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Abstract By investigating the correlation between the injection rate and pressure of subretinal tissue plasminogen activator (tPA) and air using a standard Viscous Fluid Control (VFC) system with a 38-gauge cannula, we aimed to establish guidelines for stable injections. We fabricated a retina mimicking model (RMM) with 0.25% agarose solution and an aluminum plate, and substituted submacular hemorrhage (SMH) and tPA with blood-mimicking fluid (BMF) and balanced salt solution (BSS), respectively. The diameter of the pre-bleb mimicking SMH in RMM was 1.30 ± 0.16 cm, increasing to 1.98 ± 0.24 cm and 1.83 ± 0.22 cm after bleb propagation with BSS and air, respectively. BSS injection rates were 2.86 ± 0.04 µl/sec, 6.74 ± 0.48 µl/sec and 8.55 ± 0.16 µl/sec at 8, 12, and 16 psi, respectively. Air injection rates were 37.98 ± 3.11 µl/sec, 79.01 ± 5.13 µl/sec and 156.06 ± 13.72 µl/sec at 2, 3 and 4 psi, respectively. By experimenting with different pressures in the RMM, we found 12 psi to be the minimum for proper BSS injection and 2 psi for air. These findings provide crucial parameters for safer surgery to prevent irreversible damage.

Abstract Background and Objective This study aimed to assess and compare the pharmacokinetics, safety, and tolerability of a fixed-dose combination product (FDCP) comprising four different drugs (two antihypertensive drugs, amlodipine and losartan, and two lipid-lowering agents, ezetimibe and rosuvastatin) with their separate tablets. Methods A total of 60 participants were enrolled in this open-label, randomized, single-dose crossover study. Each participant received a single dose of FDCP and individual tablets during each period, with a 14-day washout period between the periods. The pharmacokinetic parameters of amlodipine, losartan, EXP3174 (an active metabolite of losartan), rosuvastatin, free ezetimibe, and total ezetimibe were evaluated and compared. Results The pharmacokinetic profiles of amlodipine, losartan, rosuvastatin, and ezetimibe after administration of the individual products were similar to those of FDCP. The geometric mean ratios and 90% confidence intervals for maximum concentration (C max) and area under the curve (AUC) of FDCP to individual tablets were within 0.8–1.25 for all six analytes. No clinically relevant changes were observed in the vital signs or physical, biochemical, hematological, electrocardiographic, or urinalysis findings during the study, and no serious adverse events were reported. Conclusion This study demonstrated that a newly developed FDCP containing amlodipine, losartan, ezetimibe, and rosuvastatin exhibited pharmacokinetic equivalence with the individual products and met the regulatory criteria. Both formulations were well tolerated. Clinical Trial Registration This trial (NCT04322266) was retrospectively registered on 9 September 2019.

Abstract Background Immunotherapy with clodronate-encapsulated liposomes, which induce macrophage depletion, has been studied extensively. However, previously reported liposomal formulation-based drugs (Clodrosome® and m-Clodrosome®) are limited by their inconsistent size and therapeutic efficacy. Thus, we aimed to achieve consistent therapeutic effects by effectively depleting macrophages with uniform-sized liposomes. Results We developed four types of click chemistry-based liposome nanoplatforms that were uniformly sized and encapsulated with clodronate, for effective macrophage depletion, followed by conjugation with Man-N3 and radiolabeling. Functionalization with Man-N3 improves the specific targeting of M2 macrophages, and radioisotope labeling enables in vivo imaging of the liposome nanoplatforms. The functionalized liposome nanoplatforms are stable under physiological conditions. The difference in the biodistribution of the four liposome nanoplatforms in vivo were recorded using positron emission tomography imaging. Among the four platforms, the clodronate-encapsulated mannosylated liposome effectively depleted M2 macrophages in the normal liver and tumor microenvironment ex vivo compared to that by Clodrosome® and m-Clodrosome®. Conclusion The newly-developed liposome nanoplatform, with finely tuned size control, high in vivo stability, and excellent ex vivo M2 macrophage targeting and depletion effects, is a promising macrophage-depleting agent. Graphical Abstract

Abstract Polycystic ovary syndrome (PCOS) is a highly complex reproductive metabolic disorder and women with PCOS have high prevalence of non-alcoholic fatty liver disease (NAFLD). Despite both hyperandrogenism and insulin resistance are common pathophysiologies in NAFLD and PCOS, this association is still controversial. Therefore, the aim of this study is to evaluate the relationship between hyperandrogenism and NAFLD in females diagnosed with PCOS. We recruited 667 women diagnosed with PCOS and 289 women with regular menstrual cycles as control. The PCOS diagnosis was made using National Institute of Child Health and Human Disease criteria. Total and free testosterone levels (TT and TF, respectively), and free androgen index (FAI) were used as measures of hyperandrogenism. Fatty liver index and liver fat score (FLI and LFS, respectively), and hepatic steatosis index (HSI) were used to assess NAFLD. The prevalence of NAFLD in PCOS women evaluated by LFS, FLI, and HIS were 19.9, 10.3, and 32.2%, respectively. In the control group, the incidence was 2.1, 0.7, and 4.2%, respectively. Both FT and FAI levels showed significant association with increased NAFLD-related indices, after adjusting for insulin resistance and other factors (LFS (OR 3.18 (95% CI 1.53–6.63) in FT; 1.12 (1.04–1.22) in FAI), FLI (OR 2.68 (95% CI 1.43–5.03) in FT; 1.13 (1.06–1.20) in FAI), and HSI (OR 3.29 (95% CI 2.08–5.21) in FT; 1.5 (1.09–1.21) in FAI). TT did not exhibit association with any NAFLD index. In women with PCOS, significantly higher rate of NAFLD was observed compared to the control women. The FT and FAI were independently associated with NAFLD in women with PCOS. The findings suggest the possibility of hyperandrogenism contributing to the progression and/or development of NAFLD in PCOS.

Adolescence is a stage during which individuals develop social adaptability through meaningful interactions with others. During this period, students gradually expand their social networks outside the home, forming a sense of community. The aim of the current study was to explore the key predictors related to sense of community among Korean high school students and to develop supportive policies that enhance their sense of community. Accordingly, random forests and SHapley Additive exPlanations (SHAP) were applied to the 7th wave (11th graders) of the Korean Education Longitudinal Study 2013 data (n = 6,077). As a result, 6 predictors positively associated with sense of community were identified, including self-related variables, “multicultural acceptance,” “behavioral regulation strategy,” and “peer attachment,” consistent with previous findings. Newly derived variables that predict sense of community include “positive recognition of volunteering,” “creativity,” “observance of rules” and “class attitude,” which are also positively related to sense of community. The implications of these results and some suggestions for future research are also discussed.

Abstract Background Immune checkpoint inhibitors such as anti-programmed cell death protein 1 (PD1) block tumor growth by reinvigorating the immune system; however, determining their efficacy only by the changes in tumor size may prove inaccurate. As the immune cells including macrophages in the tumor microenvironment (TME) are associated with the response to anti-PD1 therapy, tumor-associated macrophages (TAMs) imaging using nanoparticles can noninvasively provide the immune enrichment status of TME. Herein, the mannosylated-serum albumin (MSA) nanoparticle was labeled with radioactive isotope 68Ga to target the mannose receptors on macrophages for noninvasive monitoring of the TME according to anti-PD1 therapy. Results B16F10-Luc and MC38-Luc tumor-bearing mice were treated with anti-PD1, and the response to anti-PD1 was determined by the tumor volume. According to the flow cytometry, the responders to anti-PD1 showed an increased proportion of TAMs, as well as lymphocytes, and the most enriched immune cell population in the TME was also TAMs. For noninvasive imaging of TAMs as a surrogate of immune cell augmentation in the TME via anti-PD1, we acquired [68Ga] Ga-MSA positron emission tomography. According to the imaging study, an increased number of TAMs in responders at the early phase of anti-PD1 treatment was observed in both B16F10-Luc and MC38-Luc tumor-bearing mice models. Conclusion As representative immune cells in the TME, non-invasive imaging of TAMs using MSA nanoparticles can reflect the immune cell enrichment status in the TME closely associated with the response to anti-PD1. As non-invasive imaging using MSA nanoparticles, this approach shows a potential to monitor and evaluate anti-tumor response to immune checkpoint inhibitors.

Background and Objectives: Chemokines have various biological functions and potential roles in the development or progression of neuroinflammatory diseases. However, the specific pathogenic roles of chemokines in the major cause for vision loss among the elderly, the leading cause of blindness in older individuals, remain elusive. Chemokines interact with their receptors expressed in the endothelium and on leukocytes. The sulfation of tyrosine residues in chemokine receptors increases the strength of ligand–receptor interaction and modulates signaling. Therefore, in the present study, we aimed to construct a human recombinant sulfated CXCR3 peptide trap (hCXCR3-S2) and mouse recombinant sulfated CXCR3 peptide trap (mCXCR3-S2) to demonstrate in vivo effects in preventing choroidal neovascularization (CNV) and chemotaxis. Materials and Methods: We generated expression vectors for mCXCR3-S2 and hCXCR3-S2 with GST domains and their respective cDNA sequences. Following overexpression in E. coli BL21 (DE3), we purified the fusion proteins from cell lysates using affinity chromatography. First, the impact of hCXCR3-S2 was validated in vitro. Subsequently, the in vivo efficacy of mCXCR3-S2 was investigated using a laser-induced CNV mouse model, a mouse model of neovascular age-related macular degeneration (AMD). Results: hCXCR3-S2 inhibited the migration and invasion of two human cancer cell lines. Intravitreal injection of mCXCR3-S2 attenuated CNV and macrophage recruitment in neovascular lesions of mouse models. These in vitro and in vivo effects were significantly stronger with CXCR3-S2 than with wild-type CXCR3 peptides. Conclusion: These findings demonstrate that the sulfated form of the CXCR3 peptide trap is a valuable tool that could be supplemented with antivascular endothelial growth factors in AMD treatment.

Single cell transcriptomics pinpoints a cell subpopulation that could be involved in inducing cellular senescence of the retinal pigment epithelium, which in turn may construe retinal degenerative disease.

Abstract Immune checkpoint inhibitors and vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR TKIs) are mainstream treatments for renal cell carcinoma (RCC). Both T cells and macrophages infiltrate the tumor microenvironment of RCC. CD47, an immune checkpoint of macrophages, transmits the “don’t eat me” signal to macrophages. We propose a novel therapeutic strategy that activates the antitumor effect of macrophages. We found that CD47 was expressed in patients with RCC, and high CD47 expression was indicative of worse overall survival in datasets from The Cancer Genome Atlas. We observed that CD47-blocking antibodies enhanced the antitumor effect of macrophages against human RCC cell lines. Trogocytosis, rather than phagocytosis, occurred and was promoted by increased cell-to-cell contact between macrophages and RCC cells. Trogocytosis induced by CD47 blockade occurred in the presence of CD11b integrin signaling in macrophages and was augmented when RCC cells were exposed to VEGFR TKIs, except for sunitinib. In conclusion, this study presents evidence that anti-CD47 blocking antibodies improve the antitumor effect of macrophages in RCC. In combination with VEGFR TKIs, CD47 blockade is a potential therapeutic strategy for patients with RCC.

Abstract The clinical implication of en face imaging of Haller vessels and macular neovascularization (MNV) in neovascular age-related macular degeneration (nAMD) is not well established. The purpose of this study is to investigate whether the early-phase morphology of en face Haller vessel and MNV is related to the injection frequency and visual outcome in treatment-naïve nAMD. En face images of Haller vessel and MNV were acquired from 52 eyes at baseline, after three loading doses and at 12 months later using optical coherence tomography (OCT) and OCT angiography. Vessel area, diameter, length, intersection number, fractal dimension, and lacunarity were calculated. Patients were classified according to the injection frequency (

Metabolic dysregulation is an important hallmark of cancer. Nicotinamide (NAM), a water‐soluble amide form of niacin (vitamin B3), is currently available as a supplement for maintaining general physiologic functions. NAM is a crucial regulator of mitochondrial metabolism and redox reactions. In this study, we aimed to identify the mechanistic link between NAM‐induced metabolic regulation and the therapeutic efficacy of NAM in triple‐negative breast cancer (TNBC). The combined analysis using multiomics systems biology showed that NAM decreased mitochondrial membrane potential and ATP production, but increased the activities of reverse electron transport (RET), fatty acid β‐oxidation and glycerophospholipid/sphingolipid metabolic pathways in TNBC, collectively leading to an increase in the levels of reactive oxygen species (ROS). The increased ROS levels triggered apoptosis and suppressed tumour growth and metastasis of TNBC in both human organoids and xenograft mouse models. Our results showed that NAM treatment leads to cancer cell death in TNBC via mitochondrial dysfunction and activation of ROS by bifurcating metabolic pathways (RET and lipid metabolism); this provides insights into the repositioning of NAM supplement as a next‐generation anti‐metabolic agent for TNBC treatment.

The Program for International Student Assessment (PISA) aims to provide comparative data on 15-year-olds’ academic performance and well-being. The purpose of the current study is to explore and compare the variables that predict the reading literacy and life satisfaction of U.S. and South Korean students. The random forest algorithm, which is a machine learning approach, was applied to PISA 2018 data (4,677 U.S. students and 6,650 South Korean students) to explore and select the key variables among 305 variables that predict reading literacy and life satisfaction. In each random forest analysis, one for the U.S. and another for South Korea, 23 variables were derived as key variables in students’ reading literacy. In addition, 23 variables in the U.S. and 26 variables in South Korea were derived as important variables for students’ life satisfaction. The multilevel analysis revealed that various student-, teacher- or school-related key variables derived from the random forest were statistically related to either U.S. and/or South Korean students’ reading literacy and/or life satisfaction. The current study proposes to use a machine learning approach to examine international large-scale data for an international comparison. The implications of the current study and suggestions for future research are discussed.

Abstract This study aimed to quantify the Haller vessel and choriocapillaris (CC) parameters in drusen subtypes in nonexudative age-related macular degeneration (AMD) and pachydrusen. Ninety-five eyes of 80 patients and 28 control eyes were categorized into soft drusen, subretinal drusenoid deposit (SDD), soft drusen plus SDD, pachydrusen, and control groups. The diameter, length and intersections of Haller vessels and the total area, size and number of CC flow voids were quantified using en face optical coherence tomography (OCT) or OCT angiography. The pachydrusen group showed the largest Haller vessel area and diameter and shortest total length but similar CC parameters to those in the control group. The soft drusen plus SDD group showed the largest CC flow void area and size, while the Haller parameters were similar to those in the control group. The area and size of the flow voids in the SDD group were smaller than those in the soft drusen plus SDD group. Based on unsupervised machine learning, the eyes were classified into 4 clusters—the control, pachydrusen, soft drusen plus SDD and soft drusen plus SDD groups. Cluster 3 showed a larger diameter and shorter total length of the Haller vessels than cluster 4.

Re-emerging viral threats have continued to challenge the medical and public health systems. It has become clear that a significant number of severe viral infection cases are due to an overreaction of the immune system, which leads to hyperinflammation. In this study, we aimed to demonstrate the therapeutic efficacy of the dexamethasone nanomedicine in controlling the symptoms of influenza virus infection. We found that the A/Wisconsin/WSLH34939/2009 (H1N1) infection induced severe pneumonia in mice with a death rate of 80%, accompanied by significant epithelial cell damage, infiltration of immune cells, and accumulation of pro-inflammatory cytokines in the airway space. Moreover, the intranasal delivery of liposomal dexamethasone during disease progression reduced the death rate by 20%. It also significantly reduced the protein level of tumor necrosis factor-alpha (TNFα), interleukin-1β (IL-1β), IL-6, and the C-X-C motif chemokine ligand 2 (CXCL2) as well as the number of infiltrated immune cells in the bronchoalveolar lavage fluids as compared to the control and free dexamethasone. The liposomal dexamethasone was mainly distributed into the monocyte/macrophages as a major cell population for inducing the cytokine storm in the lungs. Taken together, the intranasal delivery of liposomal dexamethasone may serve as a novel promising therapeutic strategy for the treatment of influenza A-induced pneumonia.

Abstract Background To investigate the clinical features of diabetic macular edema (DME) in eyes with pachychoroid phenotypes using multimodal retinal imaging. Methods We retrospectively reviewed 210 eyes from 210 DME patients and analyzed the clinical and imaging parameters, including visual acuity, central macular thickness (CMT), subfoveal choroidal thickness (SFCT) and neural retina layer thickness (NRT). The DME eyes were divided into two groups: group 1 (80 eyes with submacular detachment [SMD]) and group 2 (130 eyes without SMD). The clinical and imaging parameters of 285 eyes from 285 diabetic patients without DME were collected as a control group. Results DME eyes with pachychoroid phenotypes were more frequent in group 1 than in group 2 (53 eyes [66.25%] and 53 eyes [40.77%], respectively, P

Higher risk of major hemorrhage associated with concomitant use of dabigatran and simvastatin compared to other statins was previously reported with a suggestion of P-glycoprotein-mediated interaction. The aim of this study was to evaluate the effects of simvastatin on pharmacokinetics and anticoagulant effects of dabigatran, a direct oral anticoagulant. A total of 12 healthy subjects were enrolled in an open-label, two-period, single sequence study. Subjects were given 150 mg of dabigatran etexilate followed by 40 mg of once-daily simvastatin for seven days. Dabigatran etexilate was administered with simvastatin on the seventh day of simvastatin administration. Blood samples for pharmacokinetic and pharmacodynamic analyses were obtained until 24 h post-dose of dabigatran etexilate with or without co-administration of simvastatin. Pharmacokinetic parameters were derived from noncompartmental analysis for dabigatran etexilate, dabigatran, and dabigatran acylglucuronide. When simvastatin was co-administered, geometric mean ratios of area under time-concentration curves for dabigatran etexilate, dabigatran, and dabigatran acylglucuronide were 1.47, 1.21, and 1.57, respectively, compared to when dabigatran etexilate was administered alone. Thrombin generation assay and coagulation assay showed similar profiles between before and after co-administration of simvastatin. This study provides evidence that simvastatin treatment plays a minor role in modulating pharmacokinetics and anticoagulant effects of dabigatran etexilate.

Matrix stiffness, a critical physical property of the cellular environment, is implicated in epidermal homeostasis. In particular, matrix stiffening during the pathological progression of skin diseases appears to contribute to cellular responses of keratinocytes. However, it has not yet elucidated the molecular mechanism underlying matrix-stiffness-mediated signaling in coordination with chemical stimuli during inflammation and its effect on proinflammatory cytokine production. In this study, we demonstrated that keratinocytes adapt to matrix stiffening by increasing cell–matrix adhesion via actin cytoskeleton remodeling. Specifically, mechanosensing and signal transduction are coupled with chemical stimuli to regulate cytokine production, and interleukin-6 (IL-6) production is elevated in keratinocytes on stiffer substrates in response to 2,4-dinitrochlorobenzene. We demonstrated that β1 integrin and focal adhesion kinase (FAK) expression were enhanced with increasing stiffness and activation of ERK and the PI3K/Akt pathway was involved in stiffening-mediated IL-6 production. Collectively, our results reveal the critical role of matrix stiffening in modulating the proinflammatory response of keratinocytes, with important clinical implications for skin diseases accompanied by pathological matrix stiffening.

Epithelioid sarcomas (ESs) of the vulva are extremely rare soft tissue tumors characterized by an aggressive clinical course and a poor prognosis. The proximal type of ES occurs in the trunk and external genital area and has higher recurrence and distant metastasis rates than the distal type, which is found in the upper and lower extremities. We describe a case of a vulvar ES in a 24-year-old patient who was referred from the department of plastic surgery with protruding mushroom-like lesions in multiple areas, including the lower abdomen, whole vulva, anus, and both inguinal lesions. A biopsy of the lesions confirmed a proximal-type ES. Computed tomography and magnetic resonance imaging revealed multiple metastatic lesions in several regions, including the perineum, vagina, and inguinal regions; nodal metastases in the left external iliac and right inguinal region; and distant metastases in the lungs, pleura of the left lung, bones, and soft tissue. The patient underwent active palliative radiotherapy, followed by chemotherapy, and showed a partial response to treatment. Nineteen months after the initial diagnosis, the patient expired due to cancer progression and pneumothorax.

ObjectiveThe aims of this study were to introduce surgical guidelines, and to evaluate the feasibility and safety of a robotic single-site staging (RSSS) operation for early-stage endometrial cancer.MethodsPatients with a preoperative diagnosis of endometrial cancer (International Federation of Gynecology and Obstetrics stages IA to IB) from endometrial curettage and preoperative imaging studies were selected at Dongsan Medical Center from March 2014 to November 2015. All surgical procedures, including hysterectomy, salpingo-oophorectomy, bilateral pelvic node dissection, and cytology aspiration, were performed by robotic single-site instruments (da Vinci Si® surgical system; Intuitive Surgical, Sunnyvale, CA, USA).ResultsA total of 15 women with early-stage endometrial cancer underwent the RSSS operation. The median patient age and body mass index were 53 years (range, 37–70 years) and 25.4 kg/m2 (range, 18.3–46.4 kg/m2). The median docking time, console time, and total operative time were 8 minutes (range, 4–15 minutes), 75 minutes (range, 55–115 minutes), and 155 minutes (range, 125–190 minutes), respectively. The median retrieval of both pelvic lymph nodes was 9 (range, 6–15). There were no conversions to laparoscopy or laparotomy.ConclusionThe RSSS operation is feasible and safe in patients with early-stage endometrial cancer. In this study, operative times were reasonable, and the surgical procedure was well-tolerated by the patients. Further evaluation of patients with early-stage endometrial cancer should be performed in large-scale comparative studies using the laparoendoscopic, single-site staging operation to confirm the safety and benefits of the RSSS operation for early-stage endometrial cancer.

Imatinib is transported extracellularly by ABCB1 and ABCG2 efflux transporters and bound to alpha-1-acid glycoprotein (AGP) in the bloodstream. However, the clinical and pharmacokinetic effects of ABCB1 and ABCG2 on imatinib were inconsistent in the previous literature and have not been confirmed. Therefore, in the present study, we explored the effects of the ABCG2 and ABCB1 genetic polymorphisms on imatinib pharmacokinetics in association with plasma AGP levels in healthy subjects. Twenty-seven healthy individuals were recruited, genotyped for ABCG2 and ABCB1, and given a single oral dose of 400 mg imatinib. Plasma imatinib concentrations were measured and its pharmacokinetics was assessed with respect to ABCG2 (c.421C>A and c.34G>A) and ABCB1 (c.1236C>T, c.2677C>T/A, and c.3435C>T) genotypes, and plasma AGP levels. AGP levels showed a strong positive correlation with imatinib pharmacokinetics. ABCG2 c.421C>A single nucleotide polymorphism showed a statistically significant effect on imatinib pharmacokinetics in low plasma AGP levels groups (

The current study examined the role of family orientations on the achievement motivations (i.e., achievement goal orientations and intrinsic motivation) of high school youths of different generational status (i.e., from immigrant or non-immigrant families) when their perception of their parents’ goals and classroom goal structures were tested simultaneously as predictors. A total of 331 high school students (ninth grade; ages 13–16, with 96% of the students in the ages of 14 or 15; 141 boys and 187 girls) from one high school in the United States participated in the study, completing a series of assessments with regard to their math classes. The findings show the complex role of the family contexts (parent goals and family orientations) on the adaptive mastery goals for children of immigrant families, going beyond previous studies that reported the relationships between family orientation and performance-approach or less adaptive performance-avoidance goals. This study still found that students’ family orientations strongly predicted their desire to win over their peers with certain levels of internal pressure in order to meet their parents’ expectations, aligned with previous literature. Through examining a context beyond the classroom context, studies should continue to examine the larger family and cultural context in understanding students with diverse backgrounds.

Dapagliflozin, a selective sodium–glucose co-transporter-2 inhibitor, and linagliptin, a competitive, reversible dipeptidyl peptidase-4 inhibitor, are commonly prescribed antidiabetic medications in general clinics. Since there are several merits to combining them in a fixed-dose combination product, this study investigated the pharmacokinetic equivalence between the individual component (IC) and fixed-combination drug product (FCDP) forms of dapagliflozin and linagliptin. A randomized, open-label, single-dose crossover study was conducted. All participants (n = 48) were randomly allocated to group A (period 1: ICs, period 2: FCDP) or group B (period 1: FCDP, period 2: ICs), and each group received either a single dose of IN-C009 (FCDP) or single doses of both dapagliflozin and linagliptin. There was no statistically significant difference found between the pharmacokinetic variables of FCDP and IC. The values of estimated geometric mean ratios and the 90% confidence interval for both maximum concentration and area under the plasma drug concentration–time curve were within the range of 0.8–1.25 for both dapagliflozin and linagliptin. The results of the clinical study demonstrated comparable pharmacokinetic characteristics between IC and FCDP forms of dapagliflozin and linagliptin. The combined use of dapagliflozin and linagliptin was safe and tolerable in both formulations.

Dabigatran (DAB) is an orally administered thrombin inhibitor. Both DAB and its main metabolite dabigatran acylglucuronide (DABG) have established anticoagulant effects. Here, we aimed to compare the relative anticoagulant effects of DABG and DAB in humans. Anticoagulant effects of DAB and DABG were measured in vitro using a thrombin generation assay. Additionally, their effects on other coagulation assays including PT, aPTT, TT, and fibrinogen were compared. Both DAB and DABG showed inhibitory effects on thrombin generation in a dose-dependent manner, but DABG exhibited a weaker inhibitory effect than that of DAB. The IC50 values of DAB and DABG on thrombin generation AUC were 134.1 ng/mL and 281.9 ng/mL, respectively. DABG also exhibited weaker anticoagulant effects than DAB on PT, aPTT, and TT. The results of the present study indicate that the anticoagulant effect of DABG, a main active DAB metabolite, is weaker than that of DAB.

Abstract Background To identify novel biomarkers related to the pathogenesis of dry age-related macular degeneration (AMD), we adopted a human retinal pigment epithelial (RPE) cell culture model that mimics some features of dry AMD including the accumulation of intra- and sub-RPE deposits. Then, we investigated the aqueous humor (AH) proteome using a data-independent acquisition method (sequential window acquisition of all theoretical fragment ion mass spectrometry) for dry AMD patients and controls. Methods After uniformly pigmented polarized monolayers of human fetal primary RPE (hfRPE) cells were established, the cells were exposed to 4-hydroxy-2-nonenal (4-HNE), followed by Western blotting, immunofluorescence analysis and ELISA of cells or conditioned media for several proteins of interest. Data-dependent acquisition for identification of the AH proteome and SWATH-based mass spectrometry were performed for 11 dry AMD patients according to their phenotypes (including soft drusen and reticular pseudodrusen [RPD]) and 2 controls (3 groups). Results Increased intra- and sub-RPE deposits were observed in 4-HNE-treated hfRPE cells compared with control cultures based on APOA1, cathepsin D, and clusterin immunoreactivity. Additionally, the differential abundance of proteins in apical and basal chambers with or without 4-HNE treatment confirmed the polarized secretion of proteins from hfRPE cells. A total of 119 proteins were quantified in dry AMD patients and controls by SWATH-MS. Sixty-five proteins exhibited significantly altered abundance among the three groups. A two-dimensional principal component analysis plot was generated to identify typical proteins related to the pathogenesis of dry AMD. Among the identified proteins, eight proteins, including APOA1, CFHR2, and CLUS, were previously considered major components or regulators of drusen. Three proteins (SERPINA4, LUM, and KERA proteins) have not been previously described as components of drusen or as being related to dry AMD. Interestingly, the LUM and KERA proteins, which are related to extracellular matrix organization, were upregulated in both RPD and soft drusen. Conclusions Differential protein expression in the AH between patients with drusen and RPD was quantified using SWATH-MS in the present study. Detailed proteomic analyses of dry AMD patients might provide insights into the in vivo biology of drusen and RPD.

This study aimed to explore pharmacokinetics, pharmacodynamics, and safety/tolerability of MT921, an injectable cholic acid, after a single subcutaneous administration to healthy volunteers. A randomized, double-blinded, placebo-controlled, single dose-ascending phase 1 study enrolled 24 subjects who were assigned to three groups (60 mg, 120 mg, and 150 mg) of MT921. Blood samples were obtained for a 24-h period before and after injecting MT921 to the submental fat area. Plasma concentrations of cholic acid and deoxycholic acid were determined for pharmacokinetic analysis. Levels of free fatty acid, triglyceride, and total cholesterol were measured for pharmacodynamic analysis. Safety and tolerability were assessed until 21 days post-dose. While systemic exposure to cholic acid tended to increase as the MT921 dose increased, pharmacokinetic profiles of deoxycholic acid were similar among dose groups without showing significant changes. Pharmacodynamic profiles were comparable when measured at baseline and post-dose. The most frequent adverse events were injection site pain and edema. All adverse drug reactions resolved without treatment. MT921 appeared to be well-tolerated after an injection to the submental area at a dose up to 150 mg. Systemic exposure to cholic acid increased as the dose increased. Blood lipid profiles and deoxycholic acid levels were not affected by MT921 treatment.

Abstract The primed microenvironment of future metastatic sites, called the pre‐metastatic niche, is a prerequisite for overt metastasis. However, a mechanistic understanding of the contributions of recruited cells to the niche is hindered by complex in vivo systems. Herein, a microfluidic platform that incorporates endothelial cells and extracellular matrix (ECM) scaffolds is developed, and the distinct role of recruited monocytes and macrophages in establishing pre‐metastatic niches is delineated. It is observed that monocyte‐derived matrix metalloproteinase 9 facilitates cancer cell extravasation through destruction of endothelial tight junctions. Furthermore, subsequent cancer cell invasiveness is significantly enhanced. Close examination of ECM structures reveals that cancer cells move within characteristic “microtracks” generated by macrophages, suggesting that macrophages could serve as a compensatory mechanism for the reduced migratory capacity of cancer cells. Thus, the first evidence of monocyte/macrophage‐induced remodeling is shown, and these findings will open up new horizons for improving characterization of the pre‐metastatic niche and corresponding immunotherapies.

The aim of this study was to explore the pharmacokinetic-pharmacodynamic (PK-PD) relationship of metformin on glucose levels after the administration of 250 mg and 1000 mg of metformin in healthy volunteers.A total of 20 healthy male volunteers were randomized to receive two doses of either a low dose (375 mg followed by 250 mg) or a high dose (1000 mg followed by 1000 mg) of metformin at 12-h intervals. The pharmacodynamics of metformin was assessed using oral glucose tolerance tests before and after metformin administration. The PK parameters after the second dose were evaluated through noncompartmental analyses. Four single nucleotide polymorphisms in MATE1, MATE2-K, and OCT2 were genotyped, and their effects on PK characteristics were additionally evaluated.The plasma exposure of metformin increased as the metformin dose increased. The mean values for the area under the concentration-time curve from dosing to 12 hours post-dose (AUC0-12h) were 3160.4 and 8808.2 h·μg/L for the low- and high-dose groups, respectively. Non-linear relationships were found between the glucose-lowering effect and PK parameters with a significant inverse trend at high metformin exposure. The PK parameters were comparable among subjects with the genetic polymorphisms.This study showed a non-linear PK-PD relationship on plasma glucose levels after the administration of metformin. The inverse relationship between systemic exposure and the glucose-lowering effect at a high exposure indicates a possible role for the intestines as an action site for metformin.ClinicalTrials.gov NCT02712619.

Background: Distinguishing ovarian cancer from other gynecological malignancies is crucial for patient survival yet hindered by non-specific symptoms and limited understanding of ovarian cancer pathogenesis. Accumulating evidence suggests a link between ovarian cancer and deregulated lipid metabolism. Most studies have small sample sizes, especially for early-stage cases, and lack racial/ethnic diversity, necessitating more inclusive research for improved ovarian cancer diagnosis and prevention. Methods: Here, we profiled the serum lipidome of 208 ovarian cancer, including 93 early-stage patients with ovarian cancer and 117 nonovarian cancer (other gynecological malignancies) patients of Korean descent. Serum samples were analyzed with a high-coverage liquid chromatography high-resolution mass spectrometry platform, and lipidome alterations were investigated via statistical and machine learning (ML) approaches. Results: We found that lipidome alterations unique to ovarian cancer were present in Korean women as early as when the cancer is localized, and those changes increase in magnitude as the diseases progresses. Analysis of relative lipid abundances revealed specific patterns for various lipid classes, with most classes showing decreased abundance in ovarian cancer in comparison with other gynecological diseases. ML methods selected a panel of 17 lipids that discriminated ovarian cancer from nonovarian cancer cases with an AUC value of 0.85 for an independent test set. Conclusions: This study provides a systemic analysis of lipidome alterations in human ovarian cancer, specifically in Korean women. [ABSTRACT FROM AUTHOR]