ABSTRACT
BACKGROUND: Patients with ST-elevation myocardial infarction (STEMI) tend to be excluded or under-represented in randomized clinical trials evaluating the effects of potent P2Y12 inhibitor monotherapy after short-term dual antiplatelet therapy (DAPT). METHODS: Individual patient data were pooled from randomized clinical trials that included STEMI patients undergoing drug-eluting stent (DES) implantation and compared ticagrelor monotherapy after short-term (≤3 months) DAPT versus ticagrelor-based 12-month DAPT in terms of centrally adjudicated clinical outcomes. The co-primary outcomes were efficacy outcome (composite of all-cause death, myocardial infarction, or stroke) and safety outcome (Bleeding Academic Research Consortium type 3 or 5 bleeding) at 1 year. FINDINGS: The pooled cohort contained 2,253 patients with STEMI. The incidence of the primary efficacy outcome did not differ between the ticagrelor monotherapy group and the ticagrelor-based DAPT group (1.8% versus 2.0%; hazard ratio [HR] = 0.88; 95% confidence interval [CI] = 0.49-1.61; p = 0.684). There was no difference in cardiac death between the groups (0.6% versus 0.7%; HR = 0.89; 95% CI = 0.32-2.46; p = 0.822). The incidence of the primary safety outcome was significantly lower in the ticagrelor monotherapy group (2.3% versus 4.0%; HR = 0.56; 95% CI = 0.35-0.92; p = 0.020). No heterogeneity of treatment effects was observed for the primary outcomes across subgroups. CONCLUSIONS: In patients with STEMI treated with DES implantation, ticagrelor monotherapy after short-term DAPT was associated with lower major bleeding without an increase in the risk of ischemic events compared with ticagrelor-based 12-month DAPT. Further research is necessary to extend these findings to non-Asian patients. FUNDING: This study was funded by Biotronik (Bülach, Switzerland).
ABSTRACT
OBJECTIVES: To develop and validate a novel measure, action entropy, for assessing the cognitive effort associated with electronic health record (EHR)-based work activities. MATERIALS AND METHODS: EHR-based audit logs of attending physicians and advanced practice providers (APPs) from four surgical intensive care units in 2019 were included. Neural language models (LMs) were trained and validated separately for attendings' and APPs' action sequences. Action entropy was calculated as the cross-entropy associated with the predicted probability of the next action, based on prior actions. To validate the measure, a matched pairs study was conducted to assess the difference in action entropy during known high cognitive effort scenarios, namely, attention switching between patients and to or from the EHR inbox. RESULTS: Sixty-five clinicians performing 5 904 429 EHR-based audit log actions on 8956 unique patients were included. All attention switching scenarios were associated with a higher action entropy compared to non-switching scenarios (P < .001), except for the from-inbox switching scenario among APPs. The highest difference among attendings was for the from-inbox attention switching: Action entropy was 1.288 (95% CI, 1.256-1.320) standard deviations (SDs) higher for switching compared to non-switching scenarios. For APPs, the highest difference was for the to-inbox switching, where action entropy was 2.354 (95% CI, 2.311-2.397) SDs higher for switching compared to non-switching scenarios. DISCUSSION: We developed a LM-based metric, action entropy, for assessing cognitive burden associated with EHR-based actions. The metric showed discriminant validity and statistical significance when evaluated against known situations of high cognitive effort (ie, attention switching). With additional validation, this metric can potentially be used as a screening tool for assessing behavioral action phenotypes that are associated with higher cognitive burden. CONCLUSION: An LM-based action entropy metric-relying on sequences of EHR actions-offers opportunities for assessing cognitive effort in EHR-based workflows.
ABSTRACT
We introduce an enhanced performance organic-inorganic hybrid p-n junction photodiode, utilizing poly[bis(4-phenyl) (2,4,6-trimethylphenyl)amine] (PTAA) and ZnO, fabricated through a solution-based process at a low temperature under 100 °C. Improved interfacial electronic structure, characterized by shallower Gaussian standard deviation of the density-of-state distribution and a larger interface dipole, has resulted in a remarkable fold increase of â¼102 in signal-to-noise ratio for the device. This photodiode exhibits a high specific detectivity (2.32 × 1011 Jones, cm×Hz×W-1) and exceptional rectification ratio (5.47 × 104 at ±1 V). The primary light response, concentrated in the optimal thickness of the PTAA layer, contributes to response over the entire UVA region and rapid response speed, with rise and fall times of 0.24 and 0.64 ms, respectively. Furthermore, this work demonstrates immense potential of our device for health monitoring applications by enabling real-time and continuous measurements of UV intensity.
ABSTRACT
In this study, Anaerobic Digestion Model No.1 (ADM1) was modified to incorporate changes in biochemical parameters due to solids retention time (SRT) variations. Cattle manure (CM) and thermally hydrolyzed CM were selected for testing. Continuous anaerobic digestion reactors were operated under different SRT conditions ranging from 6.6 to 36.0 days for both samples. The biochemical parameters (kch, kli, kpr, um,ac, um,bu, um,pro, um,va, Kac, Kbu, Kpro, and Kva) for each SRT condition were determined. To modify ADM1, the equations obtained through linear regression were substituted into biochemical parameters as a function of SRT. The modified ADM1 demonstrated superior accuracy compared with conventional ADM1. This study implies the feasibility of optimizing biochemical parameters for modeling in response to changes in environmental variables.
Subject(s)
Manure , Animals , Cattle , Anaerobiosis , Bioreactors , Time Factors , Models, Biological , HydrolysisABSTRACT
In drug discovery, human organ-on-a-chip (organ chip) technology has emerged as an essential tool for preclinical testing, offering a realistic representation of human physiology, real-time monitoring, and disease modeling. Polydimethylsiloxane (PDMS) is commonly used in organ chip fabrication owing to its biocompatibility, flexibility, transparency, and ability to replicate features down to the nanoscale. However, the porous nature of PDMS leads to unintended absorption of small molecules, critically affecting the drug response analysis. Addressing this challenge, the precision drug testing organ chip (PreD chip) is introduced, an innovative platform engineered to minimize small molecule absorption while facilitating cell culture. This chip features a PDMS microchannel wall coated with a perfluoropolyether-based lubricant, providing slipperiness and antifouling properties. It also incorporates an ECM-coated semi-porous membrane that supports robust multicellular cultures. The PreD chip demonstrates its outstanding antifouling properties and resistance to various biological fluids, small molecule drugs, and plasma proteins. In simulating the human gut barrier, the PreD chip demonstrates highly enhanced sensitivity in tests for dexamethasone toxicity and is highly effective in assessing drug transport across the human blood-brain barrier. These findings emphasize the potential of the PreD chip in advancing organ chip-based drug testing methodologies.
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Herein, we report a case of uncomplicated falciparum malaria with late parasitological failure in a 45-year-old businessman returning from Ghana. The patient visited the emergency department with high fever, headache, and dizziness. He traveled without antimalarial chemoprophylaxis. Laboratory tests led to the diagnosis of uncomplicated falciparum malaria with an initial density of 37,669 parasites per µL of blood (p/µL). The patient was treated with intravenous artesunate followed by atovaquone/proguanil. He was discharged with improved condition and decreased parasite density of 887 p/µL. However, at follow-up, parasite density increased to 7,630 p/µL despite the absence of any symptoms. Suspecting treatment failure, the patient was administered intravenous artesunate and doxycycline for seven days and then artemether/lumefantrine for three days. Blood smear was negative for asexual parasitemia after re-treatment but positive for gametocytemia until day 101 from the initial diagnosis. Overall, this case highlights the risk of late parasitological failure in patients with imported uncomplicated falciparum malaria.
Subject(s)
Antimalarials , Atovaquone , Malaria, Falciparum , Plasmodium falciparum , Proguanil , Humans , Malaria, Falciparum/drug therapy , Malaria, Falciparum/diagnosis , Ghana , Antimalarials/therapeutic use , Middle Aged , Male , Plasmodium falciparum/isolation & purification , Proguanil/therapeutic use , Atovaquone/therapeutic use , Travel , Artemisinins/therapeutic use , Artesunate/therapeutic use , Parasitemia/drug therapy , Parasitemia/diagnosis , Doxycycline/therapeutic use , Drug Combinations , Treatment Failure , Artemether, Lumefantrine Drug Combination/therapeutic useABSTRACT
BACKGROUND AND AIMS: In patients with acute coronary syndrome (ACS), dual antiplatelet therapy (DAPT) with aspirin and a potent P2Y12 inhibitor is recommended for 12 months after drug-eluting stent (DES) implantation. Monotherapy with a potent P2Y12 inhibitor after short-term DAPT is an attractive option to better balance the risks of ischaemia and bleeding. Therefore, this study evaluated the efficacy and safety of ticagrelor monotherapy after short-term DAPT, especially in patients with ACS. METHODS: Electronic databases were searched from inception to 11 November 2023, and for the primary analysis, individual patient data were pooled from the relevant randomized clinical trials comparing ticagrelor monotherapy after short-term (≤3 months) DAPT with ticagrelor-based 12-month DAPT, exclusively in ACS patients undergoing DES implantation. The co-primary endpoints were ischaemic endpoint (composite of all-cause death, myocardial infarction, or stroke) and bleeding endpoint [Bleeding Academic Research Consortium (BARC) type 3 or 5 bleeding] at 1 year. RESULTS: Individual patient data from two randomized clinical trials including 5906 ACS patients were analysed. At 1 year, the primary ischaemic endpoint did not differ between the ticagrelor monotherapy and ticagrelor-based DAPT groups [1.9% vs. 2.5%; adjusted hazard ratio (HR) 0.79; 95% confidence interval (CI) 0.56-1.13; P = .194]. The incidence of the primary bleeding endpoint was lower in the ticagrelor monotherapy group (2.4% vs. 4.5%; adjusted HR 0.54; 95% CI 0.40-0.72; P < .001). The results were consistent in a secondary aggregate data meta-analysis including the ACS subgroup of additional randomized clinical trials which enrolled patients with ACS as well as chronic coronary syndrome. CONCLUSIONS: In ACS patients undergoing DES implantation, ticagrelor monotherapy after short-term DAPT was associated with less major bleeding without a concomitant increase in ischaemic events compared with ticagrelor-based 12-month DAPT. STUDY REGISTRATION: PROSPERO (ID: CRD42023476470).
Subject(s)
Acute Coronary Syndrome , Platelet Aggregation Inhibitors , Ticagrelor , Acute Coronary Syndrome/drug therapy , Ticagrelor/therapeutic use , Humans , Platelet Aggregation Inhibitors/therapeutic use , Platelet Aggregation Inhibitors/adverse effects , Platelet Aggregation Inhibitors/administration & dosage , Dual Anti-Platelet Therapy/methods , Randomized Controlled Trials as Topic , Hemorrhage/chemically induced , Drug-Eluting Stents , Purinergic P2Y Receptor Antagonists/therapeutic use , Purinergic P2Y Receptor Antagonists/administration & dosage , Percutaneous Coronary Intervention , Female , Male , Aspirin/therapeutic use , Aspirin/adverse effects , Aspirin/administration & dosageABSTRACT
An aerobic, Gram-stain-negative and short rod-shaped bacterial strain, designated M6-31T, was isolated from rice paddy soil sampled in Miryang, Republic of Korea. Growth was observed at 4-35â°C (optimum, 28â°C), pH 6.0-9.0 (optimum, pH 7.0-8.0) and in the presence of 0-4â% (w/v) NaCl (optimum, 0â% w/v). Phylogenetic analysis based on 16S rRNA gene sequences grouped strain M6-31T with Sphingobacterium bambusae IBFC2009T, Sphingobacterium griseoflavum SCU-B140T and Sphingobacterium solani MLS-26-JM13-11T in the same clade, with the 16S rRNA gene sequence similarities ranging from 95.8 to 96.6â%. A genome-based phylogenetic tree reconstructed by using all publicly available Sphingobacterium genomes placed strain M6-31T with S. bambusae KACC 22910T, 'Sphingobacterium deserti' ACCC 05744T, S. griseoflavum CGMCC 1.12966T and Sphingobacterium paludis CGMCC 1.12801T. Orthologous average nucleotide identity and digital DNA-DNA hybridization values between strain M6-31T and its closely related strains were lower than 74.6 and 22.0â%, respectively. The respiratory quinone was menaquinone-7, and the major polar lipid was phosphatidylethanolamine. The major fatty acids (>10â%) were C15â:â0 iso, C17â:â0 iso 3OH and summed feature 3. The phenotypic, chemotaxonomic and genotypic data obtained in this study showed that strain M6-31T represents a novel species of the genus Sphingobacterium, for which the name Sphingobacterium oryzagri sp. nov. (type strain M6-31T=KACC 22765T=JCM 35893T) is proposed.
Subject(s)
Bacterial Typing Techniques , DNA, Bacterial , Fatty Acids , Nucleic Acid Hybridization , Oryza , Phylogeny , RNA, Ribosomal, 16S , Sequence Analysis, DNA , Soil Microbiology , Sphingobacterium , Vitamin K 2 , Vitamin K 2/analogs & derivatives , Oryza/microbiology , RNA, Ribosomal, 16S/genetics , Fatty Acids/chemistry , Sphingobacterium/genetics , Sphingobacterium/isolation & purification , Sphingobacterium/classification , DNA, Bacterial/genetics , Republic of Korea , Vitamin K 2/analysis , Base Composition , PhosphatidylethanolaminesABSTRACT
Strain CJN36-1NT, a Gram-stain-positive, non-flagellated, strictly aerobic and short rod-shaped bacterium, was isolated from flowerpot soil sampled in the Jeonju region of the Republic of Korea. Based on 16S rRNA gene sequences and the resulting phylogenetic tree, the strain belonged to the genus Microbacterium. Strain CJN36-1NT contained a chromosome of 3.6 Mbp with a G+C content of 68.5âmol%. The strain grew at 10-37â°C (optimally at 28â°C), at pH 5.0-8.0 (optimally at pH 8.0), and in the presence of 0-7â% NaCl (w/v; optimally with 0â% NaCl). Digital DNA-DNA hybridization, average nucleotide identity and average amino acid identity values between strain CJN36-1NT and its closest related species, Microbacterium protaetiae DFW100M-13T, were 82.0, 81.2, and 23.2â%, respectively. We propose naming this novel species Microbacterium horticulturae sp. nov., with CJN36-1NT (=KACC 23027T=NBRC 116065T) as the type strain.
Subject(s)
Bacterial Typing Techniques , Base Composition , DNA, Bacterial , Fatty Acids , Microbacterium , Nucleic Acid Hybridization , Phylogeny , RNA, Ribosomal, 16S , Sequence Analysis, DNA , Soil Microbiology , RNA, Ribosomal, 16S/genetics , DNA, Bacterial/genetics , Republic of Korea , Microbacterium/geneticsABSTRACT
Background: EDTA-induced pseudothrombocytopenia (PTCP) during whole blood collection requires significant laboratory resources to obtain accurate results. We evaluated platelet-deaggregation function in EDTA-induced PTCP and platelet-clump flagging by the BC-6800Plus hematology analyzer using integrated digital image analysis. Methods: We prospectively collected 132 whole blood samples suspected of platelet clumping (102 in EDTA and 30 in sodium citrate) from 88 individuals. We compared platelet counts determined using the platelet count by impedance (PLT-I) function of the DxH 900 hematology analyzer and the PLT-I or optical platelet count (PLT-O) function of the BC-6800Plus. Platelet clumping was verified through manual inspection and the MC-80 digital image analyzer. Results: Among the 132 whole blood samples, 43 EDTA samples showed platelet clumping. The DxH 900 PLT-I and BC-6800Plus PLT-I results demonstrated a strong correlation (r=0.711) for the EDTA samples but only a moderate correlation with the BC-6800Plus PLT-O results (r=0.506 and 0.545, respectively). The BC-6800Plus PLT-O results were consistent with the sodium citrate platelet counts, with a median dissociation rate of 102.5% (range, 74.9%-123.1%). The DxH 900 and BC-6800Plus analyzers had sensitivity values of 0.79 and 0.72, respectively, for platelet-clump flagging. When integrating the MC-80 digital image analysis results, the sensitivity of BC-6800Plus improved to 0.89 (standard mode) or 1.0 (PLT-Pro mode). Conclusions: BC-6800Plus PLT-O measurement results are close to the actual values obtained by platelet deaggregation with PTCP samples. Integrating the BC-6800Plus with a digital imaging analyzer effectively improved the diagnosis of PTCP and reduced the requirement for additional laboratory procedures.
Subject(s)
Edetic Acid , Thrombocytopenia , Humans , Edetic Acid/chemistry , Edetic Acid/pharmacology , Platelet Count , Thrombocytopenia/diagnosis , Thrombocytopenia/chemically induced , Prospective Studies , Blood Platelets/cytology , Blood Platelets/drug effects , Platelet Aggregation/drug effects , Sodium Citrate , Image Processing, Computer-Assisted , Female , MaleABSTRACT
BACKGROUND: Tumor initiation and progression necessitate a metabolic shift in cancer cells. Consequently, the progression of prostate cancer (PCa), a leading cause of cancer-related deaths in males globally, involves a shift from lipogenic to glycolytic metabolism. Androgen deprivation therapy (ADT) serves as the standard treatment for advanced-stage PCa. However, despite initial patient responses, castrate resistance emerges ultimately, necessitating novel therapeutic approaches. Therefore, in this study, we aimed to investigate the role of monocarboxylate transporters (MCTs) in PCa post-ADT and evaluate their potential as therapeutic targets. METHODS: PCa cells (LNCaP and C4-2 cell line), which has high prostate-specific membrane antigen (PSMA) and androgen receptor (AR) expression among PCa cell lines, was used in this study. We assessed the expression of MCT1 in PCa cells subjected to ADT using charcoal-stripped bovine serum (CSS)-containing medium or enzalutamide (ENZ). Furthermore, we evaluated the synergistic anticancer effects of combined treatment with ENZ and SR13800, an MCT1 inhibitor. RESULTS: Short-term ADT led to a significant upregulation in folate hydrolase 1 (FOLH1) and solute carrier family 16 member 1 (SLC16A1) gene levels, with elevated PSMA and MCT1 protein levels. Long-term ADT induced notable changes in cell morphology with further upregulation of FOLH1/PSMA and SLC16A1/MCT1 levels. Treatment with ENZ, a nonsteroidal anti-androgen, also increased PSMA and MCT1 expression. However, combined therapy with ENZ and SR13800 led to reduced PSMA level, decreased cell viability, and suppressed expression of cancer stem cell markers and migration indicators. Additionally, analysis of human PCa tissues revealed a positive correlation between PSMA and MCT1 expression in tumor regions. CONCLUSIONS: Our results demonstrate that ADT led to a significant upregulation in MCT1 levels. However, the combination of ENZ and SR13800 demonstrated a promising synergistic anticancer effect, highlighting a potential therapeutic significance for patients with PCa undergoing ADT.
Subject(s)
Androgen Antagonists , Benzamides , Monocarboxylic Acid Transporters , Nitriles , Phenylthiohydantoin , Prostatic Neoplasms , Symporters , Male , Humans , Monocarboxylic Acid Transporters/metabolism , Monocarboxylic Acid Transporters/antagonists & inhibitors , Monocarboxylic Acid Transporters/genetics , Cell Line, Tumor , Phenylthiohydantoin/pharmacology , Phenylthiohydantoin/analogs & derivatives , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/pathology , Prostatic Neoplasms/metabolism , Androgen Antagonists/pharmacology , Androgen Antagonists/therapeutic use , Nitriles/pharmacology , Symporters/metabolism , Symporters/antagonists & inhibitors , Symporters/genetics , Benzamides/pharmacologyABSTRACT
Herein, a high-quality gate stack (native HfO2 formed on 2D HfSe2) fabricated via plasma oxidation is reported, realizing an atomically sharp interface with a suppressed interface trap density (Dit ≈ 5 × 1010 cm-2 eV-1). The chemically converted HfO2 exhibits dielectric constant, κ ≈ 23, resulting in low gate leakage current (≈10-3 A cm-2) at equivalent oxide thickness ≈0.5 nm. Density functional calculations indicate that the atomistic mechanism for achieving a high-quality interface is the possibility of O atoms replacing the Se atoms of the interfacial HfSe2 layer without a substitution energy barrier, allowing layer-by-layer oxidation to proceed. The field-effect-transistor-fabricated HfO2/HfSe2 gate stack demonstrates an almost ideal subthreshold slope (SS) of ≈61 mV dec-1 (over four orders of IDS) at room temperature (300 K), along with a high Ion/Ioff ratio of ≈108 and a small hysteresis of ≈10 mV. Furthermore, by utilizing a device architecture with separately controlled HfO2/HfSe2 gate stack and channel structures, an impact ionization field-effect transistor is fabricated that exhibits n-type steep-switching characteristics with a SS value of 3.43 mV dec-1 at room temperature, overcoming the Boltzmann limit. These results provide a significant step toward the realization of post-Si semiconducting devices for future energy-efficient data-centric computing electronics.
ABSTRACT
Strain BSF-3MT is a Gram-stain-positive, non-flagellated, facultative anaerobic and rod-shaped bacterium that was isolated from fermented feed collected at a cattle farm in the Daejeon region of the Republic of Korea. It was studied using polyphasic taxonomic methods. Using 16S rRNA gene sequences and the resulting phylogenetic tree, the strain was primarily identified as a member of the genus Lacticaseibacillus. Strain BSF-3MT contained a chromosome of 2.5 Mbp and a plasmid of 33.4 kbp. The G+C content of genomic DNA was 51.3âmol%. Strain BSF-3MT had the highest ortho-average nucleotide identity value of 73.7â% with Lacticaseibacillus songhuajiangensis 7-19T, its closest relative in the phylogenetic tree based on the 16S rRNA gene sequences and the phylogenomic tree based on up-to-date bacterial core genes. Based on the results of a polyphasic taxonomic study, strain BSF-3MT represents a novel species in the genus Lacticaseibacillus, for which the name Lacticaseibacillus pabuli sp. nov. is proposed. The type strain is BSF-3MT (=KACC 23028T=NBRC 116014T).
Subject(s)
Fatty Acids , Lacticaseibacillus , Animals , Cattle , Base Composition , Phylogeny , RNA, Ribosomal, 16S/genetics , Sequence Analysis, DNA , DNA, Bacterial/genetics , Bacterial Typing Techniques , Fatty Acids/chemistry , Animal FeedABSTRACT
BACKGROUND: Pregnancy-associated spontaneous coronary artery dissection (SCAD) and reversible cerebral vasoconstriction syndrome (RCVS) are rare conditions that may occur during pregnancy and the postpartum period. The coexistence of both diseases may pose a risk to patients, potentially resulting in a variety of complications and clinical manifestations. This is considered the first case of a patient who successfully recovered from a critical condition in the postpartum period, with contemporaneous SCAD and RCVS. CASE PRESENTATION: A 33-year-old female with no known medical history was referred to the emergency department after experiencing cardiac arrest, which occurred 1 week after giving birth to her third child. She complained of sudden anterior squeezing chest pain, accompanied by a headache, and eventually collapsed due to ventricular fibrillation with seizure. She was successfully resuscitated after receiving basic life support. She showed an alert mentality and did not experience any further seizure events or additional neurological symptoms. Although vital sign remained stable, the level of highly sensitive troponin I was significantly elevated. Electrocardiography revealed sinus rhythm with T-wave inversion at V1-4, while chest computed tomography (CT) demonstrated severe aspiration pneumonia. The patient was admitted to the intensive care unit due to a high requirement of O2 supply. A consultation with the neurologic department and a brain magnetic resonance angiography (MRA) were conducted for the thunderclap headache. The brain MRA demonstrated stenosis in the basilar artery, the right M2 segment, and bilateral A1 segments, along with sulcal hyperintensity on post-contrast fluid-attenuated inversion recovery (FLAIR) suggesting blood-brain barrier breakdown due to vasoconstriction. Formal echocardiography showed regional wall motion abnormality in the left anterior descending artery (LAD) territory. After the improvement of pneumonia, a coronary angiography was performed, revealing diffuse luminal narrowing from the mid to distal LAD due to a long segmental, extensive dissection. We decided to maintain the medical therapy. A follow-up coronary CT angiography performed 6 months later revealed complete remission of the dissected coronary vessel, and a brain MRA checked 3 months later showed resolved vasoconstriction of the relevant cerebral vessels. CONCLUSIONS: The physicians must be aware of pregnancy-associated complications in certain patients. Clear diagnoses and proper treatments are required in pregnant patients who may be exposed to multiple acute conditions, in order to reduce complications and achieve favorable outcomes.
ABSTRACT
Serotonin-like mimotopes were screened from the Fv-antibody library to be used as inhibitors against monoamine oxidase A (MAO-A). The Fv-antibody [corresponding to the VH region of immunoglobulin G (IgG)] consists of three complementarity-determining regions and four frame regions. The Fv-antibody library was prepared by site-directed mutagenesis of CDR3, which consists of 11 amino acid residues. Three target clones were screened from the Fv-antibody library, and the binding affinity of the screened clones to the monoclonal anti-serotonin antibody was analyzed using fluorescence-activated cell sorting. The screened Fv-antibodies were expressed as soluble proteins fused with green fluorescence protein. Additionally, the screened CDR3 regions (11 residues) of the selected Fv-antibodies were synthesized as peptides with linking amino acid residues. The binding constants (KD) of the three serotonin-like mimotopes (Fv-antibodies and peptides) were estimated using a surface plasmon resonance biosensor. The inhibitory activity (IC50) of the serotonin-like mimotopes (Fv-antibodies and peptides) was estimated separately for MAO-A and MAO-B enzymes and compared with that of conventional inhibitors. Finally, the screened serotonin-like mimotopes were used to treat a cell line (SH-SY5Y, ATCC code: CRL-2266) expressing serotonin receptors. This was done to confirm the following two aspects: (1) the binding of mimotopes to the serotonin receptors on the cell surface and (2) the inhibitory activity of mimotopes against MAO-A enzymes in the cell lysates.
ABSTRACT
Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer-related mortality worldwide. Programmed cell death ligand-1 (PD-L1) is an immune checkpoint protein that binds to programmed cell death-1 (PD-1), which is expressed in activated T cells and other immune cells and has been employed in cancer therapy, including HCC. Recently, PD-L1 overexpression has been documented in treatment-resistant cancer cells. Sorafenib is a multikinase inhibitor and the only FDA-approved treatment for advanced HCC. However, several patients exhibit resistance to sorafenib during treatment. This study aimed to assess the effect of glucose deprivation on PD-L1 expression in HCC cells. We used PD-L1-overexpressing HepG2 cells and IFN-γ-treated SK-Hep1 cells to explore the impact of glycolysis on PD-L1 expression. To validate the correlation between PD-L1 expression and glycolysis, we analyzed data from The Cancer Genome Atlas (TCGA) and used immunostaining for HCC tissue analysis. Furthermore, to modulate PD-L1 expression, we treated HepG2, SK-Hep1, and sorafenib-resistant SK-Hep1R cells with rapamycin. Here, we found that glucose deprivation reduced PD-L1 expression in HCC cells. Additionally, TCGA data and immunostaining analyses confirmed a positive correlation between the expression of hexokinase II (HK2), which plays a key role in glucose metabolism, and PD-L1. Notably, rapamycin treatment decreased the expression of PD-L1 and HK2 in both high PD-L1-expressing HCC cells and sorafenib-resistant cells. Our results suggest that the modulation of PD-L1 expression by glucose deprivation may represent a strategy to overcome PD-L1 upregulation in patients with sorafenib-resistant HCC.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Humans , Sorafenib/pharmacology , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Liver Neoplasms/drug therapy , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , B7-H1 Antigen/genetics , B7-H1 Antigen/metabolism , Sirolimus , GlucoseABSTRACT
Eunkyo-san is widely used in the treatment of severe respiratory infections. Mast cells not only serve as host cells for the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but also they also exacerbate Coronavirus disease in 2019 (COVID-19) by causing a cytokine storm. Here we investigated whether Eunkyo-san and its active compound naringenin regulate the expression of inflammatory cytokines and factors connected to viral infection in activated human mast cell line, HMC-1 cells. Eunkyo-san and naringenin significantly reduced levels of inflammatory cytokines including interleukin (IL)-1ß, IL-6, IL-8, thymic stromal lymphopoietin, and tumor necrosis factor-α without impacting cytotoxicity. Eunkyo-san and naringenin reduced levels of factors connected to SARS-CoV-2 infection such as angiotensin-converting enzyme 2 (ACE2, SARS-CoV-2 receptor), transmembrane protease/serine subfamily member 2, and tryptase in activated HMC-1 cells. Treatment with Eunkyo-san and naringenin considerably reduced expression levels of ACE2 transcription factor, AP-1 (C-JUN and C-FOS) by blocking phosphatidylinositide-3-kinase and c-Jun NH2-terminal kinases signaling pathways. In addition, Eunkyo-san and naringenin effectively suppressed activation of signal transducer and activator of transcription 3, nuclear translocation of nuclear factor-κB, and activation of caspase-1 in activated HMC-1 cells. Furthermore, Eunkyo-san and naringenin reduced expression of ACE2 mRNA in two activated mast cell lines, RBL-2H3 and IC-2 cells. The overall study findings showed that Eunkyo-san diminished the expression levels of inflammatory cytokines and ACE2, and these findings imply that Eunkyo-san is able to effectively mitigating the cytokine storm brought on by SARS-CoV-2 infection.
Subject(s)
COVID-19 , Cytokines , Humans , Animals , Cytokines/metabolism , Angiotensin-Converting Enzyme 2/metabolism , Angiotensin-Converting Enzyme 2/pharmacology , Cytokine Release Syndrome/metabolism , Mast Cells , SARS-CoV-2ABSTRACT
BACKGROUND: Stopping aspirin within 1 month after implantation of a drug-eluting stent for ticagrelor monotherapy has not been exclusively evaluated for patients with acute coronary syndrome. The aim of this study was to investigate whether ticagrelor monotherapy after <1 month of dual antiplatelet therapy (DAPT) is noninferior to 12 months of ticagrelor-based DAPT for adverse cardiovascular and bleeding events in patients with acute coronary syndrome. METHODS: In this randomized, open-label, noninferiority trial, 2850 patients with acute coronary syndrome who underwent drug-eluting stent implantation at 24 centers in South Korea were randomly assigned (1:1) to receive either ticagrelor monotherapy (90 mg twice daily) after <1 month of DAPT (n=1426) or 12 months of ticagrelor-based DAPT (n=1424) between April 24, 2019, and May 31, 2022. The primary end point was the net clinical benefit as a composite of all-cause death, myocardial infarction, definite or probable stent thrombosis, stroke, and major bleeding at 1 year after the index procedure in the intention-to-treat population. Key secondary end points were the individual components of the primary end point. RESULTS: Among 2850 patients who were randomized (mean age, 61 years; 40% ST-segment-elevation myocardial infarction), 2823 (99.0%) completed the trial. Aspirin was discontinued at a median of 16 days (interquartile range, 12-25 days) in the group receiving ticagrelor monotherapy after <1 month of DAPT. The primary end point occurred in 40 patients (2.8%) in the group receiving ticagrelor monotherapy after <1-month DAPT, and in 73 patients (5.2%) in the ticagrelor-based 12-month DAPT group (hazard ratio, 0.54 [95% CI, 0.37-0.80]; P<0.001 for noninferiority; P=0.002 for superiority). This finding was consistent in the per-protocol population as a sensitivity analysis. The occurrence of major bleeding was significantly lower in the ticagrelor monotherapy after <1-month DAPT group compared with the 12-month DAPT group (1.2% versus 3.4%; hazard ratio, 0.35 [95% CI, 0.20-0.61]; P<0.001). CONCLUSIONS: This study provides evidence that stopping aspirin within 1 month for ticagrelor monotherapy is both noninferior and superior to 12-month DAPT for the 1-year composite outcome of death, myocardial infarction, stent thrombosis, stroke, and major bleeding, primarily because of a significant reduction in major bleeding, among patients with acute coronary syndrome receiving drug-eluting stent implantation. Low event rates, which may suggest enrollment of relatively non-high-risk patients, should be considered in interpreting the trial. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03797651.
Subject(s)
Acute Coronary Syndrome , Drug-Eluting Stents , Myocardial Infarction , Percutaneous Coronary Intervention , Stroke , Thrombosis , Humans , Middle Aged , Aspirin/therapeutic use , Ticagrelor/adverse effects , Platelet Aggregation Inhibitors/therapeutic use , Acute Coronary Syndrome/drug therapy , Acute Coronary Syndrome/surgery , Drug-Eluting Stents/adverse effects , Drug Therapy, Combination , Hemorrhage/etiology , Myocardial Infarction/drug therapy , Stroke/etiology , Thrombosis/etiology , Percutaneous Coronary Intervention/adverse effects , Percutaneous Coronary Intervention/methods , Treatment OutcomeABSTRACT
An aerobic, Gram-stain-positive, rod-shaped, endospore-forming bacterial strain, designated BB3-R1T, was isolated from cow faeces sampled in Daejeon, Republic of Korea. Growth was observed at 25-45â°C (optimum, 35-40â°C) and pH 7.0-9.0 (optimum, pH 8.0), with up to 3â% (w/v) NaCl (optimum, 0â% NaCl). blast analysis of 16S rRNA gene sequences revealed the highest sequence similarity of strain BB3-R1T to Brevibacillus borstelensis NRRL NRS-818T (98.8â%) followed by Brevibacillus panacihumi JCM 15085T (97.5â%). According to 16S rRNA gene and whole-genome based phylogenetic trees, strain BB3-R1T clustered with Brevibacillus composti FJAT-54423T and B. borstelensis NRRL NRS-818T. OrthoANI and dDDH values of strain BB3-R1T with the closely related strains were lower than 77.5 and 26.8â%, respectively. The major menaquinones and polar lipids of the strain were MK-7 and phosphatidylmonomethylethanolamine, diphosphatidylglycerol, phosphatidylglycerol and phosphatidylethanolamine, respectively. The major fatty acids (>10â%) were C14â:â0 iso, C15â:â0 iso, C15â:â0 anteiso and C16â:â1 ω7c alcohol. The cell-wall peptidoglycan contained cross-linked meso-diaminopimelic acid (type A1 gamma). The phenotypic, chemotaxonomic and genotypic data obtained in this study showed that the strain represents a novel species of the genus Brevibacillus, for which the name Brevibacillus ruminantium sp. nov. (type strain BB3-R1T=KACC 22663T=NBRC 115962T) is proposed.
Subject(s)
Brevibacillus , Cattle , Animals , Fatty Acids/chemistry , Phospholipids , Sodium Chloride , Sequence Analysis, DNA , Phylogeny , RNA, Ribosomal, 16S/genetics , Bacterial Typing Techniques , DNA, Bacterial/genetics , Base CompositionABSTRACT
Optimizing the contact structure while reducing the contact resistance in advanced transistors has become an extremely challenging problem. Because the existing techniques are limited to controlling only one semiconductor type, either n- or p-type, owing to their work function differences, significant challenges are encountered in the integration of a contact structure and metal suitable for both n- and p-type semiconductors. This is a formidable drawback of the complementary metal-oxide-semiconductor (CMOS) technology. In this paper, we demonstrate the effectiveness of a metal/graphene/semiconductor (MGrS) as a universal source/drain contact structure for both n- and p-type transistors. The MGrS contact structure significantly enhanced the reverse current density (JR) and reduced the Schottky barrier height (SBH) for both semiconductor types. From the analysis of the SBH values and their relationship with the metal work function, which refers to the S-parameter, the van der Waals contact of graphene (Gr) effectively alleviated the Fermi level (FL) pinning for both semiconductor types, reducing the metal-induced gap states (MIGS) at the Gr/semiconductor interface. Furthermore, Gr effectively modulated the work function of the contact metal to yield a position favorable for each semiconductor type. Consequently, a single MGrS contact structure on a Si substrate resulted in excellent Ohmic contacts in both n- and p-type Si, with SBH values reduced to 0.012 and 0.024 eV for n- and p-type Si, respectively. This new approach for integrating the contact structures of semiconductor types will lead to extended capabilities for high-performance device applications and CMOS logical circuitry.