Inhibition of the galactosyltransferase C1GALT1 reduces osteosarcoma cell proliferation by interfering with ERK signaling and cell cycle progression.

Novel therapeutic strategies are urgently required for osteosarcoma, given the early age at onset and persistently high mortality rate. Modern transcriptomics techniques can identify differentially expressed genes (DEGs) that may serve as biomarkers and therapeutic targets, so we screened for DEGs in osteosarcoma. We found that osteosarcoma cases could be divided into fair and poor survival groups based on gene expression profiles. Among the genes upregulated in the poor survival group, siRNA-mediated knockdown of the glycosylation-related gene C1GALT1 suppressed osteosarcoma cell proliferation in culture. Gene expression, phosphorylation, and glycome array analyses also demonstrated that C1GALT1 is required to maintain ERK signaling and cell cycle progression. Moreover, the C1GALT1 inhibitor itraconazole suppressed osteosarcoma cell proliferation in culture, while doxycycline-induced shRNA-mediated knockdown reduced xenograft osteosarcoma growth in mice. Elevated C1GALT1 expression is a potential early predictor of poor prognosis, while pharmacological inhibition may be a feasible treatment strategy for osteosarcoma.

Phase transformation behavior and mechanical properties of HyFlex EDM nickel-titanium endodontic rotary instrument: Evaluation at body temperature.

Background/purpose: Temperature-dependent phase compositional changes influence the mechanical properties of heat-treated nickel-titanium (NiTi) rotary instruments. This study evaluated the phase composition, bending properties, and cyclic fatigue resistance of HyFlex EDM NiTi rotary instruments against differently heat-treated and non-heat-treated NiTi instruments at body temperature (BT). Materials and methods: HyFlex EDM OneFile (EDM) instruments, heat-treated HyFlex CM (CM) and Twisted File (TF) instruments, and non-heat-treated K3 instruments (size #25/.08) were subjected to differential scanning calorimetry, and the martensitic, R-phase, and reverse transformation starting and finishing temperatures were determined. A cantilever bending test and a cyclic fatigue test were conducted at BT (37 °C ± 1.0 °C), and the bending load and number of cycles to failure (NCF) were recorded. Statistical analysis was performed using Kruskal-Wallis and Mann-Whitney U tests (α = 0.05). Results: TF and K3 had reverse transformation finishing temperatures lower than BT, while those for EDM and CM were higher than BT. The bending loads at a 0.5 mm deflection were in the order of EDM < TF < CM < K3 (P < 0.05), and those at a 2.0 mm deflection were EDM < CM and TF < K3 (P < 0.05). EDM had the highest NCF among the four instruments (P < 0.05). Conclusion: The EDM instrument had a reverse transformation finishing temperature higher than BT indicating its martensite/R-phase composition at BT. The EDM instrument had superior flexibility and greater resistance to cyclic fatigue than the CM, TF, and K3 instruments at BT.

Effect of preset torque setting on torque/force generation, shaping ability and surface changes of nickel titanium rotary instrument in different root canal curvature locations: An ex vivo study.

The aim of this study was to evaluate how preset torque settings influence the torque, vertical force, and root canal-centering ability of ProGlider and ProTaper NEXT nickel-titanium rotary instruments in canals with different curvature locations. Based on micro-computed tomography, mesial roots of human mandibular molars (25°-40° curvature) were allocated to the apical curvature (apical 1-5 mm) or the middle curvature (apical 5-9 mm) groups, and mandibular incisors (curvature <5°) to the straight canal group. Each group was subjected to automated instrumentation and torque/force measurement with the preset torque of 1, 2.5, or 5 N•cm. Canal-centering ratios were determined with micro-computed tomography. Instrument fracture occurred only in the 2.5 and 5 N•cm groups in curved canals. The preset torque setting and curvature location did not influence canal shaping ability.

Variations in the inner core affect the pharmacokinetics of indomethacin-encapsulated polymeric micelles.

Hydrophobic ion pairing (HIP) is a drug encapsulation technology that uses electrostatic interactions between a drug and an additive. However, although polymeric micelles can encapsulate hydrophobic drugs in the core, the encapsulated drug often leaks. Therefore, we designed polymeric micelles with HIP functionalized in a hydrophobic inner core using three diblock copolymers comprising polypeptides with different ratios of polar and hydrophobic amino acids and polyethylene glycol (PEG) to encapsulate indomethacin (IND). The three IND-encapsulated HIP micelles showed different area under the curve (AUC) values as an index of blood retention after intravenous injection in mice. Despite having the same PEG shell, IND-PEG-poly(H/F)n showed a 1.56-fold higher AUC than IND-PEG-poly(D/F)n. PEG interface morphologies were evaluated to determine the differences in pharmacokinetic parameters caused by changes in inner core HIP patterns. The micellarized diblock copolymer was desorbed from IND-PEG-poly(D/F)n due to electrostatic repulsion between IND and the diblock copolymer comprising aspartic acid. Our results suggest that changes in the HIP patterns of the micelle inner core affected the PEG interface morphologies, such as PEG density and diblock copolymer desorption from micelles. These phenomena might lead to changes in the interaction of plasma proteins and drug dispositions.

Development of Taste Sensor with Lipid/Polymer Membranes for Detection of Umami Substances Using Surface Modification.

A taste sensor employs various lipid/polymer membranes with specific physicochemical properties for taste classification and evaluation. However, phosphoric acid di(2-ethylhexyl) ester (PAEE), employed as one of the lipids for the taste sensors, exhibits insufficient selectivity for umami substances. The pH of sample solutions impacts the dissociation of lipids to influence the membrane potential, and the response to astringent substances makes accurate measurement of umami taste difficult. This study aims to develop a novel taste sensor for detecting umami substances like monosodium L-glutamate (MSG) through surface modification, i.e., a methodology previously applied to taste sensors for non-charged bitter substance measurement. Four kinds of modifiers were tested as membrane-modifying materials. By comparing the results obtained from these modifiers, the modifier structure suitable for measuring umami substances was identified. The findings revealed that the presence of carboxyl groups at para-position of the benzene ring, as well as intramolecular H-bonds between the carboxyl group and hydroxyl group, significantly affect the effectiveness of a modifier in the umami substance measurement. The taste sensor treated with this type of modifier showed excellent selectivity for umami substances.

A purified diet affects intestinal epithelial proliferation and barrier functions through gut microbial alterations.

The gut microbiota plays a crucial role in maintaining epithelial barrier function. Although multiple studies have demonstrated the significance of dietary factors on the gut microbiota and mucosal barrier function, the impact of a purified diet, which has long been used in various animal experiments, on intestinal homeostasis remains to be elucidated. Here, we compared the impact of two different types of diets, a crude diet and an AIN-93G-formula purified diet, on epithelial integrity and the gut microbiota. Purified diet-fed mice exhibited shorter villi and crypt lengths and slower epithelial turnover, particularly in the ileum. In addition, antimicrobial products, including REG3γ, were substantially decreased in purified diet-fed mice. Purified diet feeding also suppressed α1,2-fucosylation on the epithelial surface. Furthermore, the purified diet induced metabolic rewiring to fatty acid oxidation and ketogenesis. 16S ribosomal RNA gene sequencing of the ileal contents and mucus layer revealed distinct gut microbiota compositions between the purified and crude diet-fed mice. Purified diet feeding reduced the abundance of segmented filamentous bacteria (SFB), which potently upregulate REG3γ and fucosyltransferase 2 (Fut2) by stimulating group 3 innate lymphoid cells (ILC3s) to produce IL-22. These observations illustrate that the intake of a crude diet secures epithelial barrier function by facilitating SFB colonization, whereas a purified diet insufficiently establishes the epithelial barrier, at least partly owing to the loss of SFB. Our data suggest that the influence of purified diets on the epithelial barrier integrity should be considered in experiments using purified diets.

Association of the Timing of Atrial Fibrillation Detection and Insular Involvement With the Risk of Embolic Events After Acute Ischemic Stroke.

OBJECTIVE: Atrial fibrillation (AF) detected after insular stroke might arise from autonomic and inflammatory mechanisms triggered by insular damage, and be associated with a low embolic risk. We assessed the association of the timing of AF detection and insular involvement with the risk of embolic events after acute ischemic stroke. METHODS: Acute ischemic stroke patients with AF who underwent brain magnetic resonance imaging at baseline were enrolled. Patients were classified according to the timing of AF detection (AF detected after stroke [AFDAS] or known AF [KAF]) and insular involvement. The primary outcome was embolic events defined as recurrent ischemic stroke, transient ischemic attack, and systemic embolism within 90 days. RESULTS: Of 1,548 patients, 360 had AFDAS with insular cortex lesions (+I), 409 had AFDAS without insular cortex lesions (-I), 349 had KAF+I, and 430 had KAF-I. Cumulative incidence rates of embolic events at 90 days in patients with AFDAS+I, AFDAS-I, KAF+I, and KAF-I were 0.8%, 3.5%, 4.9%, and 3.3%, respectively. Patients with AFDAS-I (adjusted hazard ratio 5.04, 95% confidence interval 1.43-17.75), KAF+I (6.18, 1.78-21.46), and KAF-I (5.26, 1.48-18.69) had a significantly higher risk of embolic events than those with AFDAS+I. INTERPRETATION: Acute ischemic stroke patients with AFDAS and insular cortex lesions had a lower risk of embolic events than those who had AFDAS without insular cortex lesions or those with KAF, regardless of insular involvement. ANN NEUROL 2024;95:338-346.

CASZ1 upregulates PI3K-AKT-mTOR signaling and promotes T-cell acute lymphoblastic leukemia.

CASZ1 is a conserved transcription factor involved in neural development, blood vessel assembly and heart morphogenesis. CASZ1 has been implicated in cancer, either suppressing or promoting tumor development depending on the tissue. However, the impact of CASZ1 on hematological tumors remains unknown. Here, we show that the T-cell oncogenic transcription factor TAL1 is a direct positive regulator of CASZ1, that T-cell acute lymphoblastic leukemia (T-ALL) samples at diagnosis overexpress CASZ1b isoform, and that CASZ1b expression in patient samples correlates with PI3KAKT- mTOR signaling pathway activation. In agreement, overexpression of CASZ1b in both Ba/F3 and T-ALL cells leads to the activation of PI3K signaling pathway, which is required for CASZ1b-mediated transformation of Ba/F3 cells in vitro and malignant expansion in vivo. We further demonstrate that CASZ1b cooperates with activated NOTCH1 to promote T-ALL development in zebrafish, and that CASZ1b protects human T-ALL cells from serum deprivation and treatment with chemotherapeutic drugs. Taken together, our studies indicate that CASZ1b is a TAL1-regulated gene that promotes T-ALL development and resistance to chemotherapy.

Myeloid/natural killer (NK) cell precursor acute leukemia as a distinct leukemia type.

Myeloid/natural killer (NK) cell precursor acute leukemia (MNKPL) has been described on the basis of its unique immunophenotype and clinical phenotype. However, there is no consensus on the characteristics for identifying this disease type because of its rarity and lack of defined distinctive molecular characteristics. In this study, multiomics analysis revealed that MNKPL is distinct from acute myeloid leukemia, T cell acute lymphoblastic leukemia, and mixed-phenotype acute leukemia (MPAL), and NOTCH1 and RUNX3 activation and BCL11B down-regulation are hallmarks of MNKPL. Although NK cells have been classically considered to be lymphoid lineage-derived, the results of our single-cell analysis using MNKPL cells suggest that NK cells and myeloid cells share common progenitor cells. Treatment outcomes for MNKPL are unsatisfactory, even when hematopoietic cell transplantation is performed. Multiomics analysis and in vitro drug sensitivity assays revealed increased sensitivity to l-asparaginase and reduced levels of asparagine synthetase (ASNS), supporting the clinically observed effectiveness of l-asparaginase.

Biologic and clinical features of childhood gamma delta T-ALL: identification of STAG2/LMO2 γδ T-ALL as an extremely high risk leukemia in the very young.

PURPOSE: Gamma delta T-cell receptor-positive acute lymphoblastic leukemia (γδ T-ALL) is a high-risk but poorly characterized disease. METHODS: We studied clinical features of 200 pediatric γδ T-ALL, and compared the prognosis of 93 cases to 1,067 protocol-matched non-γδ T-ALL. Genomic features were defined by transcriptome and genome sequencing. Experimental modeling was used to examine the mechanistic impacts of genomic alterations. Therapeutic vulnerabilities were identified by high throughput drug screening of cell lines and xenografts. RESULTS: γδ T-ALL in children under three was extremely high-risk with 5-year event-free survival (33% v. 70% [age 3-<10] and 73% [age ≥10], P =9.5 x 10 -5 ) and 5-year overall survival (49% v. 78% [age 3-<10] and 81% [age ≥10], P =0.002), differences not observed in non-γδ T-ALL. γδ T-ALL in this age group was enriched for genomic alterations activating LMO2 activation and inactivating STAG2 inactivation ( STAG2/LMO2 ). Mechanistically, we show that inactivation of STAG2 profoundly perturbs chromatin organization by altering enhancer-promoter looping resulting in deregulation of gene expression associated with T-cell differentiation. Drug screening showed resistance to prednisolone, consistent with clinical slow treatment response, but identified a vulnerability in DNA repair pathways arising from STAG2 inactivation, which was efficaciously targeted by Poly(ADP-ribose) polymerase (PARP) inhibition, with synergism with HDAC inhibitors. Ex-vivo drug screening on PDX cells validated the efficacy of PARP inhibitors as well as other potential targets including nelarabine. CONCLUSION: γδ T-ALL in children under the age of three is extremely high-risk and enriched for STAG2/LMO2 ALL. STAG2 loss perturbs chromatin conformation and differentiation, and STAG2/LMO2 ALL is sensitive to PARP inhibition. These data provide a diagnostic and therapeutic framework for pediatric γδ T-ALL. SUPPORT: The authors are supported by the American and Lebanese Syrian Associated Charities of St Jude Children's Research Hospital, NCI grants R35 CA197695, P50 CA021765 (C.G.M.), the Henry Schueler 41&9 Foundation (C.G.M.), and a St. Baldrick's Foundation Robert J. Arceci Innovation Award (C.G.M.), Gabriella Miller Kids First X01HD100702 (D.T.T and C.G.M.) and R03CA256550 (D.T.T. and C.G.M.), F32 5F32CA254140 (L.M.), and a Garwood Postdoctoral Fellowship of the Hematological Malignancies Program of the St Jude Children's Research Hospital Comprehensive Cancer Center (S.K.). This project was supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180820, UG1CA189859, U24CA114766, U10CA180899, U10CA180866 and U24CA196173. DISCLAIMER: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding agencies were not directly involved in the design of the study, gathering, analysis and interpretation of the data, writing of the manuscript, or decision to submit the manuscript for publication.

GP2-expressing cells: a new guardian with divergent functions in the intestine, eyes, and nose.

GP (glycoprotein)-2, originally identified as a predominant membranous component of pancreatic acinar cells, has attracted the interest of researchers in mucosal immunology for its role as a functional molecule specific for antigen-sampling cells in the intestinal Peyer's patches. GP2 is involved in the detection of pathological bacteria and is also histologically useful for the identification of the M cell lineage and their differentiation in lymphoid tissues. Subsequent immunohistochemistry for GP2 has revealed a broad distribution of M cells and related cells in the nasopharyngeal lymphoid tissues, conjunctiva, tear duct, and airway. Especially, GP2 cells in the paranasal sinuses and tear duct have been identified as novel types of epithelial cells. The systematic administration of RANKL can induce extra-M cells in conventional epithelia of body. The production and release of GP2 by conjunctival goblet cells and several mucous glands suggests leading roles for mucous cells in protection, including the entrapment of microorganisms for infections. The ocular surface and conjunctiva are connected to the lacrimal sac, nasolacrimal duct, and further nasal cavity, comprising another canal that passes through the body. The broad distribution of GP2-expressingcells may indicate its function as a new guardian in the intestine, eyes, and nose, all of which are exposed to external milieu.

Phase transformation and mechanical properties of heat-treated nickel-titanium rotary endodontic instruments at room and body temperatures.

BACKGROUND: The aim of this study was to evaluate the phase composition, phase transformation temperatures, bending property, and cyclic fatigue resistance of different heat-treated nickel-titanium (NiTi) rotary instruments with the same tip diameter and taper at room (RT; 25 ± 1 °C) and body (BT; 37 ± 1 °C) temperatures. METHODS: Five heat-treated NiTi rotary instruments, HyFlex EDM (EDM), HyFlex CM (CM), Vortex Blue (VB), RE file CT (RE) and JIZAI, and a non-heat-treated NiTi rotary instrument (Mtwo) with a size 40, 0.04 taper were investigated. Temperature-dependent phase transformation was examined with differential scanning calorimetry (DSC). The bending loads of the instruments at RT and BT were evaluated using a cantilever-bending test. Cyclic fatigue resistance at RT and BT was measured using a dynamic test, during which the instruments were rotated in combination with a 2-mm back-and-forth motion in an artificial curved canal, and the number of cycles to failure (NCF) was determined. The results were analyzed using two-way repeated measures analysis of variance, a simple main effect test, and the Bonferroni test (α = 0.05). RESULTS: DSC results indicated that EDM and Mtwo were primarily composed of martensite/R-phase and austenite, respectively, while the other heat-treated instruments were composed of a mix of martensite/R-phase and austenite at the tested temperatures. Regardless of the temperature setting, the bending loads of heat-treated instruments were significantly lower than those of Mtwo (p < 0.05). EDM showed the lowest bending loads and highest NCF at both temperatures (p < 0.05). CM, VB, and JIZAI showed significantly higher bending loads at BT than at RT (p < 0.05). The NCF of all the heat-treated instruments, except VB, was lower at BT than at RT (p < 0.05). At BT, the NCF of CM, VB, RE, and JIZAI were not significantly higher than that of Mtwo (p > 0.05). CONCLUSIONS: Heat-treated NiTi instruments exhibited lower bending loads and higher NCF values than Mtwo. However, this tendency was less pronounced at BT than at RT, especially in the NCF values of instruments with a mixture of martensite/R-phase and austenite phases at the tested temperatures.

Dynamic torque and screw-in force of four different glide path instruments assessed in simulated single- and double-curved canals: An in vitro study.

Background/purpose: The glide path instruments are the introductory instruments into the canals; thus, they should be durable enough to withstand torsional stress/screw-in force. This study aimed to investigate the torque and screw-in force of TruNatomy Glider (TN), ProGLIDER (PG), Hyflex EDM (EDM) and Dent Craft RE (RE) glide path instruments in single- and double-curved canals. Materials and methods: Each instrument brand was divided into two groups (n = 7 each) according to the canal configuration. Torque and screw-in force were recorded during automated instrumentation of simulated resin canals with XSmart IQ cordless motor after the canal patency was checked with a #10 K-file. The values were statistically analyzed using the Kolmogorov-Smirnov test followed by the Kruskal Wallis test and the Mann-Whitney U test with Bonferroni correction (α = 0.05). Results: TN produced significantly higher torque than RE in single-curved canals and PG in double-curved canals (P < 0.05). EDM yielded significantly higher screw-in force than TN and RE in single-curved canals (P < 0.05), but there was no significant difference in double-curved canals (P > 0.05). A significant effect of different canal configurations was only detected for screw-in force in EDM (P < 0.05). Conclusion: TN in single-curved canals and RE in double-curved canals yielded higher torque values, while EDM exhibited greater screw-in force in both canal configurations. No effect of different canal configurations was detected for torque, but a significant impact was detected for screw-in force in EDM.

Electrical Properties of Taste Sensors with Positively Charged Lipid Membranes Composed of Amines and Ammonium Salts.

Currently, taste sensors utilizing lipid polymer membranes are utilized to assess the taste of food products quantitatively. During this process, it is crucial to identify and quantify basic tastes, e.g., sourness and sweetness, while ensuring that there is no response to tasteless substances. For instance, suppression of responses to anions, like tasteless NO3- ions contained in vegetables, is essential. However, systematic electrochemical investigations have not been made to achieve this goal. In this study, we fabricated three positively charged lipid polymer membranes containing oleylamine (OAm), trioctylemethylammonium chloride (TOMACl), or tetradodecylammonium bromide (TDAB) as lipids, and sensors that consist of these membranes to investigate the potential change characteristics of these sensors in solutions containing different anions (F-, Cl-, Br-, NO3-, I-). The ability of each anion solution to reduce the positive charge on membranes and shift the membrane potential in the negative direction was in the following order: I- > NO3- > Br- > Cl- > F-. This order well reflected the order of size of the hydrated ions, related to their hydration energy. Additionally, the OAm sensor displayed low ion selectivity, whereas the TOMACl and TDAB sensors showed high ion selectivity related to the OAm sensor. Such features in ion selectivity are suggested to be due to the variation in positive charge with the pH of the environment and packing density of the OAm molecule in the case of the OAm sensor and due to the strong and constant positive charge created by complete ionization of lipids in the case of TOMACl and TDAB sensors. Furthermore, it was revealed that the ion selectivity varies by changing the lipid concentration in each membrane. These results contribute to developing sensor membranes that respond to different anion species selectively and creating taste sensors capable of suppressing responses to tasteless anions.

Influence of different kinematics on stationary and dynamic torsional behavior of JIZAI nickel-titanium rotary instruments: An in vitro study.

Background/purpose: Using conventional approach to examine stationary torque of nickel-titanium rotary instruments contradicts the clinical condition, and its validity for motions involving clockwise and counterclockwise rotations is questionable. This study aimed to examine the effect of different kinematics on the torsional behavior using a JIZAI instrument (#25/.04) under stationary/dynamic test conditions using clinical torque limit settings. Materials and methods: In the stationary test, the 5-mm tip of JIZAI was fixed in a cylinder-shaped vise and rotated in continuous rotation (CR) with auto-torque-reverse, optimum-torque-reverse (OTR), or reciprocation (REC) until fracture (n = 10, each). In the dynamic test, straight and severe curved canals were instrumented with JIZAI using the single-length technique with CR, OTR, or REC (n = 10, each). The stationary torque at fracture, time to fracture (Tf), dynamic torque, and screw-in force were recorded using automated-shaping-device with torque/force measuring unit. One-way ANOVA or Kruskal-Wallis test and Mann-Whitney U test with Bonferroni correction were used for statistical analysis (⍺ = 0.05). Results: The kinematics did not influence the stationary or dynamic torques (P > 0.05); however, did influence the screw-in force in straight canals (P < 0.05). REC had significantly longer Tf, and severe curved canals yielded significantly greater torque and screw-in force in CR (P < 0.05). Conclusion: Under the present experimental conditions, parameters other than torque showed significant effects on different kinematics. The dynamic torque and screw-in force of OTR were similar to the other rotational modes and not influenced by the canal curvature.

Dysfunction of Foxp3+ Regulatory T Cells Induces Dysbiosis of Gut Microbiota via Aberrant Binding of Immunoglobulins to Microbes in the Intestinal Lumen.

Foxp3+ regulatory T (Treg) cells prevent excessive immune responses against dietary antigens and commensal bacteria in the intestine. Moreover, Treg cells contribute to the establishment of a symbiotic relationship between the host and gut microbes, partly through immunoglobulin A. However, the mechanism by which Treg cell dysfunction disturbs the balanced intestinal microbiota remains unclear. In this study, we used Foxp3 conditional knockout mice to conditionally ablate the Foxp3 gene in adult mice and examine the relationship between Treg cells and intestinal bacterial communities. Deletion of Foxp3 reduced the relative abundance of Clostridia, suggesting that Treg cells have a role in maintaining Treg-inducing microbes. Additionally, the knockout increased the levels of fecal immunoglobulins and immunoglobulin-coated bacteria. This increase was due to immunoglobulin leakage into the gut lumen as a result of loss of mucosal integrity, which is dependent on the gut microbiota. Our findings suggest that Treg cell dysfunction leads to gut dysbiosis via aberrant antibody binding to the intestinal microbes.

Elevated enhancer-oncogene contacts and higher oncogene expression levels by recurrent CTCF inactivating mutations in acute T cell leukemia.

Monoallelic inactivation of CCCTC-binding factor (CTCF) in human cancer drives altered methylated genomic states, altered CTCF occupancy at promoter and enhancer regions, and deregulated global gene expression. In patients with T cell acute lymphoblastic leukemia (T-ALL), we find that acquired monoallelic CTCF-inactivating events drive subtle and local genomic effects in nearly half of t(5; 14) (q35; q32.2) rearranged patients, especially when CTCF-binding sites are preserved in between the BCL11B enhancer and the TLX3 oncogene. These solitary intervening sites insulate TLX3 from the enhancer by inducing competitive looping to multiple binding sites near the TLX3 promoter. Reduced CTCF levels or deletion of the intervening CTCF site abrogates enhancer insulation by weakening competitive looping while favoring TLX3 promoter to BCL11B enhancer looping, which elevates oncogene expression levels and leukemia burden.

Development and Optimization of a Highly Sensitive Sensor to Quinine-Based Saltiness Enhancement Effect.

The saltiness enhancement effect can be produced by adding specific substances to dietary salt (sodium chloride). This effect has been used in salt-reduced food to help people forge healthy eating habits. Therefore, it is necessary to objectively evaluate the saltiness of food based on this effect. In a previous study, sensor electrodes based on lipid/polymer membrane with Na+ ionophore have been proposed to quantify the saltiness enhanced by branched-chain amino acids (BCAAs), citric acid, and tartaric acid. In this study, we developed a new saltiness sensor with the lipid/polymer membrane to quantify the saltiness enhancement effect of quinine by replacing a lipid that caused an unexpected initial drop in the previous study with another new lipid. As a result, the concentrations of lipid and ionophore were optimized to produce an expected response. Logarithmic responses have been found on both NaCl samples and quinine-added NaCl samples. The findings indicate the usage of lipid/polymer membranes on novel taste sensors to evaluate the saltiness enhancement effect accurately.

Pharmacokinetic/Pharmacodynamic Models of an Alzheimer's Drug, Donepezil, in Rats.

To investigate the relationship between the pharmacokinetics (PK) and pharmacodynamics (PD) of donepezil (Don), simultaneous examination of the PK of Don and the change in acetylcholine (ACh) in the cerebral hippocampus was analyzed using microdialysis in rats. Don plasma concentrations reached their maximum at the end of a 30-minute infusion. The maximum plasma concentrations (Cmaxs) of the major active metabolite, 6-O-desmethyl donepezil, were 9.38 and 13.3 ng/ml at 60 minutes after starting infusions at 1.25 and 2.5 mg/kg doses, respectively. The amount of ACh in the brain increased shortly after the start of the infusion and reached the maximum value at about 30 to 45 minutes, then decreased to the baseline with a slight delay from the transition of the Don concentration in plasma at a 2.5 mg/kg dose. However, the 1.25 mg/kg group showed little increase in ACh in the brain. The PK/PD models of Don, which were constructed using a general 2-compartment PK model with/without Michaelis-Menten metabolism and the suppressive effect of conversion of ACh to choline using an ordinary indirect response model, were able to effectively simulate Don's plasma and ACh profiles. The ACh profile in the cerebral hippocampus at a 1.25 mg/kg dose was effectively simulated using both constructed PK/PD models and parameters obtained at a 2.5 mg/kg dose by the PK/PD models and indicated that Don largely had no effect on ACh. When these models were used to simulate at 5 mg/kg, the Don PK were nearly linear, whereas the ACh transition had a different profile to lower doses. SIGNIFICANCE STATEMENT: Efficacy/safety of a drug and its pharmacokinetics (PK) are closely correlated. Therefore, it is important to understand the relationship between the drug's PK and its pharmacodynamics (PD). A quantitative procedure of achieving these goals is the PK/PD analysis. We constructed the PK/PD models of donepezil in rats. These models can predict the acetylcholine-time profiles from the PK. The modeling technique is a potential therapeutic application to predict the effect when changes in the PK are caused by pathological condition and co-administered drugs.

Safety outcomes of early initiation of antithrombotic agents within 24 h after intravenous alteplase at 0.6 mg/kg.

BACKGROUND: We examined outcome of acute ischemic stroke (AIS) with administration of antithrombotics within 24 h after intravenous low-dose alteplase. METHODS: Consecutive AIS patients who were treated with intravenous alteplase at 0.6 mg/kg from 2005 to 2021 were retrospectively included in our single-center registry. Patients were classified into two groups: those who received antithrombotics within 24 h after intravenous alteplase (early initiation group) and those who did not (control group). Safety outcomes were any intracranial hemorrhage (ICH), symptomatic ICH (sICH) within 36 h after onset, and death within 3 months. sICH was defined as any ICH with a ≥ 4-point increase in the National Institutes of Health Stroke Scale (NIHSS) score or death within 36 h. RESULTS: Of 1111 patients (women, 426; median age, 76 [interquartile range, 69-83] years; median NIHSS score, 11 [6-19]; cardioembolism, 580 [52.2%]), early initiation group comprised 58 patients (22; 72 [65-80] years; 7 [4-12]; 11 [19.0%]) and control group comprised 1053 patients (404; 77 [69-84] years; 11 [6-19]; 569 [54.1%]). No significant between-group differences were observed in the incidence of any ICH (17.2% vs. 21.6%; adjusted odds ratio [aOR], 1.18; 95% confidence interval [CI], 0.57-2.44), sICH (0% vs. 0.9%, P = 1.00), or death within 3 months (5.2% vs. 6.7%; aOR, 1.23; 95% CI, 0.36-4.23). CONCLUSIONS: Early initiation of antithrombotics after intravenous alteplase at 0.6 mg/kg did not increase the rate of sICH or death within 3 months and may be used with caution in patients with advanced neurological deterioration.