Characteristics of T-Cell Receptor Repertoire for Differential Response to Methotrexate Treatment for Rheumatoid Arthritis.

BACKGROUND: Methotrexate (MTX) serves as the initial treatment for rheumatoid arthritis (RA). However, a substantial proportion of RA patients, estimated between 30% and 50%, do not respond positively to MTX. While the T-cell receptor (TCR) is crucial for the immune response during RA, its role in differentiating MTX responsiveness has not been thoroughly investigated. METHODS: This study used next-generation sequencing to analyze the TCR ß-chain complementary determining region sequences in peripheral blood mononuclear cells obtained from RA patients before MTX treatment. This study aimed to compare the characteristics of the TCR repertoire between the MTX responder and non-responder groups. RESULTS: The study identified a significant difference in the TRBV6-6 gene (p = .003) concerning MTX treatment response. Additionally, a significant difference was found in the number of "3" nucleotide deletions at the 5'Jdels site (p = .023) in the VDJ rearrangement. CONCLUSION: These findings suggest distinct TCR repertoire characteristics between MTX responder and non-responder groups among RA patients. This discovery offers new insights into understanding the variable responses of RA patients to MTX therapy.

Preparation, Characterization and Evaluation of Nintedanib Amorphous Solid Dispersions with Enhanced Oral Bioavailability.

The dissolution and bioavailability challenges posed by poorly water-soluble drugs continue to drive innovation in pharmaceutical formulation design. Nintedanib (NDNB) is a typical BCS class II drug that has been utilized to treat idiopathic pulmonary fibrosis (IPF). Due to the low solubility, its oral bioavailability is relatively low, limiting its therapeutical effectiveness. It is crucial to enhance the dissolution and the oral bioavailability of NDNB. In this study, we focused on the preparation of amorphous solid dispersions (ASD) using hot melt extrusion (HME). The formulation employed Kollidon® VA64 (VA64) as the polymer matrix, blended with the NDNB at a ratio of 9:1. HME was conducted at temperatures ranging from 80 °C to 220 °C. The successful preparation of ASD was confirmed through various tests including polarized light microscopy (PLM), X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR), and thermogravimetric analysis (TGA). The in-vitro cumulative release of NDNB-ASD in 2 h in a pH 6.8 medium was 8.3-fold higher than that of NDNB (p < 0.0001). In a pH 7.4 medium, it was 10 times higher (p < 0.0001). In the in-vivo pharmacokinetic experiments, the area under curve (AUC) of NDNB-ASD was 5.3-fold higher than that of NDNB and 2.2 times higher than that of commercially available soft capsules (Ofev®) (p < 0.0001). There was no recrystallization after 6 months under accelarated storage test. Our study indicated that NDNB-ASD can enhance the absorption of NDNB, thus providing a promising method to improve NDNB bioavailability in oral dosages.

MAX-DOAS Measurements of Tropospheric NO2 and HCHO Vertical Profiles at the Longfengshan Regional Background Station in Northeastern China.

The vertical profiles of nitrogen dioxide (NO2) and formaldehyde (HCHO) in the troposphere at the Longfengshan (LFS) regional atmospheric background station (127°36' E, 44°44' N, 330.5 m above sea level) from 24 October 2020 to 13 October 2021 were retrieved from solar scattering spectra by multi-axis differential optical absorption spectroscopy (MAX-DOAS). We analyzed the temporal variations of NO2 and HCHO as well as the sensitivity of ozone (O3) production to the concentration ratio of HCHO to NO2. The largest NO2 volume mixing ratios (VMRs) occur in the near-surface layer for each month, with high values concentrated in the morning and evening. HCHO has an elevated layer around the altitude of 1.4 km consistently. The means ± standard deviations of vertical column densities (VCDs) and near-surface VMRs were 4.69 ± 3.72 ×1015 molecule·cm-2 and 1.22 ± 1.09 ppb for NO2, and they were 1.19 ± 8.35 × 1016 molecule·cm-2 and 2.41 ± 3.26 ppb for HCHO. The VCDs and near-surface VMRs for NO2 were high in the cold months and low in the warm months, while HCHO presented the opposite. The larger near-surface NO2 VMRs appeared in the condition associated with lower temperature and higher humidity, but this relationship was not found between HCHO and temperature. We also found the O3 production at the Longfengshan station was mainly in the NOx-limited regime. This is the first study presenting the vertical distributions of NO2 and HCHO in the regional background atmosphere of northeastern China, which are significant to enhancing the understanding of background atmospheric chemistry and regional ozone pollution processes.

Anticoagulant Activity and Structural Characterization of Polysaccharide from Abalone (Haliotis discus hannai Ino) Gonad.

In this study, we aimed at characterizing the structure and the anticoagulant activity of a polysaccharide fraction (AGP33) isolated from the gonads of Haliotis discus hannai Ino. AGP33 was extracted by enzymatic hydrolysis and purified by ion-exchange and gel-filtration chromatography. The backbone fraction of AGP33 (BAGP33), which appeared to contain of mannose, glucose and galactose, was prepared by partial acid hydrolysis. According to methylation and nuclear magnetic resonance (NMR) spectroscopy, the backbone of AGP33 was identified as mainly consisting of 1→3-linked, 1→4-linked, and 1→6-linked monosaccharides. AGP33 is a sulfated polysaccharide with sulfates occur at 3-O- and 4-O-positions. It prolonged thromboplastin time (APTT), thrombin time (TT) and prothrombin time (PT) compared to a saline control solution in a dosage-dependent manner. AGP33 exhibited an extension (p < 0.01) of APTT compared to the saline group at concentrations higher than 5 µg/mL. AGP33 exhibited higher anticoagulant activity than its desulfated product (AGP33-des) and BAGP33. The results showed that polysaccharide with higher molecular weight and sulfate content demonstrated greater anticoagulant activity.

Development of an innovative eugenol and borax-based orodispersible film for enhanced treatment of mouth ulcers.

Orodispersible films (ODFs) have emerged as an advanced and patient-friendly delivery system due to ease of administration, improved patient compliance, quick release and taste-masking of active pharmaceutical ingredients. This research reports the preparation of the ODF containing eugenol and borax (EB-ODF) by a solvent casting technique for treating mouth ulcers. The EB-ODF consisted of vinyl pyrrolidone/vinyl acetate copolymer (Kollidon® VA64, VA64) and hydroxypropyl methylcellulose (HPMC-K250) as the film formers where eugenol and borax were loaded. The thickness of the EB-ODF obtained was 0.119 ± 0.001 mm and the tensile strength was 13.1 ± 1.1 N/mm2 (p > 0.05). The prepared films disintegrated in the oral cavity within 30 s and over 90% of the eugenol was released from the film in the first 5 min. Furthermore, the combined application of eugenol and borax, loaded in EB-ODF, displayed notable synergetic antibacterial property against both gram-negative and gram-positive bacteria. In an in-vivo study on a rat model with chemical burn-induced oral ulcers, the EB-ODF treatment group had a 100% reduction in ulcer area (p > 0.05) after 10 days of treatment and demonstrated a 38.7% higher reduction in oral ulcer area compared to the Dingpeng Cream treatment group (p < 0.0001). The EB-ODF treatment group showed minimal oral irritation, scoring only 1 point and a 65% preference in the taste tests (p < 0.0001). In summary, EB-ODF had successfully overcome the poor palatability of commercially available formulation and provided notable potential for further ulcer treatment product development.

Comparison of methods to improve fracture risk assessment in chinese diabetic postmenopausal women: a case-control study.

PURPOSE: This study evaluated the predictive power of adjusted FRAX and standard FRAX models based on the actual prevalence of osteoporosis in type 2 diabetic (T2DM) postmenopausal women, and to explore the optimal strategy to better predicted fracture risk in postmenopausal women with diabetes in China. METHODS: We recruited 434 patients from community-medical centers, 217 with T2DM and 217 without T2DM (non-T2DM). All participants completed self-reported questionnaires detailing their characteristics and risk factors. Bone mineral density (BMD) and spinal radiographs were evaluated. The China FRAX model calculated all scores. The area under the receiver operator characteristic curve (ROC-AUC) evaluated the sensitivity, specificity, and accuracy for predicting 10-year risk for major (MOF) and hip (OHF) osteoporotic fractures in T2DM patients. RESULTS: T2DM patients had higher BMD but lower average FRAX values than non-T2DM patients. The unadjusted FRAX ROC-AUC was 0.774, significantly smaller than that for 0.5-unit femoral neck T-score-adjusted FRAX (0.800; p = 0.004). Rheumatoid arthritis (RA; AUC = 0.810, p = 0.033) and T-score (AUC = 0.816, p = 0.002) adjustments significantly improved fracture prediction in T2DM patients. CONCLUSIONS: Femoral neck T-score adjustment might be the preferred method for predicting MOF and OHF in Chinese diabetic postmenopausal women, while RA adjustment only effectively predicted HF risk.