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Purpose Translocator protein 18-kDa (TSPO) positron emission tomography (PET) is a valuable tool to detect neuroinflammed areas in a broad spectrum of neurodegenerative diseases. However, the clinical application of second-generation TSPO ligands as biomarkers is limited because of the presence of human rs6971 polymorphism that affects their binding. Here, we describe the ability of a new TSPO ligand, [18F]BS224, to identify abnormal TSPO expression in neuroinflammation independent of the rs6971 polymorphism. Methods An in vitro competitive inhibition assay of BS224 was conducted with [3H]PK 11195 using membrane proteins isolated from 293FT cells expressing TSPO-wild type (WT) or TSPO-mutant A147T (Mut), corresponding to a high-affinity binder (HAB) and low-affinity binder (LAB), respectively. Molecular docking was performed to investigate the interaction of BS224 with the binding sites of rat TSPO-WT and TSPO-Mut. We synthesized a new 18F-labeled imidazopyridine acetamide ([18F]BS224) using boronic acid pinacol ester 6 or iodotoluene tosylate precursor 7, respectively, via aromatic 18F-fluorination. Dynamic PET scanning was performed up to 90 min after the injection of [18F]BS224 to healthy mice, and PET imaging data were obtained to estimate its absorbed doses in organs. To evaluate in vivo TSPO-specific uptake of [18F]BS224, lipopolysaccharide (LPS)-induced inflammatory and ischemic stroke rat models were used. Results BS224 exhibited a high affinity (Ki = 0.51 nM) and selectivity for TSPO. The ratio of IC50 values of BS224 for LAB to that for HAB indicated that the TSPO binding affinity of BS224 has low binding sensitivity to the rs6971 polymorphism and it was comparable to that of PK 11195, which is not sensitive to the polymorphism. Docking simulations showed that the binding mode of BS224 is not affected by the A147T mutation and consequently supported the observed in vitro selectivity of [18F]BS224 regardless of polymorphisms. With optimal radiochemical yield (39 ± 6.8%, decay-corrected) and purity (> 99%), [18F]BS224 provided a clear visible image of the inflammatory lesion with a high signal-to-background ratio in both animal models (BPND = 1.43 ± 0.17 and 1.57 ± 0.37 in the LPS-induced inflammatory and ischemic stroke rat models, respectively) without skull uptake. Conclusion Our results suggest that [18F]BS224 may be a promising TSPO ligand to gauge neuroinflammatory disease-related areas in a broad range of patients irrespective of the common rs6971 polymorphism.

DHP107 is a newly developed lipid‐based oral formulation of paclitaxel. We evaluated the in vivo tissue pharmacokinetics (PKs) of DHP107 in mice and patients using positron emission tomography (PET). Radioisotope‐labeled [3H]DHP107 and [18F]DHP107 for oral administration were formulated in the same manner as the manufacturing process of DHP107. In vivo tissue PK were assessed in healthy ICR mice and breast cancer xenografted SCID mice. Two patients with metastatic breast cancer were clinically evaluated for absorption at the target lesion after internal absorbed dose estimation. Whole‐body PET/computed tomography data were acquired in healthy and xenografted mice and in patients up to 10–24 h after administration. Tissue [18F]DHP107 signals were plotted against time and PK parameters were determined. The amounts of radioactivity in various organs and excreta were determined using a beta‐counter and are expressed as the percentage of injected dose (ID). Oral [18F]DHP107 was well‐absorbed and reached the target lesion in mice and patients with breast cancer. Significant amounts of radioactivity were found in the stomach, intestine, and liver after oral administration of [3H]‐ and [18F]DHP107 in healthy mice. The [18F]DHP107 reached a peak distribution of 0.7–0.8%ID in the tumor at 5.6–7.3 h in the xenograft model. The [18F]DHP107 distribution in patients with metastatic breast cancer was the highest at 3–4 h postadministration. Systemic exposures after administration of a DHP107 therapeutic dose were comparable with those in previous studies. PET using radioisotope‐labeled drug candidates is useful for drug development and can provide valuable information that can complement plasma PK data, particularly in early phase clinical trials.

Lung cancer can be divided into non-small cell lung cancer (NSCLC) and small cell lung cancer, and the incidence and mortality rate are continuously increasing. In many cases, lung cancer cannot be completely treated with surgery, so chemotherapy is used in parallel; however, the treatment often fails due to drug resistance. Therefore, it is necessary to develop a new therapeutic agent with a new target. The expression of sphingosine kinase promotes cancer cell growth and survival and induces resistance to chemotherapeutic agents. Sphingosine-1-phosphate (S1P), produced by sphingosine kinase (SK), has been shown to regulate cancer cell death and proliferation. PF-543, currently known as an SK inhibitor, has been reported to demonstrate low anticancer activity in several cancers. Therefore, in this study, a derivative of PF-543 capable of increasing anticancer activity was synthesized and its efficacy was evaluated by using an NSCLC cell line and xenograft animal model. Based on the cytotoxic activity of the synthesized compound on lung cancer cells, the piperidine forms (Compounds 2 and 4) were observed to exhibit superior anticancer activity than the pyrrolidine forms of the head group (Compounds 1 and 3). Compounds 2 and 4 showed inhibitory effects on SK1 and SK2 activity, and S1P produced by SK was reduced by both compounds. Compounds 2 and 4 demonstrated an increase in the cytotoxicity in the NSCLC cells through increased apoptosis. As a result of using an SK1 and SK2 siRNA model to determine whether the cytotoxic effects of Compounds 2 and 4 were due to SK1 and SK2 inhibition, it was found that the cytotoxic effect of the derivative was SK1 and SK2 dependent. The metabolic stability of Compounds 2 and 4 was superior compared to PF-543, and the xenograft experiment was performed using Compound 4, which had more excellent MS. Compound 4 demonstrated the inhibition of tumor formation. The results of this experiment suggest that the bulky tail structure of PF-543 derivatives is effective for mediating anticancer activity, and the results are expected to be applied to the treatment of NSCLC.

Sphingosine kinase (SK) is involved in the growth of cells, including cancer cells. However, which of its two isotypes—SK1 and SK2—is more favorable for cancer growth remains unclear. Although PF-543 strongly and selectively inhibits SK1, its anticancer effect is not high, and the underlying reason remains difficult to explain. We previously determined that the tail group of PF-543 is responsible for its low metabolic stability (MS). In this study, compounds containing aromatic or aliphatic tails in the triazole group were synthesized, and changes in the SK-inhibitory effect and anticancer activity of PF-543 were assessed using pancreatic cancer cells. The compounds with aliphatic tails showed high inhibitory effects on pancreatic cancer cells but slightly lower selectivity for SK1. A compound with an introduced aliphatic tail activated protein phosphatase 2A (PP2A), showing an effect similar to that of FTY720. Molecular docking analysis revealed that the PP2A-binding form of this newly synthesized compound was different from that noted in the case of FTY720. This compound also improved the MS of PF-543. These results indicate that the tail structure of PF-543 influences MS.

The objectives of study was to evaluate the vertical space of flying insects using YST (yellow sticky traps) trapping in a strawberry farm with a high-raised bed system; with assuming the presence of species-specific flying zone. The experimental farm used styrofoam beds (width 30 cm, depth 20 cm) placed on a supporting frame 70 cm high. Small YSTs (12.5 × 7.5 cm, single sticky side) were installed vertically around the high-raised bed system in a 3 × 7 configuration (column × row) vertically at 30-cm intervals, reaching 270 cm high, and spaced 50 cm apart horizontally. The trap positions within the second-ranking (here referred to as ‘zone’) to attract thrips were 60 cm traps above the top of the bed center (TBC), 30 cm traps above the side of the bed (SOB), and 70 cm traps from the ground on the SOB. The attraction zone of whiteflies was the same as that of the thrips except of the 60 cm traps above the SOB. The zones for leafhoppers were formed in all 60 cm traps above the top of the bed (TOB), the 90 cm side traps above the TOB, and 30 cm traps above the TBC. Aphids were frequently attracted at all 90 cm traps above the TBC and 60 cm above the TBC. Sciarid pests were mostly attracted to the traps placed just below the bed center. The zones of natural enemies (total) were formed in 30 cm above the TBC and 70 cm from the ground at the SOB. Thus, the zone 60 cm above the TBC was common position where various pests were frequently attracted with reducing a harmful effect on natural enemies. Consequently, our results could be used as a guideline for the use of YSTs in strawberry farms with high-raised bed systems until new directions are developed.

Fall armyworm, Spodoptera frugiperda (J.E. Smith), is a notorious invasive pest native to subtropical and tropical regions in the Western Hemisphere. It has recently invaded and established in south Asian countries and in South Korea only seasonally. Longevity, survival, and fecundity of fall armyworm were examined at different temperatures (16, 20, 24, 28, and 32°C) and an oviposition model was developed. The maximum observed fecundity was 1,485 eggs per female at 22.0°C, which decreased to ca. 815 eggs at 32.0°C. Female longevity decreased as the temperature increased up to 24°C, and then was constant around 13–14 d until temperature reached 32°C, ranging from 33.1 d at 16.0°C to 13.1 d at 32.0°C. Temperature-dependent total fecundity (TDF) was well described by the extreme value function. Age-specific cumulative oviposition rate (AOR) and age-specific survival rate (ASR) curves were fitted to logistic and sigmoid functions, respectively. The model of female adults’ aging rate (1/mean longevity) as a function of temperature was used to calculate the physiological age of fall armyworm females in AOR and ASR models. Three temperature-dependent components of TDF, AOR, and ASR were incorporated to construct the oviposition model, and it was simulated to project corn damage with tentative parameters. When 10 fall armyworm females were assumed, a total of 68–74 corn ears with kernel damage were predicted. Such loss was estimated to be US$75–83 currently in the Korean market.

Targeted protein degradation allows targeting undruggable proteins for therapeutic applications as well as eliminating proteins of interest for research purposes. While several degraders that harness the proteasome or the lysosome have been developed, a technology that simultaneously degrades targets and accelerates cellular autophagic flux is still missing. In this study, we develop a general chemical tool and platform technology termed AUTOphagy-TArgeting Chimera (AUTOTAC), which employs bifunctional molecules composed of target-binding ligands linked to autophagy-targeting ligands. AUTOTACs bind the ZZ domain of the otherwise dormant autophagy receptor p62/Sequestosome-1/SQSTM1, which is activated into oligomeric bodies in complex with targets for their sequestration and degradation. We use AUTOTACs to degrade various oncoproteins and degradation-resistant aggregates in neurodegeneration at nanomolar DC50 values in vitro and in vivo. AUTOTAC provides a platform for selective proteolysis in basic research and drug development.

The global climate change has led to the distribution of Bactrocera dorsalis from its origin in Southeast Asia to mainland China, which is situated at latitudes similar to Jeju Island, South Korea. In order to evaluate the establishment of B. dorsalis in Korea, it is necessary to determine the climate suitability. When the parameters of CLIMEX model were adjusted to include Wuhan region in China as the northern limit, the model outputs explained well the distribution and occurrence characteristics (namely the annual number of generations) of B. dorsalis in major distribution regions in the world. In IPCC/RCP 8.5 scenario, the establishment of B. dorsalis was suitable to a small part of Jeju Island in the 2010s. The range might gradually spread until the 2090s, with many parts of the lowlands of Jeju Island being marginal to optimal in suitability. The present CLIMEX model with parameters that adjusted to known northern limit will be useful for annual risk mapping to facilitate a monitoring system for early detection of a possible founder population of B. dorsalis in Jeju, South Korea.

Cellular homeostasis requires the sensing of and adaptation to intracellular oxygen (O(2)) and reactive oxygen species (ROS). The Arg/N-degron pathway targets proteins that bear destabilizing N-terminal residues for degradation by the proteasome or via autophagy. Under normoxic conditions, the N-terminal Cys (Nt-Cys) residues of specific substrates can be oxidized by dioxygenases such as plant cysteine oxidases and cysteamine (2-aminoethanethiol) dioxygenases and arginylated by ATE1 R-transferases to generate Arg-CysO(2)(H) (R-C(O2)). Proteins bearing the R-C(O2) N-degron are targeted via Lys48 (K48)–linked ubiquitylation by UBR1/UBR2 N-recognins for proteasomal degradation. During acute hypoxia, such proteins are partially stabilized, owing to decreased Nt-Cys oxidation. Here, we show that if hypoxia is prolonged, the Nt-Cys of regulatory proteins can be chemically oxidized by ROS to generate Arg-CysO(3)(H) (R-C(O3)), a lysosomal N-degron. The resulting R-C(O3) is bound by KCMF1, a N-recognin that induces K63-linked ubiquitylation, followed by K27-linked ubiquitylation by the noncanonical N-recognin UBR4. Autophagic targeting of Cys/N-degron substrates is mediated by the autophagic N-recognin p62/SQTSM-1/Sequestosome-1 through recognition of K27/K63-linked ubiquitin (Ub) chains. This Cys/N-degron–dependent reprogramming in the proteolytic flux is important for cellular homeostasis under both chronic hypoxia and oxidative stress. A small-compound ligand of p62 is cytoprotective under oxidative stress through its ability to accelerate proteolytic flux of K27/K63-ubiquitylated Cys/N-degron substrates. Our results suggest that the Nt-Cys of conditional Cys/N-degron substrates acts as an acceptor of O(2) to maintain both O(2) and ROS homeostasis and modulates half-lives of substrates through either the proteasome or lysosome by reprogramming of their Ub codes.

This study aims to compare the predicting performance of coronary atherosclerosis between Framingham Risk Score (FRS) and Pooled Cohort Equations (PCE) in moderate to high-risk patients who meet the target low-density lipoprotein cholesterol (LDL-C) level of Korean dyslipidemia guidelines. Among 1207 patients aged 40 to 65 who underwent coronary computed tomography angiography at outpatient for chest discomfort, we included 414 moderate-risk patients (non-diabetes) and 86 high-risk patients (diabetes). They were divided into 3 groups according to FRS and PCE, then compared with coronary artery calcification score (CACS) and plaque burden degree strata. We presented receiver operating characteristic curves for the presence of coronary artery calcification (CAC) and any plaque. In moderate-risk patients, the distribution of CACS and plaque burden degree according to FRS and PCE risk strata showed significant differences between groups and a consistent trend (P .001). Both FRS and PCE showed good discrimination for the presence of CAC [area under the curve (AUC); 0.711 vs 0.75, P = .02] and any plaque (AUC; 0.72 vs 0.756, P = .025). However, in high-risk patients, there was no significant differences or consistent trend between groups and the AUC values of FRS and PCE were (0.537 vs 0.571, P = .809) for CAC and (0.478 vs 0.65 P = .273) for any plaque showing poor discrimination. In predicting coronary atherosclerosis in moderate to high-risk patients who meet the target LDL-C level of Korean dyslipidemia guidelines, both FRS and PCE can be used in moderate-risk patients but not in high-risk patients.

[68Ga]PSMA-11 is a prostate-specific membrane antigen (PSMA)-targeting radiopharmaceutical for diagnostic PET imaging. Its application can be extended to targeted radionuclide therapy (TRT). In this study, we characterize the biodistribution and pharmacokinetics of [68Ga]PSMA-11 in PSMA-positive and negative (22Rv1 and PC3, respectively) tumor-bearing mice and subsequently estimated its internal radiation dosimetry via voxel-level dosimetry using a dedicated Monte Carlo simulation to evaluate the absorbed dose in the tumor directly. Consequently, this approach overcomes the drawbacks of the conventional organ-level (or phantom-based) method. The kidneys and urinary bladder both showed substantial accumulation of [68Ga]PSMA-11 without exhibiting a washout phase during the study. For the tumor, a peak concentration of 4.5 ± 0.7 %ID/g occurred 90 min after [68Ga]PSMA-11 injection. The voxel- and organ-level methods both determined that the highest absorbed dose occurred in the kidneys (0.209 ± 0.005 Gy/MBq and 0.492 ± 0.059 Gy/MBq, respectively). Using voxel-level dosimetry, the absorbed dose in the tumor was estimated as 0.024 ± 0.003 Gy/MBq. The biodistribution and pharmacokinetics of [68Ga]PSMA-11 in various organs of subcutaneous prostate cancer xenograft model mice were consistent with reported data for prostate cancer patients. Therefore, our data supports the use of voxel-level dosimetry in TRT to deliver personalized dosimetry considering patient-specific heterogeneous tissue compositions and activity distributions.

[68Ga]PSMA-11 is a prostate-specific membrane antigen (PSMA)-targeting radiopharmaceutical for diagnostic PET imaging. Its application can be extended to targeted radionuclide therapy (TRT). In this study, we characterize the biodistribution and pharmacokinetics of [68Ga]PSMA-11 in PSMA-positive and negative (22Rv1 and PC3, respectively) tumor-bearing mice and subsequently estimated its internal radiation dosimetry via voxel-level dosimetry using a dedicated Monte Carlo simulation to evaluate the absorbed dose in the tumor directly. Consequently, this approach overcomes the drawbacks of the conventional organ-level (or phantom-based) method. The kidneys and urinary bladder both showed substantial accumulation of [68Ga]PSMA-11 without exhibiting a washout phase during the study. For the tumor, a peak concentration of 4.5 ± 0.7 %ID/g occurred 90 min after [68Ga]PSMA-11 injection. The voxel- and organ-level methods both determined that the highest absorbed dose occurred in the kidneys (0.209 ± 0.005 Gy/MBq and 0.492 ± 0.059 Gy/MBq, respectively). Using voxel-level dosimetry, the absorbed dose in the tumor was estimated as 0.024 ± 0.003 Gy/MBq. The biodistribution and pharmacokinetics of [68Ga]PSMA-11 in various organs of subcutaneous prostate cancer xenograft model mice were consistent with reported data for prostate cancer patients. Therefore, our data supports the use of voxel-level dosimetry in TRT to deliver personalized dosimetry considering patient-specific heterogeneous tissue compositions and activity distributions.

Purpose Translocator protein 18-kDa (TSPO) positron emission tomography (PET) is a valuable tool to detect neuroinflammed areas in a broad spectrum of neurodegenerative diseases. However, the clinical application of second-generation TSPO ligands as biomarkers is limited because of the presence of human rs6971 polymorphism that affects their binding. Here, we describe the ability of a new TSPO ligand, [18F]BS224, to identify abnormal TSPO expression in neuroinflammation independent of the rs6971 polymorphism. Methods An in vitro competitive inhibition assay of BS224 was conducted with [3H]PK 11195 using membrane proteins isolated from 293FT cells expressing TSPO-wild type (WT) or TSPO-mutant A147T (Mut), corresponding to a high-affinity binder (HAB) and low-affinity binder (LAB), respectively. Molecular docking was performed to investigate the interaction of BS224 with the binding sites of rat TSPO-WT and TSPO-Mut. We synthesized a new 18F-labeled imidazopyridine acetamide ([18F]BS224) using boronic acid pinacol ester 6 or iodotoluene tosylate precursor 7, respectively, via aromatic 18F-fluorination. Dynamic PET scanning was performed up to 90 min after the injection of [18F]BS224 to healthy mice, and PET imaging data were obtained to estimate its absorbed doses in organs. To evaluate in vivo TSPO-specific uptake of [18F]BS224, lipopolysaccharide (LPS)-induced inflammatory and ischemic stroke rat models were used. Results BS224 exhibited a high affinity (Ki = 0.51 nM) and selectivity for TSPO. The ratio of IC50 values of BS224 for LAB to that for HAB indicated that the TSPO binding affinity of BS224 has low binding sensitivity to the rs6971 polymorphism and it was comparable to that of PK 11195, which is not sensitive to the polymorphism. Docking simulations showed that the binding mode of BS224 is not affected by the A147T mutation and consequently supported the observed in vitro selectivity of [18F]BS224 regardless of polymorphisms. With optimal radiochemical yield (39 ± 6.8%, decay-corrected) and purity (> 99%), [18F]BS224 provided a clear visible image of the inflammatory lesion with a high signal-to-background ratio in both animal models (BPND = 1.43 ± 0.17 and 1.57 ± 0.37 in the LPS-induced inflammatory and ischemic stroke rat models, respectively) without skull uptake. Conclusion Our results suggest that [18F]BS224 may be a promising TSPO ligand to gauge neuroinflammatory disease-related areas in a broad range of patients irrespective of the common rs6971 polymorphism. Supplementary Information The online version contains supplementary material available at 10.1007/s00259-021-05617-4.

To make a meaningful response logic to future exchange rate pressures, we monitor the determinants of the current account and exchange rate. First, according to the analysis of current account determinants, the current account imbalance will gradually ease from a long-term and structural perspective if the domestic financial market develops or access to the international financial market is strengthened. In addition, existing structural current account estimates that do not take into account international financial market conditions may have underestimated the structural current account balance of emerging countries such as Korea. Second, based on the analysis of the currency determinants, we can argue that the weak won is structurally inevitable due to the weak yuan.

Purpose Translocator protein 18-kDa (TSPO) positron emission tomography (PET) is a valuable tool to detect neuroinfammed areas in a broad spectrum of neurodegenerative diseases. However, the clinical application of second-generation TSPO ligands as biomarkers is limited because of the presence of human rs6971 polymorphism that afects their binding. Here, we describe the ability of a new TSPO ligand, [ 18F]BS224, to identify abnormal TSPO expression in neuroinfammation independent of the rs6971 polymorphism. Methods An in vitro competitive inhibition assay of BS224 was conducted with [3H]PK 11195 using membrane proteins isolated from 293FT cells expressing TSPO-wild type (WT) or TSPO-mutant A147T (Mut), corresponding to a high-afnity binder (HAB) and low-afnity binder (LAB), respectively. Molecular docking was performed to investigate the interaction of BS224 with the binding sites of rat TSPO-WT and TSPO-Mut. We synthesized a new 18F-labeled imidazopyridine acetamide ([18F]BS224) using boronic acid pinacol ester 6 or iodotoluene tosylate precursor 7, respectively, via aromatic 18F-fuorination. Dynamic PET scanning was performed up to 90 min after the injection of [18F]BS224 to healthy mice, and PET imaging data were obtained to estimate its absorbed doses in organs. To evaluate in vivo TSPO-specifc uptake of [18F] BS224, lipopolysaccharide (LPS)-induced infammatory and ischemic stroke rat models were used. Results BS224 exhibited a high afnity (Ki=0.51 nM) and selectivity for TSPO. The ratio of IC50 values of BS224 for LAB to that for HAB indicated that the TSPO binding afnity of BS224 has low binding sensitivity to the rs6971 polymorphism and it was comparable to that of PK 11195, which is not sensitive to the polymorphism. Docking simulations showed that the binding mode of BS224 is not afected by the A147T mutation and consequently supported the observed in vitro selectivity of [ 18F]BS224 regardless of polymorphisms. With optimal radiochemical yield (39±6.8%, decay-corrected) and purity (>99%), [18F]BS224 provided a clear visible image of the infammatory lesion with a high signal-to-background ratio in both animal models (BPND =1.43±0.17 and 1.57±0.37 in the LPS-induced infammatory and ischemic stroke rat models, respectively) without skull uptake. Conclusion Our results suggest that [ 18F]BS224 may be a promising TSPO ligand to gauge neuroinfammatory disease-related areas in a broad range of patients irrespective of the common rs6971 polymorphism.

Human exposure to microplastics contained in food has become a significant concern owing to the increasing accumulation of microplastics in the environment. In this paper, we summarize the presence of microplastics in food and the analytical methods used for isolation and identification of microplastics. Although a large number of studies on seafood such as fish and shellfish exist, estimating the overall human exposure to microplastics via food consumption is difficult owing to the lack of studies on other food items. Analytical methods still need to be optimized for appropriate recovery of microplastics in various food matrices, rendering a quantitative comparison of different studies challenging. In addition, microplastics could be added or removed from ingredients during processing or cooking. Thus, research on processed food is crucial to estimate the contribution of food to overall human microplastic consumption and to mitigate this exposure in the future.

Whether M1 occlusions proximal (pM1) and distal (dM1) to the lenticulostriate perforators result in different clinical outcomes after mechanical thrombectomy (MT) is unknown. We retrospectively compared the clinical outcomes and baseline characteristics of patients with these two types of occlusions.From March 2010 to May 2019, we performed MT for 141 M1 occlusions, including pM1 occlusions (n = 58) and dM1 occlusions (n = 83).Good clinical outcomes (modified Rankin Scale score 0 to 2) were achieved in 28 out of 58 (48.3%) patients with pM1 occlusions and 46 out of 83 (55.4%) patients with dM1 occlusions without significance (p = 0.493). Cardioembolic occlusions represented 19 out of 58 (32.6%) pM1 occlusions and 53 out of 83 (63.9%) dM1 occlusions, and atherosclerotic occlusions represented 37 out of 58 (63.8%) pM1 occlusions and 27 out of 83 (32.5%) dM1 occlusions, with significance (p = 0.001). Rescue treatments, such as balloon angioplasty or stenting, were needed more for pM1 occlusions than dM1 occlusions (21 out of 58 (36.2%) vs. 8 out of 83 (9.8%), p 0.001). The multivariable logistic regression analysis demonstrated that the need for rescue treatment was associated with pM1 occlusions (adjusted odds ratio; 3.804, 95% confidence interval; 1.306-11.082, p = 0.014).In our series, pM1 and dM1 occlusions did not significantly differ in good clinical outcomes. Our study also showed that pM1 occlusions were more strongly associated with atherosclerotic occlusions, while dM1 occlusions were more strongly associated with cardioembolic occlusions, and rescue treatments were needed more often for pM1 occlusions than dM1 occlusions.

PF-543, the most potent sphingosine kinase (SK) inhibitor, does not demonstrate effective anticancer activity in some cancer cells, unlike other known SK1 inhibitors. PF-543 has a non-lipid structure with a unique toluene backbone, however, the importance of this structure remains unclear. Therefore, the purpose of this study was to investigate changes in SK inhibitory and anticancer activities and to explore the role of the tolyl group structure of PF-543 through various modifications. We transformed the methyl group of PF-543 into hydrogen, fluorine, and hydroxy. PF-543 derivatives in which the methyl group was substituted by hydrogen and fluorine (compound 5) demonstrated SK1 inhibitory and anticancer activities similar to PF-543. Moreover, we performed molecular modeling studies of PF-543 and compound 5. To assess the metabolic stability of PF-543 and compound 5, we determined their degree of degradation using the liver microsomes of four different animal species (human, dog, rat, and mouse). However, both PF-543 and compound 5 showed poor microsomal stability. Therefore, for the medical applications of PF-543, the structural modifications of its other parts may be necessary. Our results provide important information for the design of additional PF-543 analogs.