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Canadian Journal of Gastroenterology &... 2024To use hepatic uptake index (HUI) of liver lobes on gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI)...
Lobe-Based Hepatic Uptake Index of Gd-EOB-DTPA on Contrast-Enhanced MRI to Quantitatively Discriminate between Compensated and Decompensated Hepatitis B-Related Cirrhosis.
PURPOSE
To use hepatic uptake index (HUI) of liver lobes on gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) to discriminate between patients with hepatitis B-related cirrhosis in compensated and decompensated statuses.
METHODS
Forty-four consecutive patients with hepatitis B-related cirrhosis who underwent Gd-EOB-DTPA-enhanced MRI were divided into compensated and decompensated statuses based on clinical evaluation. Volume and signal intensity of individual lobes were retrospectively measured to calculate HUI of the right liver lobe (RHUI), medial (MHUI) and lateral (LHUI) left liver lobes, and caudate lobe (CHUI). Spearman's rank correlation analyses were performed to evaluate relationships of lobe-based HUI with Child-Pugh and model for end-stage liver disease (MELD) scoring system scores in compensated and decompensated statuses. The Mann-Whitney U-test was used to compare the lobe-based HUI between compensated and decompensated statuses. The performance of lobe-based HUI in distinguishing cirrhosis was evaluated using receiver operating characteristic (ROC) analysis, and the area under the ROC curve (AUC) was calculated as a measure of accuracy. Delong's method was used for statistical analysis to elucidate which HUI is optimal.
RESULTS
Compensated and decompensated liver cirrhosis were confirmed in 25 (56.82%) and 19 (43.18%) patients, respectively. According to Spearman's rank correlation analysis, RHUI, MHUI, LHUI, and CHUI were all significantly associated with Child-Pugh and MELD scores (all values <0.05). Receiver operating characteristic analysis demonstrated that among all lobe-based HUI parameters, RHUI could best perform the previous discrimination with a cut-off of 485.73 and obtain an AUC of 0.867. The AUC of RHUI improved and was significantly different from that of MHUI, LHUI, and CHUI ( = 0.03, = 0.007, and < 0.001, respectively, Delong's test).
CONCLUSIONS
The RHUI could help quantitatively discriminate hepatitis B-related cirrhosis between compensated and decompensated statuses.
Topics: Humans; Gadolinium DTPA; Liver Cirrhosis; Female; Male; Contrast Media; Middle Aged; Magnetic Resonance Imaging; Retrospective Studies; Liver; Adult; ROC Curve; Aged; Severity of Illness Index; Hepatitis B
PubMed: 38947874
DOI: 10.1155/2024/6623848 -
ACS Omega Jun 2024This study aimed to increase the stability and solubility of the Algerian L. (ASHO) essential oil through nanoencapsulation. Nanoemulsions of ASHO (MF-ASHEO) were...
This study aimed to increase the stability and solubility of the Algerian L. (ASHO) essential oil through nanoencapsulation. Nanoemulsions of ASHO (MF-ASHEO) were developed to evaluate their antioxidant and antimicrobial potential, stability, and cytotoxicity using microfluidization at 150 MPa for five cycles. MF-ASHO showed 8 compounds (99.56%) vs ASHEO's 26 compounds (95.46%). Carvacrol increased to 94.51%, replacing γ-terpinene, which decreased to 0.43%. The MF-ASHEO nanoemulsion had a mean particle size of 41.72 nm, a monomodal size distribution pattern, a mean ζ-potential of -39.4 mV, and a polydispersity index (PDI) mean value of 0.291. Micrographs showed spherical nanoparticles with varying diameters in nm. ASHEO was more toxic than MF-ASHEO against HepG2, Vero, and WI-38, according to the MTT and WST-1 assays. ASHEO demonstrated antiradical and antibacterial activity and inhibited biofilm formation. It also had an enhanced antifungal effect and reduced mycotoxin production. The MF-ASHEO sample showed no activity except in reducing mycotoxin production, where it performed better than ASHEO. and ADME results confirmed the inhibitory action of carvacrol on the key enzymes of the aflatoxin biosynthetic mechanism and the target proteins associated with bactericidal/bacteriostatic effects. The microfluidization process dramatically affects not only the oil's volatile content but also its biological activity.
PubMed: 38947844
DOI: 10.1021/acsomega.4c00315 -
MedRxiv : the Preprint Server For... Jun 2024Differences in amyloid positron emission tomography (PET) radiotracer pharmacokinetics and binding properties lead to discrepancies in amyloid-β uptake estimates....
BACKGROUND
Differences in amyloid positron emission tomography (PET) radiotracer pharmacokinetics and binding properties lead to discrepancies in amyloid-β uptake estimates. Harmonization of tracer-specific biases is crucial for optimal performance of downstream tasks. Here, we investigated the efficacy of ComBat, a data-driven harmonization model, for reducing tracer-specific biases in regional amyloid PET measurements from [ F]-florbetapir (FBP) and [ C]-Pittsburgh Compound-B (PiB).
METHODS
One-hundred-thirteen head-to-head FBP-PiB scan pairs, scanned from the same subject within ninety days, were selected from the Open Access Series of Imaging Studies 3 (OASIS-3) dataset. The Centiloid scale, ComBat with no covariates, ComBat with biological covariates, and GAM-ComBat with biological covariates were used to harmonize both global and regional amyloid standardized uptake value ratios (SUVR). Intraclass correlation coefficient (ICC) and mean standardized absolute error (MsAE) were computed to measure the absolute agreement between tracers. Additionally, longitudinal amyloid SUVRs from an anti-amyloid drug trial were simulated using linear mixed effects modeling. Differences in rates-of-change between simulated treatment and placebo groups were tested, and change in statistical power/Type-I error after harmonization was quantified.
RESULTS
In the head-to-head tracer comparison, the best ICC and MsAE were achieved after harmonizing with ComBat with no covariates for the global summary SUVR. ComBat with no covariates also performed the best in harmonizing regional SUVRs. In the clinical trial simulation, harmonization with both Centiloid and ComBat increased statistical power of detecting true rate-of-change differences between groups and decreased false discovery rate in the absence of a treatment effect. The greatest benefit of harmonization was observed when groups exhibited differing FPB-to-PiB proportions.
CONCLUSIONS
ComBat outperformed the Centiloid scale in harmonizing both global and regional amyloid estimates. Additionally, ComBat improved the detection of rate-of-change differences between clinical trial groups. Our findings suggest that ComBat is a viable alternative to Centiloid for harmonizing regional amyloid PET analyses.
PubMed: 38947044
DOI: 10.1101/2024.06.14.24308952 -
Research Square Jun 2024Fragile X syndrome (FXS) is a rare neurodevelopmental disorder caused by a CGG repeat expansion ≥ 200 repeats in 5' untranslated region of the FMR1 gene, leading...
Fragile X syndrome (FXS) is a rare neurodevelopmental disorder caused by a CGG repeat expansion ≥ 200 repeats in 5' untranslated region of the FMR1 gene, leading to intellectual disability and cognitive difficulties, including in the domain of communication. A recent phase 2a clinical trial testing BPN14770, a phosphodiesterase 4D inhibitor, showed improved cognition in 30 adult males with FXS on drug relative to placebo. The initial study found significant improvements in clinical measures assessing cognition, language, and daily functioning in addition to marginal improvements in electroencephalography (EEG) results for the amplitude of the N1 event-related potential (ERP) component. EEG results suggest BPN14770 improved neural hyperexcitability in FXS. The current study investigated the relationship between BPN14770 pharmacokinetics (PK) and the amplitude of the N1 ERP component from the initial data. Consistent with the original group-level finding in period 1 of the study, participants who received BPN14770 in the period 1 showed a significant correlation between N1 amplitude and serum concentration of BPN14770. These findings strengthen the validity of the original result, indicating that BPN14770 improves cognitive performance by modulating neural hyperexcitability. This study represents the first report of significant correlation between a reliably abnormal EEG marker and serum concentration of a novel pharmaceutical in FXS.
PubMed: 38946987
DOI: 10.21203/rs.3.rs-4474353/v1 -
International Journal of Nanomedicine 2024Angiogenesis is a physiological process of forming new blood vessels that has pathological importance in seemingly unrelated illnesses like cancer, diabetes, and various... (Review)
Review
Angiogenesis is a physiological process of forming new blood vessels that has pathological importance in seemingly unrelated illnesses like cancer, diabetes, and various inflammatory diseases. Treatment targeting angiogenesis has shown promise for these types of diseases, but current anti-angiogenic agents have critical limitations in delivery and side-effects. This necessitates exploration of alternative approaches like biomolecule-based drugs. Proteins, lipids, and oligonucleotides have recently become popular in biomedicine, specifically as biocompatible components of therapeutic drugs. Their excellent bioavailability and potential bioactive and immunogenic properties make them prime candidates for drug discovery or drug delivery systems. Lipid-based liposomes have become standard vehicles for targeted nanoparticle (NP) delivery, while protein and nucleotide NPs show promise for environment-sensitive delivery as smart NPs. Their therapeutic applications have initially been hampered by short circulation times and difficulty of fabrication but recent developments in nanofabrication and NP engineering have found ways to circumvent these disadvantages, vastly improving the practicality of biomolecular NPs. In this review, we are going to briefly discuss how biomolecule-based NPs have improved anti-angiogenesis-based therapy.
Topics: Humans; Angiogenesis Inhibitors; Theranostic Nanomedicine; Neovascularization, Pathologic; Animals; Liposomes; Nanostructures; Neoplasms; Drug Delivery Systems; Oligonucleotides; Proteins; Lipids; Nanoparticles
PubMed: 38946886
DOI: 10.2147/IJN.S459928 -
International Journal of Nanomedicine 2024It is well-established that osteoclast activity is significantly influenced by fluctuations in intracellular pH. Consequently, a pH-sensitive gated nano-drug delivery...
BACKGROUND
It is well-established that osteoclast activity is significantly influenced by fluctuations in intracellular pH. Consequently, a pH-sensitive gated nano-drug delivery system represents a promising therapeutic approach to mitigate osteoclast overactivity. Our prior research indicated that naringin, a natural flavonoid, effectively mitigates osteoclast activity. However, naringin showed low oral availability and short half-life, which hinders its clinical application. We developed a drug delivery system wherein chitosan, as gatekeepers, coats mesoporous silica nanoparticles loaded with naringin (CS@MSNs-Naringin). However, the inhibitory effects of CS@MSNs-Naringin on osteoclasts and the underlying mechanisms remain unclear, warranting further research.
METHODS
First, we synthesized CS@MSNs-Naringin and conducted a comprehensive characterization. We also measured drug release rates in a pH gradient solution and verified its biosafety. Subsequently, we investigated the impact of CS@MSNs-Naringin on osteoclasts induced by bone marrow-derived macrophages, focusing on differentiation and bone resorption activity while exploring potential mechanisms. Finally, we established a rat model of bilateral critical-sized calvarial bone defects, in which CS@MSNs-Naringin was dispersed in GelMA hydrogel to achieve in situ drug delivery. We observed the ability of CS@MSNs-Naringin to promote bone regeneration and inhibit osteoclast activity in vivo.
RESULTS
CS@MSNs-Naringin exhibited high uniformity and dispersity, low cytotoxicity (concentration≤120 μg/mL), and significant pH sensitivity. In vitro, compared to Naringin and MSNs-Naringin, CS@MSNs-Naringin more effectively inhibited the formation and bone resorption activity of osteoclasts. This effect was accompanied by decreased phosphorylation of key factors in the NF-κB and MAPK signaling pathways, increased apoptosis levels, and a subsequent reduction in the production of osteoclast-specific genes and proteins. In vivo, CS@MSNs-Naringin outperformed Naringin and MSNs-Naringin, promoting new bone formation while inhibiting osteoclast activity to a greater extent.
CONCLUSION
Our research suggested that CS@MSNs-Naringin exhibited the strikingly ability to anti-osteoclasts in vitro and in vivo, moreover promoted bone regeneration in the calvarial bone defect.
Topics: Flavanones; Animals; Osteoclasts; Bone Regeneration; Silicon Dioxide; Hydrogen-Ion Concentration; Nanoparticles; Rats; Mice; Rats, Sprague-Dawley; Chitosan; Male; Drug Liberation; Porosity; Drug Carriers; Bone Resorption; RAW 264.7 Cells; Drug Delivery Systems; Cell Differentiation
PubMed: 38946884
DOI: 10.2147/IJN.S456545 -
Journal of Biomedical Materials... Jul 2024In this study, we evaluated the drug release behavior of diameter customized TiO nanotube layers fabricated by anodization with various applied voltage sequences:...
In this study, we evaluated the drug release behavior of diameter customized TiO nanotube layers fabricated by anodization with various applied voltage sequences: conventional constant applied potentials of 20 V (45 nm) and 60 V (80 nm), a 20/60 V stepped potential (50 nm [two-diameter]), and a 20-60 V swept potential (49 nm [full-tapered]) (values in parentheses indicate the inner tube diameter at the top part of nanotube layers). The structures of the 50 nm (two-diameter) and 49 nm (full-tapered) samples had smaller inner diameters at the top part of nanotube layers than that of the 80 nm sample, while the outer diameters at the bottom part of nanotube layers were almost the same size as the 80 nm sample. The 80 nm sample, which had the largest nanotube diameter and length, exhibited the greatest burst release, followed by the 50 nm (two-diameter), 49 nm (full-tapered), and 45 nm samples. The initial burst released drug amounts and release rates from the 50 nm (two-diameter) and 49 nm (full-tapered) samples were significantly suppressed by the smaller tube top. On the other hand, the largest proportion of the slow released drug amount to the total released drug amount was observed for the 50 nm (two-diameter) sample. Thus, 50 nm (two-diameter) achieved suppressed initial burst release and large storage capacity. Therefore, this study has, for the first time, applied TiO nanotube layers with modulated diameters (two-diameter and full-tapered) to the realization of a localized drug delivery system (LDDS) with customized drug release properties.
Topics: Titanium; Nanotubes; Drug Delivery Systems; Drug Liberation; Particle Size
PubMed: 38946669
DOI: 10.1002/jbm.b.35445 -
Expert Review of Anticancer Therapy Jul 2024ABBV-184, a novel survivin peptide-targeting T-cell receptor (TCR)/anti-CD3 bispecific protein, demonstrated preclinical T-cell activation and cytotoxicity toward...
BACKGROUND
ABBV-184, a novel survivin peptide-targeting T-cell receptor (TCR)/anti-CD3 bispecific protein, demonstrated preclinical T-cell activation and cytotoxicity toward HLA-A2:01-positive tumor lines. This first-in-human trial evaluated ABBV-184 monotherapy in patients with acute myeloid leukemia (AML) and non-small cell lung cancer (NSCLC).
RESEARCH DESIGN AND METHODS
This phase 1 multicenter, open-label, dose escalation trial (NCT04272203) enrolled adult patients with relapsed/refractory AML or NSCLC with an HLA-A2:01 restricted genotype. Patients received ABBV-184 at 0.07 ug/kg initially, with 2- to 3-fold dose increases. The primary objective was determining the ABBV-184 recommended phase 2 dose. Secondary objectives included safety, tolerability, pharmacokinetics, and immunogenicity assessments.
RESULTS
Fifteen patients enrolled in the dose escalation (8 AML and 7 NSCLC). ABBV-184 doses ranged from 0.07 mg/kg-0.7 µg/kg, with a half-life of approximately 13-29 hours. Transient cytokine increases were observed at all dose levels, and in patients with NSCLC, transient peripheral blood lymphocyte decreases were observed. The most frequently reported treatment-emergent adverse events (TEAEs) were anemia, diarrhea, and headache. Grade 1-2 infusion-related reaction (IRR) and cytokine release syndrome (CRS) TEAEs were reported.
CONCLUSIONS
ABBV-184 was well tolerated and demonstrated preliminary evidence of CD3 engagement with transient cytokine increases and peripheral lymphocyte decreases.
CLINICAL TRIAL REGISTRATION
NCT04272203.
PubMed: 38946484
DOI: 10.1080/14737140.2024.2373888 -
Journal of Drug Targeting Jul 2024Overexpression of permeability-glycoprotein (P-gp) transporter leads to multidrug resistance (MDR) through cellular exclusion of chemotherapeutics. Co-administration of...
Overexpression of permeability-glycoprotein (P-gp) transporter leads to multidrug resistance (MDR) through cellular exclusion of chemotherapeutics. Co-administration of P-gp inhibitors and chemotherapeutics is a promising approach for improving the efficacy of therapy. Nevertheless, problems in pharmacokinetics, toxicity, and solubility limit the application of P-gp inhibitors. Herein, we developed a novel all-in-one hybrid nanoparticle system to overcome MDR in doxorubicin-resistant breast cancer. Firstly, folic acid-modified doxorubicin-loaded mesoporous silica nanoparticles (MSN) were prepared and then loaded into PEGylated poly(lactic-co-glycolic acid) (PLGA) nanoparticles along with a P-gp inhibitor, elacridar. This hybrid nanoparticle system had high drug loading capacity, enabled both passive and active targeting of tumor tissues, and exhibited sequential and pH-triggered release of drugs. In vitro and in vivo studies in doxorubicin-resistant breast cancer demonstrated the ability of the hybrid nanoparticles to reverse P-gp-mediated drug resistance. The nanoparticles were efficiently taken up by the breast cancer cells and delivered elacridar, in vitro. Biodistribution studies demonstrated substantial accumulation of the folate receptor-targeted PLGA/MSN hybrid nanoparticles in tumor-bearing mice. Moreover, deceleration of the tumor growth was remarkable in the animals administered with the doxorubicin and elacridar co-loaded hybrid nanoparticles when compared to those treated with the marketed liposomal doxorubicin (Caelyx®) or its combination with elacridar.
PubMed: 38946465
DOI: 10.1080/1061186X.2024.2374034 -
European Review For Medical and... Jun 2024Eur Rev Med Pharmacol Sci 2023; 27 (24): 12103-12111-DOI: 10.26355/eurrev_202312_34808-PMID: 38164872, published online on December 22, 2023. After publication, the...
Eur Rev Med Pharmacol Sci 2023; 27 (24): 12103-12111-DOI: 10.26355/eurrev_202312_34808-PMID: 38164872, published online on December 22, 2023. After publication, the authors found that Table III's legend was the same as that of Table II. Therefore, Table III's legend has been corrected as follows: Table III. Plasma PK parameters following repeat doses of IV NAC 600 mg (n = 24). There are amendments to this paper. The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/34808.
PubMed: 38946388
DOI: 10.26355/eurrev_202406_36449