients with cancer as it provides suitable interventions based on patients' responses and allows the regularly collected PROs to be easily viewed for streamlined care.

Age-related macular degeneration (AMD), often triggered by endothelial barrier disruption through vascular endothelial growth factor (VEGF), is a leading cause of blindness. This study investigated the inhibitory effects of phenolic compounds on VEGF-induced endothelial cell proliferation, migration, angiogenesis, and permeability using human retinal microvascular endothelial cells (hRECs). Thirty-seven polyphenolic compounds were selected from various databases based on their antioxidant properties, abundance in food, and solubility. These compounds significantly reduced migration, tube formation, and endothelial permeability in VEGF-stimulated hRECs. Notably, formononetin, eriodictyol, biochanin A, and p-coumaric acid were more effective in suppressing VEGF-induced angiogenesis and endothelial permeability than lutein. Molecular docking simulations revealed that formononetin, eriodictyol, and biochanin A had relatively lower binding energies with VEGF receptor 2 (VEGFR2) than lutein and sorafenib. These findings highlight the potential of phenolic compounds to be used as VEGFR2 inhibitors and an alternative strategy for preventing AMD., Competing Interests: AUTHOR DISCLOSURE STATEMENT The authors declare no conflict of interest., (© 2024 The Korean Society of Food Science and Nutrition.)

Background: Lipoprotein(a) (Lp[a]) is associated with the development of aortic valve calcification., Objectives: The aim of this study was to evaluate the association between the serum level of Lp(a) and the development of severe degenerative aortic stenosis (AS) and subsequent aortic valve replacement (AVR)., Methods: A total of 44,742 patients with Lp(a) measurements and echocardiography at baseline evaluation between 2000 and 2020 were included from a single tertiary heart center. The primary outcome was the development of severe degenerative AS, defined as a transaortic maximal velocity of ≥4.0 m/s., Results: During a median follow-up period of 6.8 years (Q1-Q3: 2.3-12.4 years), severe degenerative AS was diagnosed in 472 patients (1.1%), and subsequent AVR was performed in 387 patients (0.9%). Lp(a) levels were associated with risk for severe degenerative AS, with levels of 30 to 50, 50 to 100, and >100 mg/dL demonstrating adjusted HRs of 1.02 (95% CI: 0.78-1.34; P  = 0.88), 1.18 (95% CI: 0.91-1.53; P  = 0.22), and 1.96 (95% CI: 1.31-2.94; P  = 0.001) compared to <30 mg/dL. Similarly, the risk for AVR due to severe degenerative AS was significantly associated with higher levels of Lp(a) (>100 mg/dL) (adjusted HR: 2.05; 95% CI: 1.31-3.19; P  = 0.002). Such associations were not observed in the development of severe bicuspid ( P  = 0.63) or rheumatic ( P  = 0.96) AS., Conclusions: Lp(a) levels >100 mg/dL were significantly associated with risk for severe degenerative AS and subsequent AVR, regardless of the baseline severity of AS. Such associations were not observed in other etiologies of severe AS., Competing Interests: This research was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, funded by the Ministry of Health and Welfare, Republic of Korea (grant HC19C0022). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

The relationship between aging and RNA biogenesis and trafficking is attracting growing interest, yet the precise mechanisms are unknown. The THO complex is crucial for mRNA cotranscriptional maturation and export. Herein, we report that the THO complex is closely linked to the regulation of lifespan. Deficiencies in Hpr1 and Tho2, components of the THO complex, reduced replicative lifespan (RLS) and are linked to a novel Sir2-independent RLS control pathway. Although transcript sequestration in hpr1Δ or tho2Δ mutants was countered by exosome component Rrp6, loss of this failed to mitigate RLS defects in hpr1Δ. However, RLS impairment in hpr1Δ or tho2Δ was counteracted by the additional expression of Nrd1-specific mutants that interacted with Rrp6. This effect relied on the interaction of Nrd1, a transcriptional regulator of aging-related genes, including ribosome biogenesis or RNA metabolism genes, with RNA polymerase II. Nrd1 overexpression reduced RLS in a Tho2-dependent pathway. Intriguingly, Tho2 deletion mirrored Nrd1 overexpression effects by inducing arbitrary Nrd1 chromatin binding. Furthermore, our genome-wide ChIP-seq analysis revealed an increase in the recruitment of Nrd1 to translation-associated genes, known to be related to aging, upon Tho2 loss. Taken together, these findings underscore the importance of Tho2-mediated Nrd1 escorting in the regulation of lifespan pathway through transcriptional regulation of aging-related genes., (© 2024 The Authors. Aging Cell published by Anatomical Society and John Wiley & Sons Ltd.)

Aralia elata (Miq.) Seem. (AES; family Araliaceae) is a medicinal plant and has been reported to have various bioactivities, including anticancer and hepatotoxicity protective activities. However, no studies have investigated the biological activities of AES or its extracts on skin. To address this, we aimed to explore the effect of AES-flower-derived absolute-type essential oil (AESFEO) on skin-related biological activities, especially skin wound healing and whitening-related responses in skin cells (human-derived keratinocytes [HaCaT cells] and melanocytes [B16BL6 cells]) and to identify the components of AESFEO. Cell biological activities were analyzed using WST and BrdU incorporation assays, ELISA, or by immunoblotting. In HaCaT cells, AESFEO promoted proliferation, type IV collagen production, and enhanced the phosphorylations of Erk1/2, p38 MAPK, JNK, and Akt. In B16BL6 cells, AESFEO reduced serum-induced proliferation, α-MSH-stimulated increases in melanin synthesis and tyrosinase activity, and α-MSH-induced increases in MITF, tyrosinase, TRP-1, and TRP-2 expressions. In addition, AESFEO inhibited the phosphorylation of Erk1/2, p38 MAPK, and JNK in α-MSH-stimulated B16BL6 cells. Eighteen compounds were identified in AESFEO by GC/MS. These results suggest that AESFEO has beneficial effects on keratinocyte activities related to skin wound healing and melanocyte activities related to inhibition of skin pigmentation. AESFEO may serve as a useful natural substance for developing agents that facilitate skin wound healing and inhibit melanogenesis.

Objective: This study aimed to analyze the effect of Smart Cancer Care program on the quality of life and ease of chemotherapy continuation in cancer patients and the effect of additional tele-management on frequency of use and satisfaction with the Smart Cancer Care program., Methods: 'Smart Cancer Care' is a mobile program that allows cancer patients undergoing chemotherapy to report symptoms of adverse events and receive remote management. In this study, patients were randomly assigned to three groups: Group A, who received only classical face-to-face management; Group B, who used the Smart Cancer Care program as addition; and Group C, who used the Smart Cancer Care program and received telephone management. After 12 weeks of follow-up, the effectiveness of using the Smart Cancer Care program was analyzed by examining the quality of life, ease of maintaining chemotherapy, and unplanned hospital visits in each group. The frequency of use and satisfaction with the Smart Cancer Care program were also analyzed., Results: Cancer patients who used the Smart Cancer Care program had 1.93-fold (1.15-3.25) higher overall quality of life than those who did not. This became 2.33-fold (1.34-4.04) higher when phone care was added. Patients with tele-management were significantly more likely to use the Smart Cancer Care program (odds ratio (OR) = 25.80; 95% confidence interval (CI), 11.28-58.97)., Conclusions: A mobile self-reported management program has a positive effect on the quality of life of cancer patients undergoing chemotherapy. Tele-management is conducive to active and effective use of this program., Competing Interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

As the main form of digital trade, cross-border e-commerce plays an important role, allowing China to expand its opening-up and promote the optimal foreign trade structure. It also provides opportunities for Chinese enterprises to develop digital technology. From the perspective of the establishment of China's cross-border e-commerce comprehensive pilot zone (CBECPZ), this article uses the multi-period DID method to examine the effects of cross-border e-commerce on enterprise digital technology innovation based on listed companies in the Shanghai and Shenzhen stock markets from 2007 to 2020. The CBECPZ dramatically promotes enterprise digital technology innovation. The mechanism test shows that the CBECPZ promotes digital technology innovation by financing constraint alleviation, digital transformation, and producer service industry agglomeration. The heterogeneity test shows that the direct effect is more significant in the enterprises of large-scale, non-state-owned, with high ICT correlation and in areas with strong government resource allocation capabilities. The research findings have important reference value for how to utilize cross-border e-commerce to promote digital technology innovation, and they also provide directional references for other developing countries to develop cross-border e-commerce., 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., (© 2024 The Authors.)

To investigate alteration of outer nuclear layer (ONL) and choroidal vascularity index (CVI) in different status of central serous chorioretinopathy (CSC). A retrospective review of 65 CSC eyes with subretinal fluid (manifest CSC) and 40 control eyes was conducted in a single tertiary university hospital. Differences in best-corrected visual acuity (BCVA), ONL, and CVI were compared. CVI was assessed both in the entire choroid (CVI-EC) and around the 1500 μm leakage area (CVI-1500). Measurements were repeated after the subretinal fluid resorption (quiescent CSC), and compared. CSC eyes showed worse BCVA, thinner ONL and greater CVI than controls. Quiescent CSC showed a recovery of ONL compared to the manifest CSC, along with the BCVA improvement. The resolution of the CSC revealed a decrease across all three choroidal areas (total, stromal and luminal), with a more pronounced reduction in the stromal than in the luminal choroidal area, leading to an increase in the CVI. This phenomenon was shown in both CVI-EC and CVI-1500. Conclusively, ONL thickness can be used as a quantitative biomarker for photoreceptor function in CSC. Increased CVI may reflect a disease activity. The stromal choroidal area is particularly sensitive in illustrating leakage from the choroidal vasculature., (© 2024. The Author(s).)

Background: N-(3-fluoropropyl)-2β-carboxymethoxy-3β-(4-iodophenyl) nortropane (FP-CIT), the representative cocaine derivative used in dopamine transporter imaging, is a promising biomarker, as it reflects the severity of Parkinson's disease (PD). 123 I- and 18 F-labeled FP-CIT has been used for PD diagnosis. However, preclinical studies evaluating [ 18 F]FP-CIT as a potential diagnostic biomarker are scarce. Among translational research advancements from bench to bedside, translating preclinical findings into clinical practice is one-directional. The aim of this study is to employ a circular approach, beginning back from the preclinical stage, progressing to the supplementation of [ 18 F]FP-CIT, and subsequently returning to clinical application. We investigated the pharmacokinetic properties of [ 18 F]FP-CIT and its efficacy for PD diagnosis using murine models., Results: Biodistribution, metabolite and excretion analyses were performed in mice and PD models were induced in rats using 6-hydroxydopamine (6-OHDA). The targeting efficiency of [ 18 F]FP-CIT for the dopamine receptor was assessed through animal PET/CT imaging. Subsequently, correlation analysis was conducted between animal PET/CT imaging results and immunohistochemistry (IHC) targeting tyrosine hydroxylase. Rapid circulation was confirmed after [ 18 F]FP-CIT injection. [ 18 F]FP-CIT reached the highest uptake of 23.50 ± 12.46%ID/g in the striatum 1 min after injection, and it was rapidly excreted within 60 min. The major metabolic organs of [ 18 F]FP-CIT were confirmed to be the intestines, liver, and kidneys. Its uptake in the intestine was approximately 5% ID/g. The uptake in the liver gradually increased, with excretion beginning after reaching a maximum after 60 min. The kidneys exhibited rapid elimination after 10 min. In the excretion study, rapid elimination was verified, with 21.46 ± 9.53% of the compound excreted within a 6 h period. Additionally, the efficacy of [ 18 F]FP-CIT PET was demonstrated in the PD model, with a high correlation with IHC for both the absolute value (R = 0.803, p = 0.0017) and the ratio value (R = 0.973, p = 0.0011)., Conclusions: This study fills the gap regarding insufficient preclinical studies on [ 18 F]FP-CIT, including its ADME, metabolites, and efficiency. The pharmacological results, including accurate diagnosis, rapid circulation, and [ 18 F]FP-CIT excretion, provide complementary evidence that [ 18 F]FP-CIT can be used safely and efficiently to diagnose PD in clinics, although it is already used in clinics., (© 2024. The Author(s).)

The tumor microenvironment (TME) is formed by several immune cells. Notably, tumor-associated macrophages (TAMs) are existed in the TME that induce angiogenesis, metastasis, and proliferation of cancer cells. Recently, a point-mutated variant of IL-32θ was discovered in breast cancer tissues, which suppressed migration and proliferation through intracellular pathways. Although the relationship between cancer and IL-32 has been previously studied, the effects of IL-32θ on TAMs remain elusive. Recombinant human IL-32θ (rhIL-32θ) was generated using an Escherichia coli expression system. To induce M0 macrophage polarization, THP-1 cells were stimulated with PMA. After PMA treatment, the cells were cultured with IL-4 and IL-13, or rhIL-32θ. The mRNA level of M1 macrophage markers (IL-1β, TNFα, inducible nitric oxide synthase) were increased by rhIL-32θ in M0 macrophages. On the other hand, the M2 macrophage markers (CCL17, CCL22, TGFβ, CD206) were decreased by rhIL-32θ in M2 macrophages. rhIL-32θ induced nuclear translocation of the NF-κB via regulation of the MAPK (p38) pathway. In conclusion, point-mutated rhIL-32θ induced the polarization to M1-like macrophages through the MAPK (p38) and NF-κB (p65/p50) pathways., Competing Interests: Conflict of Interest: The authors declare no potential conflicts of interest., (Copyright © 2024. The Korean Association of Immunologists.)

Acute liver failure is an infrequent yet fatal condition marked by rapid liver function decline, leading to abnormalities in blood clotting and cognitive impairment among individuals without prior liver ailments. The primary reasons for liver failure are infection with hepatitis virus or overdose of certain medicines, such as acetaminophen. Phaeodactylum tricornutum (PT), a type of microalgae known as a diatom species, has been reported to contain an active ingredient with anti-inflammatory and anti-obesity effects. In this study, we evaluated the preventive and therapeutic activities of PT extract in acute liver failure. To achieve our purpose, we used two different acute liver failure models: acetaminophen- and D-GalN/LPS-induced acute liver failure. PT extract showed protective activity against acetaminophen-induced acute liver failure through attenuation of the inflammatory response. However, we failed to demonstrate the protective effects of PT against acute liver injury in the D-GalN/LPS model. Although the PT extract did not show protective activity against two different acute liver failure animal models, this study clearly demonstrates the importance of considering the differences among animal models when selecting an acute liver failure model for evaluation.

Background: TRF1, TRF2, and TERT (Telomerase reverse transcriptase) are telomere-associated factors that regulate telomere length. Genetic changes in these genes may be associated with cancer pathogenesis; however, this relationship has not yet been comprehensively elucidated in lung cancer., Aim: : Exploring the clinicopathologic and prognostic values of TRF1, TRF2, and TERT mRNA expression in non-small cell lung cancers (NSCLC)., Methods: : The clinical significance of TRF1, TRF2, and TERT expression in 141 patients with NSCLC was investigated. Additionally, these findings were supported by the open big data from The Cancer Genome Atlas (TCGA)., Results: : TRF1 and TRF2 expression levels tended to be associated with smoking, and TERT expression was positively correlated with age. The survival analysis showed that TRF1 expression predicted a better prognosis for squamous cell carcinoma (SCC), whereas TRF2 expression was associated with a shorter survival in adenocarcinoma. TCGA data also showed a better prognosis for SCC with TRF1 expression. However, the TRF2 results were not in agreement with our data., Conclusions: : We present the clinical and prognostic values of TRF1, TRF2, and TERT expression in NSCLC tissues and TCGA. Our findings suggest that TRF1 expression is a possible prognostic marker for NSCLC, particularly SCC., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Chae et al.)

Acute coronary syndromes (ACS) often result from the rupture or erosion of high-risk coronary atherosclerotic plaques (ie, vulnerable plaques). Advances in intracoronary imaging such as intravascular ultrasound, optical coherence tomography, or near-infrared spectroscopy have improved the identification of vulnerable plaques, characterized by large plaque burden, small minimal luminal area, thin fibrous cap, and large lipid content. Although pharmacology, including lipid-lowering agents, and intensive risk-factor control are pivotal for management of vulnerable plaques and secondary prevention, recurrent events tend to accrue despite intensive pharmacotherapy. Therefore, it has been hypothesized that local preventive percutaneous coronary intervention may passivate these vulnerable plaques, preventing the occurrence of plaque-related ACS. However, solid evidence is lacking on its use for treatment of non-flow-limiting vulnerable plaques. As such, the optimal management of vulnerable plaques has not been established. Herein, we have reviewed the diagnosis and management of vulnerable plaques, focusing on systematic pharmacology and focal treatments., Competing Interests: The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Background: Although several studies deal with breakthrough reactions (BTRs) in patients with contrast media (CM) hypersensitivity reactions, the phenomenon is still unclear. Therefore, this study aimed to analyse in depth patients with BTR in two countries., Methods: We retrospectively analysed the electronic medical records of in- and outpatients (random sample enrolment) from two academic hospitals of tertiary care (Seoul/South Korea, with a special monitoring system exclusively for CM hypersensitivity, and Bern/Switzerland, manually operated) with respect to basic epidemiological data, number of BTRs per patient, and severity grades of severity in follow-up analyses. The study period lasted from 2013 (2000 Bern) to 2017., Results: We identified 445 BTR-patients (91.5% from Seoul) with 691 BTRs (94.5% from Seoul). Most reactions were mild, 11% moderate and 3.9% severe. In Seoul, we found patients with up to 10 BTRs, and in Bern, there were only patients with one BTR. Fatal reactions or deaths did not occur. In most cases, the severity of the BTRs and of the index reactions were identical (80.8%). Mild index reactions remained constant in 90.6%. In contrast, in moderate index reactions the severity decreased/remained identically in 86.8% and increased in 13.2%. In severe index reactions, 55.6% of BTR reactions were severe again, in 44.4% the severity decreased. In 158 BTRs (22.9%) the culprit iodinated contrast medium (ICM) of the index reaction induced the BTR. In the other 482 BTRs (69.8%) the culprit ICM was changed to another non-culprit ICM., Conclusions: To the best of our knowledge, this is the largest study on patients with BTRs, and the first study showing BTRs in two centers in two countries of two continents. The main differences between the two centers result from the different hospital size, the number of patients, and the different documentation [manual (Bern) vs. electronical screening (Seoul)]. BTRs are no contraindications for further ICM-application. We recommend performing an allergy skin test as basis for the decision-making process of the next contrast-enhanced image-guided examination., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-23-912/coif). The authors have no conflicts of interest to declare., (2024 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Background: As recognized by the World Health Organization in 2016 with its inclusion in the International Classification of Diseases, Tenth Revision as M62.84, and by South Korea in 2021 as M62.5, the diagnostic guidelines for sarcopenia vary globally. Despite its prevalence in older populations, data on sarcopenia in Koreans aged 60 and above is scarce, highlighting the need for research on its prevalence in this demographic., Methods: Utilizing the 2022 Korea National Health and Nutrition Examination Survey dataset, sarcopenia was assessed among 1,946 individuals aged 60 or older according to the Asian Working Group for Sarcopenia 2019 criteria, incorporating grip strength and bioelectrical impedance analysis measurements. Statistical analyses were performed to differentiate categorical and continuous variables using logistic regression and Student's t-tests, respectively., Results: The prevalence of sarcopenia was found to increase with age, with the highest prevalence observed in the oldest age group (80 years and older). The overall prevalence of sarcopenia in our study population was 6.8%. Among men, the prevalence of sarcopenia was 5.5% in the 60 or older age group, 9.6% in the 70 or older age group, and 21.5% in the 80 or older age group. Among women, the prevalence of sarcopenia was 7.9%, 10.5%, and 25.9%, respectively., Conclusions: This study highlights the significant burden of sarcopenia in elderly Koreans, particularly among the oldest individuals. These findings call for targeted interventions to manage and prevent sarcopenia, along with further research on its risk factors, consequences, and effective mitigation strategies.

Background: We aimed to evaluate whether the administration of remimazolam as a maintenance agent for general anesthesia affects the occurrence of hypotension compared with sevoflurane when switching to the beach chair position (BCP). Methods: We conducted a prospective randomized controlled trial from June 2023 to October 2023 in adult patients undergoing orthopedic surgery under general anesthesia in the BCP. A total of 78 participants were randomly allocated to the remimazolam (R) or sevoflurane (S) groups. The primary outcome was the incidence of hypotension that occurred immediately after switching to a BCP. The secondary outcomes included differences between the study groups in perioperative blood pressure (BP), heart rate (HR), endotracheal tube extubation time, postoperative complications, and hospital length of stay (LOS). Results: The incidence of hypotension immediately after switching to a BCP was significantly higher in the S group. The risk factors associated with hypotension included sevoflurane administration and a high baseline systolic BP. In the receiver operating characteristic curve analysis for the occurrence of hypotension after the transition to a BCP, the cutoff value for systolic BP was 142 mmHg. The perioperative BP and HR were higher in the R group at several timepoints. Postoperative endotracheal tube extubation time was shorter in the R group. There were no significant differences in the postoperative complications or hospital LOS between the two groups. Conclusions: Remimazolam should be considered as an anesthetic agent to prevent hypotension when switching to BCP, and hypotension may occur frequently in patients with high baseline BP.

Purpose: To assess the association between pattern changes in hemoglobin levels over time and the incidence of dementia using trajectories in females aged 55-79 years., Materials and Methods: We conducted a retrospective cohort study using females of aged 55-79 years from the National Health Insurance Service National Health Screening Cohort in Korea. To identify hemoglobin trajectories over eight years (2002-2009), we performed a three-step approach comprising measures of change, factor analysis, and cluster analysis. Univariate and multivariate Cox proportional hazard models were used to assess the associations between hemoglobin trajectories and the incidence of dementia., Results: We included 20,195 of 235,742 female participants. New dementia (N = 2664) was developed during follow-up period (2010-2015). Five hemoglobin trajectories were identified: high, mid, low, increasing, and decreasing. With high as a reference, the hazard ratios (HRs) for low and decreasing trajectories were significant, 1.28 (95% confidence interval [CI], 1.13-1.45) and 1.21 (95% CI, 1.10-1.34) in univariate models, respectively. However, only the HR for the decreasing trajectory was significant, 1.12 (95% CI, 1.01-1.24) after adjustment for confounders., Conclusion: The decreasing trajectory of hemoglobin levels within the normal range was associated with dementia. Even females aged 55-79 years without anemia might be vulnerable to dementia development risk., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Lee 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.)

Cave crickets (Rhaphidophoridae) are insects of an ancient and wingless lineage within Orthoptera that are distributed worldwide except in Antarctica, and each subfamily has a high level of endemicity. Here, we show the comprehensive phylogeny of cave crickets using multi-gene datasets from mitochondrial and nuclear loci, including all extant subfamilies for the first time. We reveal phylogenetic relationships between subfamilies, including the sister relationship between Anoplophilinae and Gammarotettiginae, based on which we suggest new synapomorphies. Through biogeographic analyses based on divergence time estimations and ancestral range reconstruction, we propose novel hypotheses regarding the biogeographic history of cave crickets. We suggest that Gammarotettiginae in California originated from the Asian lineage when Asia and the Americas were connected by the Bering land bridge, and the opening of the western interior seaway affected the division of Ceuthophilinae from Tropidischiinae in North America. We estimate that Rhaphidophoridae originated at 138 Mya throughout Pangea. We further hypothesize that the loss of wings in Rhaphidophoridae could be the result of their adaptation to low temperatures in the Mesozoic era., (© 2024. The Author(s).)

Background: The mechanisms leading to lung fibrosis are still under investigation. This study aimed to demonstrate whether antacids could prevent the development of interstitial lung disease (ILD)., Methods: This population-based longitudinal cohort study was conducted between January 2006 and December 2010 in South Korea. Eligible subjects were ≥40 years of age, exposed to proton pump inhibitors (PPI)±histamine-2 receptor antagonists (H-2 blockers) or H-2 blockers only, and had no history of ILD between 2004 and 2005. Exposure to antacids was defined as the administration of either PPI or H-2 receptor antagonists for &gt;14 days, whereas underexposure was defined as antacid treatment administered for less than 14 days. Newly developed ILDs, including idiopathic pulmonary fibrosis (IPF), were counted during the 5-year observation period. The association between antacid exposure and ILD development was evaluated using adjusted Cox regression models with variables, such as age, sex, smoking history, and comorbidities., Results: The incidence rates of ILD with/without antacid use were 43.2 and 33.8/100,000 person-years, respectively and those of IPF were 14.9 and 22.9/100,000 person-years, respectively. In multivariable analysis, exposure to antacid before the diagnosis of ILD was independently associated with a reduced development of ILD (hazard ratio [HR], 0.57; 95% confidence interval [CI], 0.45 to 0.71; p&lt;0.001), while antacid exposure was not associated with development of IPF (HR, 0.88; 95% CI, 0.72 to 1.09; p=0.06)., Conclusion: Antacid exposure may be independently associated with a decreased risk of ILD development.

Primary human dermal papilla cells (HDPCs) are often preferred in studies on hair growth and regeneration. However, primary HDPCs are limited by their reduced proliferative capacity, decreased hair induction potential, and extended doubling times at higher passages. To overcome these limitations, pTARGET vectors containing human papillomavirus16 (HPV16) E6/E7 oncogenes were transfected into HDPCs and selected using G-148 to generate immortalized cells here. HPV16 E6/E7 oncogenes were efficiently transfected into primary HDPCs. Immortalized HDPC showed higher proliferative activity than primary HDPC, confirming an increased proliferation rate. Expression of p53 and pRb proteins was downregulated by E6 and E7, respectively. E6/E7 expressing HDPC cells revealed that cyclin-dependent kinase (CDK) inhibitor p21 expression was decreased, while cell cycle-related genes and proteins (CDK2 and cyclin E) and E2F family genes were upregulated. Immortalized HDPCs maintained their responsiveness to Wnt/β-catenin pathway and hair follicle formation capability, as indicated by their aggregative properties and stemness. E6/E7 immortalized HDPCs may facilitate in vitro hair growth and regeneration studies.

Background: The COVID-19 pandemic posed numerous obstacles to psychosocial wellbeing for children. We conducted a longitudinal study to evaluate child mental health and social risks during the pandemic., Methods: Participants were 172 caregivers of children aged 6-11 years old who attended well child visits within 6 months before pandemic onset at an urban safety net hospital in the US. Prepandemic data was extracted from the electronic medical record, and surveys were administered at three time points between August 2020 and July 2021. We measured mental health symptoms with the Pediatric Symptom Checklist-17, social risks (e.g., food and housing insecurity) with the THRIVE questionnaire, and school modality (in-person, hybrid, remote)., Results: Compared to pre-pandemic, children had significantly higher PSC-17 total scores (overall mental health symptoms) and THRIVE total scores (total burden of social risks) at all three mid-pandemic waves. Using longitudinal mixed models accounting for time, social risks, and school modality, both social risks (B = 0.37, SE = 0.14, p < 0.01) and school modality were significantly associated with PSC-17 scores (B = - 1.95, SE = 0.63, p < 0.01). Children attending in-person school had fewer mental health symptoms than those attending remote or hybrid school., Conclusion: Mental health symptoms and social risks remained significantly higher fifteen months after the onset of the COVID-19 pandemic compared to prepandemic. In-person attendance at school appeared protective against persistently elevated mental health symptoms., (© 2024. The Author(s).)

Vutiglabridin, which affects the pharmacokinetics (PKs) of food, is currently under clinical development for the treatment of obesity. This study aimed to evaluate the effects of low- and high-fat meals on PKs of vutiglabridin in healthy male subjects. A randomized, open-label, single-dose, three-period, six-sequence crossover study was conducted. The subjects received a single oral dose of vutiglabridin 480 mg in a fasted state, 30 min after the intake of a low-fat meal (total 500-600 kcal, fat content 100-125 kcal) and high-fat meal (total 800-1000 kcal, fat content 500-600 kcal), with a 21-day washout period. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) for maximum plasma concentration (C max ) and area under the plasma concentration-time curve to the last measurable timepoint (AUC last ) were calculated. After intake of low- and high-fat meals, systemic exposure to vutiglabridin was increased, and the time to reach C max (T max ) was delayed compared to that in the fasted state. The GMRs (90% CIs) of low-fat meal to fasted state for C max and AUC last were 2.14 (1.76-2.60) and 2.15 (1.92-2.42), respectively, and those of high-fat meal to fasted state were 3.07 (2.53-3.72) and 3.00 (2.67-3.37), respectively. The median T max was delayed by 1.5 h in both fed states compared with that in the fasted state. The study drug was well-tolerated after administration in both the fed and fasted states. Food ingestion substantially increased the extent of oral vutiglabridin absorption in healthy subjects, and this enhancement increased with the fat content of the meal., (© 2024 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Immune cells rely on transient physical interactions with other immune and non-immune populations to regulate their function 1 . To study these 'kiss-and-run' interactions directly in vivo, we previously developed LIPSTIC (labelling immune partnerships by SorTagging intercellular contacts) 2 , an approach that uses enzymatic transfer of a labelled substrate between the molecular partners CD40L and CD40 to label interacting cells. Reliance on this pathway limited the use of LIPSTIC to measuring interactions between CD4 + T helper cells and antigen-presenting cells, however. Here we report the development of a universal version of LIPSTIC (uLIPSTIC), which can record physical interactions both among immune cells and between immune and non-immune populations irrespective of the receptors and ligands involved. We show that uLIPSTIC can be used, among other things, to monitor the priming of CD8 + T cells by dendritic cells, reveal the steady-state cellular partners of regulatory T cells and identify germinal centre-resident T follicular helper cells on the basis of their ability to interact cognately with germinal centre B cells. By coupling uLIPSTIC with single-cell transcriptomics, we build a catalogue of the immune populations that physically interact with intestinal epithelial cells at the steady state and profile the evolution of the interactome of lymphocytic choriomeningitis virus-specific CD8 + T cells in multiple organs following systemic infection. Thus, uLIPSTIC provides a broadly useful technology for measuring and understanding cell-cell interactions across multiple biological systems., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

In cancer treatment, multi-target approach has paid attention to a reasonable strategy for the potential agents. We investigated whether (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol (MMPP) could exert an anticancer effect by dual-regulating VEGFR2 and PPARγ. MMPP showed modulating effects in TNBC type (MDA-MB-231 and MDA-MB-468) and luminal A type (MCF7) breast cancer cell lines. MMPP enhanced PPARγ transcriptional activity and inhibited VEGFR2 phosphorylation. MMPP-induced signaling by VEGFR2 and PPARγ ultimately triggered the downregulation of AKT activity. MMPP exhibited anticancer effects, as evidenced by growth inhibition, inducement of apoptosis, and suppression of migration and invasion. At the molecular level, MMPP activated pro-apoptotic proteins (caspase3, caspase8, caspase9, and bax), while inhibiting the anti-apoptotic proteins (bcl2). Additionally, MMPP inhibited the mRNA expressions of EMT-promoting transcription factors. Therefore, our findings showed molecular mechanisms of MMPP by regulating VEGFR2 and PPARγ, and suggested that MMPP has potential to treat breast cancer.

Background: Sex-related disparities in clinical outcomes following transcatheter aortic valve replacement (TAVR) and the impact of sex on clinical outcomes after TAVR among different racial groups are undetermined., Objectives: This study assessed whether sex-specific differences in baseline clinical and anatomical characteristics affect clinical outcomes after TAVR and investigated the impact of sex on clinical outcomes among different racial groups., Methods: The TP-TAVR (Trans-Pacific TAVR) registry is a multinational cohort study of patients with severe aortic stenosis who underwent TAVR at 2 major centers in the United States and 1 major center in South Korea. The primary outcome was a composite of death from any cause, stroke, or rehospitalization after 1 year., Results: The incidence of the primary composite outcome was not significantly different between sexes (27.9% in men vs 28% in women; adjusted HR: 0.97; 95% CI: 0.79-1.20). This pattern was consistent in Asian (23.5% vs 23.3%; adjusted HR: 0.99; 95% CI: 0.69-1.41) and non-Asian (30.8% vs 31.6%; adjusted HR: 0.95; 95% CI: 0.72-1.24) cohorts, without a significant interaction between sex and racial group ( P for interaction = 0.74). The adjusted risk for all-cause mortality was similar between sexes, regardless of racial group. However, the adjusted risk of stroke was significantly lower in male patients than in female patients, which was more prominent in the non-Asian cohort., Conclusions: Despite significantly different baseline and procedural characteristics, there were no sex-specific differences in the adjusted 1-year rates of primary composite outcomes and all-cause mortality, regardless of different racial groups. (Transpacific TAVR registry [TP-TAVR]; NCT03826264)., Competing Interests: This study was supported by a grant (2020IF0016) from the Asan Institute for Life Sciences and Corporate Relations of Asan Medical Center (Seoul, South Korea) with the NAVER Corp (Seongnam, Korea). This study was also funded in part by the CVRF (Seoul, South Korea), Edwards Lifesciences, and Medtronic. Dr Yeung has received institutional research support from Edwards Lifesciences. Dr Fearon has received institutional research support from Edwards Lifesciences. Dr Malaisrie has received institutional research support from Edwards Lifesciences, Medtronic, Cryolife, and Terumo Aortic. Dr S.-J. Park has received receiving grants from Edwards Lifesciences, Medtronic, and Abbott. Dr D.-W. Park has received research grants and consultancy and speaker fees from Edwards Lifesciences, Medtronic, Abbott, and Daiichi-Sankyo during the study. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (© 2024 The Authors.)

Rehabilitation improves symptoms, quality of life, and survival in patients with chronic respiratory or cardiovascular disease. We evaluated smartphone application-based rehabilitation programs for patients with chronic respiratory or cardiovascular diseases. This was a single-center prospective single arm study. Participants underwent smartphone application-based pulmonary or cardiac rehabilitation for 12 weeks. A total of 93 participants were recruited, and 75 visited after rehabilitation. Their median age was 67.0 (interquartile range, 60.0-70.8) years, and 60 (80.0%) were men. For patients with chronic respiratory disease (n = 41), VO 2 peak (median 13.7 to 15.4 ml/kg/min, P = 0.049), chronic obstructive pulmonary disease assessment test (median 14 to 6, P < 0.001), Euro-QoL 5-Dimension 5-Level (EQ-5D-5L) index (median 0.795 to 0.862, P = 0.001), and Health-related Quality of Life Instrument with 8 Items (HINT-8) index (median 0.784 to 0.855, P < 0.001) were significantly improved. For patients with chronic cardiovascular disease (n = 34), VO 2 peak (median 21.8 to 23.3, P = 0.007), EQ-5D-5L index (median 0.871 to 1.000, P = 0.037), and HINT-8 index (median 0.890 to 0.903, P < 0.001) were significantly improved. The smartphone application-based rehabilitation program improved exercise capacity and quality of life in patients with chronic respiratory or cardiovascular disease.Trial registration: https://clinicaltrials.gov/ct2/show/NCT05383950 (20/05/2022)., (© 2024. The Author(s).)

Overactive bladder (OAB) is a symptom-based syndrome defined by urinary urgency, frequency, and nocturia with or without urge incontinence. The causative pathology is diverse; including bladder outlet obstruction (BOO), bladder ischemia, aging, metabolic syndrome, psychological stress, affective disorder, urinary microbiome, localized and systemic inflammatory responses, etc. Several hypotheses have been suggested as mechanisms of OAB generation; among them, neurogenic, myogenic, and urothelial mechanisms are well-known hypotheses. Also, a series of local signals called autonomous myogenic contraction, micromotion, or afferent noises, which can occur during bladder filling, may be induced by the leak of acetylcholine (ACh) or urothelial release of adenosine triphosphate (ATP). They can be transmitted to the central nervous system through afferent fibers to trigger coordinated urgency-related detrusor contractions. Antimuscarinics, commonly known to induce smooth muscle relaxation by competitive blockage of muscarinic receptors in the parasympathetic postganglionic nerve, have a minimal effect on detrusor contraction within therapeutic doses. In fact, they have a predominant role in preventing signals in the afferent nerve transmission process. β3-adrenergic receptor (AR) agonists inhibit afferent signals by predominant inhibition of mechanosensitive Aδ-fibers in the normal bladder. However, in pathologic conditions such as spinal cord injury, it seems to inhibit capsaicin-sensitive C-fibers. Particularly, mirabegron, a β3-agonist, prevents ACh release in the BOO-induced detrusor overactivity model by parasympathetic prejunctional mechanisms. A recent study also revealed that vibegron may have 2 mechanisms of action: inhibition of ACh from cholinergic efferent nerves in the detrusor and afferent inhibition via urothelial β3-AR.

Objective: 177 Lutetium [Lu] Ludotadipep is a novel prostate-specific membrane antigen targeting therapeutic agent with an albumin motif added to increase uptake in the tumors. We assessed the biodistribution and dosimetry of [ 177 Lu]Ludotadipep in patients with metastatic castration-resistant prostate cancer (mCRPC)., Materials and Methods: Data from 25 patients (median age, 73 years; range, 60-90) with mCRPC from a phase I study with activity escalation design of single administration of [ 177 Lu]Ludotadipep (1.85, 2.78, 3.70, 4.63, and 5.55 GBq) were assessed. Activity in the salivary glands, lungs, liver, kidneys, and spleen was estimated from whole-body scan and abdominal SPECT/CT images acquired at 2, 24, 48, 72, and 168 h after administration of [ 177 Lu]Ludotadipep. Red marrow activity was calculated from blood samples obtained at 3, 10, 30, 60, and 180 min, and at 24, 48, and 72 h after administration. Organ- and tumor-based absorbed dose calculations were performed using IDAC-Dose 2.1., Results: Absorbed dose coefficient (mean ± standard deviation) of normal organs was 1.17 ± 0.81 Gy/GBq for salivary glands, 0.05 ± 0.02 Gy/GBq for lungs, 0.14 ± 0.06 Gy/GBq for liver, 0.77 ± 0.28 Gy/GBq for kidneys, 0.12 ± 0.06 Gy/GBq for spleen, and 0.07 ± 0.02 Gy/GBq for red marrow. The absorbed dose coefficient of the tumors was 10.43 ± 7.77 Gy/GBq., Conclusion: [ 177 Lu]Ludotadipep is expected to be safe at the dose of 3.7 GBq times 6 cycles planned for a phase II clinical trial with kidneys and bone marrow being the critical organs, and shows a high tumor absorbed dose., Competing Interests: Chansoo Park is an employee of FutureChem Co., Ltd., and Dae Yoon Chi is its chief executive officer. Seunggyun Ha has consultant agreement with FutureChem. Joo Hyun O has consultant agreements with FutureChem and Novartis, and as a member of the editorial board of the Korean Journal of Radiology, she was not involved in the editorial evaluation or decision to publish this article. All remaining authors have declared no conflicts of interest., (Copyright © 2024 The Korean Society of Radiology.)