Antigen escape as a shared mechanism of resistance to BCMA-directed therapies in multiple myeloma.

B-cell maturation antigen (BCMA)-targeting therapeutics have dramatically improved outcomes in relapsed/refractory multiple myeloma (RRMM). However, whether the mechanisms of resistance between these therapies are shared and how the identification of such mechanisms before therapy initiation could refine clinical decision-making remains undefined. We analyzed outcomes for 72 RRMM patients treated with teclistamab, a CD3 x BCMA bispecific antibody (BsAb), 42% (30/72) of whom had prior BCMA-directed therapy exposure. Malignant plasma cell BCMA expression was present in all BCMA therapy-naïve patients. Prior therapy-mediated loss of plasma cell BCMA expression before teclistamab treatment, measured by immunohistochemistry, was observed in 3 patients, none of whom responded to teclistamab, and one of whom also did not respond to ciltacabtagene autoleucel. Whole exome sequencing of tumor DNA from one patient revealed biallelic loss of TNFRSF17 following treatment with belantamab mafodotin. Low-to-undetectable peripheral blood soluble BCMA levels correlated with the absence of BCMA expression by bone marrow plasma cells. Thus, although rare, loss of BCMA expression following TNFRSF17 gene deletions can occur following any BCMA-directed therapy and prevents response to subsequent anti-BCMA-directed treatments, underscoring the importance of verifying the presence of a target antigen.

Prognostic significance of soluble CD25 in patients with sepsis: a prospective observational study.

OBJECTIVES: The diagnosis of sepsis is challenging, the need for sensitive and specific diagnostic and prognostic biomarkers has not been met. Soluble CD25 (sCD25) is a readily available biomarker reported to represent the severity of the disease. This study aimed to assess the association between sCD25 and mortality in patients with sepsis. METHODS: In total, 329 adult patients with sepsis were screened through a prospective, observational study. We investigated the severity scores and sCD25 levels at admission to the intensive care unit (ICU), defined by sepsis (sepsis-3). The prognostic value of sCD25 was assessed using receiver operating characteristic (ROC) curves and binary logistic regression models in predicting unfavourable outcome. The correlations between variables and severity of disease were analysed by Spearman correlation tests. RESULTS: After entering the ICU, the sCD25 level and sequential organ failure assessment (SOFA) score were significantly higher in nonsurvivors than in survivors. The prognostic values estimated by the ROC curves were 0.678 for sCD25 and 0.945 for SOFA score at ICU admission. sCD25 had a modest ability to predict poor outcome. Logistic regression showed that increased levels of sCD25 were independently associated with unfavourable outcome. Spearman correlation tests showed that sCD25 levels were positively correlated with disease severity. CONCLUSIONS: In sepsis patients, increased sCD25 levels were independently associated with poor clinical outcomes. Further research is needed to improve the understanding of the pathophysiology of this relationship.

Antioxidant and Hypoglycemic Activity of Sequentially Extracted Fractions from Pingguoli Pear Fermentation Broth and Identification of Bioactive Compounds.

Pear fruits have been reported to contain abundant bioactive compounds and exhibit antidiabetic activity. In this study, Pingguoli pear (Pyrus pyrifolia cv.'Pingguoli') fermentation broth was sequentially extracted by five solvents with increasing polarity (petroleum ether, chloroform, ethyl acetate, n-butanol, and water) to evaluate its antioxidant and hypothermic activities, and then the main compounds of the fraction with the highest activity were assessed, which might be responsible for such activities. The results showed that the ethyl acetate fraction (EAF) exhibited the highest antioxidant activity according to DPPH (IC50 = 0.238 mg/mL), ABTS (IC50 = 0.293 mg/mL), and FRAP (IC50 = 0.193 mg/mL) assays. The in vitro hypoglycemic activity assay showed that EAF exhibited the strongest inhibitory effect, with IC50 values of 0.34 and 0.95 mg/mL for α-amylase and α-glucosidase, respectively. The glucose consumption in HepG2 cells treated with EAF was significantly increased to 252%, compare with control group. Liquid chromatography-mass spectrometry analysis implied that the main compounds, 3'-C-glucosylisoliquiritigenin, robustside D, caffeic acid, and chlorogenic acid may be potential candidates for the antioxidant and hypoglycemic activities of the EAF. This study suggested that EAF of Pingguoli pear fermentation broth could be utilized for development of potential functional food and antidiabetic agents.

[Omics molecular subtyping, prognostic prediction and individualized treatment of prostate cancer: Advances in studies].

Prostate cancer (PCa) is a most common malignancy in males. It has a greater heterogeneity than other cancers, which poses a real challenge to the clinical diagnosis, classification and prognostic monitoring. At present, high-, medium- and low-risk PCa patients are classified mainly by Gleason scores and the PSA level, which, however, fail to reveal the diverse molecular heterogeneity and precisely distinguish the molecular subtypes of PCa. With the development of high-throughput sequencing, more and more studies on the molecular classification of the malignancy have paved the theoretical ground for the early diagnosis, efficacy prediction and individualized treatment of PCa. This study reviews the molecular classification, prognosis prediction and individualized treatment of PCa to date, hoping to contribute to the development of the precise treatment of PCa.

Platelet-rich plasma promotes bone formation, restrains adipogenesis and accelerates vascularization to relieve steroids-induced osteonecrosis of the femoral head.

Steroid-associated necrosis of the femoral head (SANFH) is one of the most common and refractory chronic diseases with increasing incidence. The typical pathological changes of SANFH include decreased osteogenic differentiation, enhanced intramedullary adipocytes deposition and impaired osseous circulation. In this study, we investigated the effects and potential mechanisms of Platelet-rich plasma (PRP) on SANFH. Sixty Sprague-Dawley rats were randomly divided into the control, PRP donor, model, and PRP groups. Compared to the model group, PRP treatment significantly increased the hemorheological indexes and serum levels of bone gla-protein (BGP) and vascular endothelial growth factor (VEGF), while decreased the levels of triglyceride (TG) and total cholesterol (TC). Meanwhile, Micro-CT and histopathological stain (Hematoxylin-eosin and Alcian blue-hematoxylin/orange G staining) were performed on the femoral head for morphological and histopathological evaluation, indicating that bone trabecular microstructure and bone mineral density (BMD) were significantly improved after PRP treatment. Immunohistochemical analysis revealed that PRP remarkably up-regulated the expression of osteogenic markers including ß-catenin and alkaline phosphatase (ALP), angiogenic markers containing VEGF and platelet endothelial cell adhesion molecule-1 (CD31), while down-regulated adipogenic markers involving fatty acid-binding protein (FABP-4), and peroxisome proliferator-activated receptor gamma (PPAR-γ) in SANFH rat models. In summary, for the first time, PRP was demonstrated to prevent the development of SANFH through stimulating bone formation and vascularization as well as retarding adipogenesis.

Co-delivery of gambogenic acid and VEGF-siRNA with anionic liposome and polyethylenimine complexes to HepG2 cells.

Background and objective: The combination of two or more different mechanisms of drugs in the treatment of cancer has become one of the effective methods. The purpose of this study was to successfully prepare a non-viral delivery system that could efficiently co-delivery siRNA and gambogenic acid (GNA) to improve the anti-cancer efficiency in HepG2 cells. Methods: The delivery system was prepared by a two-step method. First, the GNA-anionic liposome took shape by a solvent evaporation method, and then the liposome was bound to the PEI/siRNA complex by electrostatic interaction to form the final carrier system (lipopolyplexes). Agarose gel electrophoresis, MTT, particle size and zeta potential were detected to analyse the lipopolyplexes formation. The transfection efficiency of siRNA was determined by confocal laser scanning microscopy and flow cytometry. Western blotting was used to assess the VEGF protein expression levels of HepG2 cells. The cell apoptosis assay was used to assess the anti-tumour superiority of lipopolyplexes. Results: GNA-PEI/siRNA-liposome (lipopolyplexes) are significantly less cytotoxicity compared to PEI mediated carriers. Simultaneously, the results of flow cytometry and confocal laser scanning microscopy indicated that the lipopolyplexes could successfully carry siRNA into the cytoplasm, and the western-blot result evidence that the delivery system has a potential for VEGF to express down. Also compared with the control group, the results of apoptosis test suggest that the lipopolyplexes can significantly promote cell apoptosis. Conclusion: The delivery system has a potential in the combination of various drugs for cancer therapy in future.

Green Ferrate(VI) for Multiple Treatments of Fracturing Wastewater: Demulsification, Visbreaking, and Chemical Oxygen Demand Removal.

Fracturing wastewater is often highly emulsified, viscous, and has a high chemical oxygen demand (COD), which makes it difficult to treat and recycle. Ferrate(VI) is a green oxidant that has a high redox potential and has been adopted for the efficient oxidation of fracturing wastewater to achieve triple effects: demulsification, visbreaking, and COD removal. Firstly, optimal conditions were identified to build a model for fast and efficient treatment. Secondly, wastewater treatment using ferrate oxidation was investigated via demulsification, visbreaking, and COD removal. Finally, a mechanism for ferrate oxidation was proposed for the three effects using Fourier-transform infrared (FT-IR) spectroscopy and scanning electron microscopy (SEM). The theoretical and experimental data demonstrated that the ferrate oxidation achieved the three desired effects. When ferrate was added, the demulsification efficiency increased from 56.2% to 91.8%, the total viscosity dropped from 1.45 cp to 1.10 cp, and the total removal rate of COD significantly increased to 74.2%. A mechanistic analysis showed that the strongly-oxidizing ferrate easily and efficiently oxidized the O/W interfacial film materials, viscous polymers, and compounds responsible for the COD, which was a promising result for the triple effects.

RBFOX3 Regulates the Chemosensitivity of Cancer Cells to 5-Fluorouracil via the PI3K/AKT, EMT and Cytochrome-C/Caspase Pathways.

BACKGROUND/AIMS: RBFOX3, an RNA-binding fox protein, plays an important role in the differentiation of neuronal development, but its role in the chemosensitivity of hepatocellular carcinoma (HCC) to 5-FU is unknown. METHODS: In this study, we examined the biological functions of RBFOX3 and its effect on the chemosensitivity of HCC cells to 5-FU in vitro and in a mouse xenograft model. RESULTS: RBFOX3 was found to have elevated expression in HCC cell lines and tissue samples, and its knockdown inhibited HCC cell proliferation. Moreover, knockdown of RBFOX3 improved the inhibitory effect of 5-fluorouracil (5-FU) on cell proliferation, migration and invasion, and enhanced the apoptosis induced by 5-FU. However, overexpression of RBFOX3 reduced the inhibitory effect of 5-fluorouracil (5-FU) on cell proliferation, migration and invasion, and decreased the apoptosis induced by 5-FU. We further elucidated that RBFOX3 knockdown synergized with 5-FU to inhibit the growth and invasion of HCC cells through PI3K/AKT and epithelial-mesenchymal transition (EMT) signaling, and promote apoptosis by activating the cytochrome-c/caspase signaling pathway. Finally, we validated that RBFOX3 regulated 5-FU-mediated cytotoxicity in HCC in mouse xenograft models. CONCLUSIONS: The findings from this study indicate that RBFOX3 regulates the chemosensitivity of HCC to 5-FU in vitro and in vivo. Therefore, targeting RBFOX3 may improve the inhibition of HCC growth and progression by 5-FU, and provide a novel potential therapeutic strategy for HCC.

Multiple effects of magnesium isoglycyrrhizinate on the disposition of docetaxel in docetaxel-induced liver injury.

1. Magnesium isoglycyrrhizinate (MgIg) has been extensively used in treating liver injury which is the common adverse reaction of docetaxel (DOC). Due to the narrow therapeutic window, small changes in pharmacokinetic profiles can alter the toxicity and therapeutic efficacy of DOC significantly. The study aimed to explore the effects of MgIg on the disposition of DOC and the potential mechanism in DOC-induced liver injury. 2. Pharmacokinetics and tissues distribution behaviors showed that there was no significant difference between DOC group (DOCG) and MgIg + DOC group (MDOCG). The mRNA and protein levels of cytochrome P450 3A1 (CYP3A1) in liver, intestine, and kidney were significantly upregulated, and the P-glycoprotein (P-gp) was obviously downregulated in MDOCG when compared with DOCG. 3. Immunoglobulin M (IgM), CD8+ were upregulated in DOCG; while in MDOCG, IgM, CD8+ recovered to normal levels and complement C3; CD4+ were upregulated. 4. MgIg had no significant effects on the disposition of DOC in docetaxel-induced liver injury. Additional, potential drug-drug interaction may happen if MgIg co-administered with antitumor drugs which are the substrates of CYP3A4 or P-gp. Hepatoprotective mechanism of MgIg perhaps was through upregulation of C3, CD4+ and downregulation of IgM, CD8+.

The long-term effect of 1550 nm erbium:glass fractional laser in acne vulgaris.

We evaluated the short-term and long-term effects of the 1550 nm erbium:glass (Er:glass) fractional laser in the treatment of facial acne vulgaris. Forty-five (9 male and 36 female) acne patients were treated 4 times at 4-week intervals with the following parameters: 169 spot density and 15-30 mJ/cm(2) fluence. There was no control group. The laser spots were adjustable (maximum overlap: 20%) according to the treatment area, and delivered in rows in order to cover all the face. Clinical photographs were taken. The IGA scores and lesion counts were performed for each treatment. Their current state was obtained by phone call follow-up to determine the long-term effect and photographs were offered by themselves or taken in hospital. After four treatments, all patients had an obvious reduction of lesion counts and IGA score and the peak lesion counts decreased to 67.7% after the initial four treatment sessions. For long-term effect, 8 patients lost follow-up, hence 37 patients were followed-up. 8 patients were 2-year follow up, 27 at the 1-year follow-up, and all patients at the half-year follow-up. The mean percent reduction was 72% at the half-year follow-up, 79 at the 1-year follow-up and 75% at the 2-year follow-up. Side effects and complications were limited to transient erythema and edema, and few patients suffered from transient acne flare-ups and sensitivity. All patients responded that their skin was less prone to oiliness. In conclusion, acne can be successfully treated by 1550 nm Er:glass fractional laser, with few side effects and prolonged acne clearing.

Serum uric acid is neuroprotective in Chinese patients with acute ischemic stroke treated with intravenous recombinant tissue plasminogen activator.

BACKGROUND: Exogenous uric acid (UA) is a neuroprotective antioxidant that reinforces the benefits of intravenous recombinant tissue plasminogen activator thrombolysis in animal thromboembolic stroke. However, whether serum uric acid (SUA) also increases the benefits of thrombolysis in Chinese patients with acute ischemic stroke (AIS) has yet to be fully defined. METHODS: A total of 216 consecutive AIS patients of Chinese origin treated with intravenous thrombolysis were enrolled in a prospective stroke registry. Demographic and clinical characteristics, conventional risk factors, important laboratory data, and neurologic course were prospectively recorded. Functional outcomes were assessed with the modified Rankin Scale (mRS) score on day 90 by telephone calls. Receiver operating characteristic curves and binary logistic regression models were used to examine the performance of SUA in predicting excellent outcomes (mRS, 0-1). RESULTS: SUA levels were significantly higher in patients with excellent outcomes than those in patients with poor outcomes (331.46 ± 103.39 versus 277.69 ± 105.62, P = .008). SUA had a modest power for predicting excellent outcomes as suggested by area under the curve of .665 ± .052, P = .003. In multivariate models, increased SUA levels (adjusted odds ratio, 1.005; 95% confidence interval, 1.002-1.009; P = .033) were associated with excellent outcomes independently of the effect of possible confounders. Spearman correlation tests indicated that there was an inverse correlation between SUA levels and stroke severity. CONCLUSIONS: Increased SUA levels are associated with excellent outcomes in Chinese patients with AIS treated with intravenous thrombolysis, giving additional support to administration of exogenous UA as an adjuvant to thrombolysis.

Fenofibrate enhances radiosensitivity of esophageal squamous cell carcinoma by suppressing hypoxia-inducible factor-1α expression.

Radiation therapy is widely used in esophageal squamous cell carcinoma (ESCC). Promoting radiation sensitivity is important. Recent studies have shown that fenofibrate can inhibit the growth of several cancer lines and hypoxia-inducible factor-1α (HIF-1α) expression in MCF-7 cells. However, few studies on the radiosensitive effect of fenofibrate on ESCCs under hypoxic condition have been conducted. In this study, we assessed the radiosensitive effects of fenofibrate on human ESCC cells. In vitro experiments showed the inhibition of cytotoxic effects after ionizing irradiation. We measured cell viability and clonogenic survival rate. Flow cytometry showed that fenofibrate pretreatment promoted apoptosis. The in vivo data also suggest that fenofibrate had radiosensitizing effects in ECA-109 cells xenografted into nude mice. Western blot and immunohistochemical analyses revealed that the HIF-1α and vascular endothelial growth factor (VEGF) protein content decreased by fenofibrate. Thus, the inhibition of HIF-1α and VEGF expression in ESCC cells contributed to the radiosensitive effect. These data suggest that fenofibrate may be a potential radiosensitive drug.

Specific aerobic granules can be developed in a completely mixed tank reactor by bioaugmentation using micro-mycelial pellets of Phanerochaete chrysosporium.

Aerobic granules were firstly developed in a completely mixed tank reactor (CMTR) by seeding micro-mycelial pellets (MMPs) of Phanerochaete chrysosporium. During phenol wastewater treatment, sludge granulation rate reached 67 % after 15-day operation. The granules in CMTR are different from aerobic granules described in literature in morphology, and a majority of them are rod-shaped or rodlike sludge besides spherical granules. The polymorphic granules, having no essential difference with aerobic granules previously reported, achieve advantages over conventional activated sludge in settling ability, biomass concentration, density, integrity coefficient and removal ability to phenol wastewater. The optimized parameters for sludge granulation in CMTR including temperature, inoculum quantity, rotary speed and superficial air upflow velocity are 30 °C, 5­7 g/l, 150 rpm, and 0.5 cm/s, respectively. Analysis on sludge granulation mechanism indicates that MMPs not only result in the formation of aerobic granules containing MMPs as nuclei, but also induce the formation of biogranules which do not have MMP at their cores. The work challenges the general belief that the homogenous circular flow pattern of microbial aggregates is necessary for aerobic sludge granulation.

Simulation of wastewater treatment by aerobic granules in a sequencing batch reactor based on cellular automata.

In the present paper, aerobic granules were developed in a sequencing batch reactor (SBR) using synthetic wastewater, and 81 % of granular rate was obtained after 15-day cultivation. Aerobic granules have a 96 % BOD removal to the wastewater, and the reactor harbors a mount of biomass including bacteria, fungi and protozoa. In view of the complexity of kinetic behaviors of sludge and biological mechanisms of the granular SBR, a cellular automata model was established to simulate the process of wastewater treatment. The results indicate that the model not only visualized the complex adsorption and degradation process of aerobic granules, but also well described the BOD removal of wastewater and microbial growth in the reactor. Thus, CA model is suitable for simulation of synthetic wastewater treatment. This is the first report about dynamical and visual simulation of treatment process of synthetic wastewater in a granular SBR.

Source and trajectories of inhaled particles from a surrounding environment and its deposition in the respiratory airway.

The inhalation exposure to airborne particles is investigated using a newly developed computational model that integrates the human respiratory airway with a human mannequin and at an enclosed room environment. Three free-stream air flow velocities (0.05, 0.20, and 0.35 m s⁻¹) that are in the range of occupational environments are used. Particles are released from different upstream locations and their trajectories are shown, which revealed that the trajectory paths of 80 µm particles that are inhaled are the same from the three different upstream planes evaluated. Smaller particles, 1 and 10 µm, exhibited different inhalation paths when released from different upstream distances. The free-stream velocity also has an effect on the particle trajectory particularly for larger particles. The aspiration efficiency for an extended range of particle sizes was evaluated. Reverse particle tracking matches the deposition in the respiratory airway with its initial particle source location. This can allow better risk assessments, and dosimetry determination due to inhalation exposure to contaminant sources.

Evaluation of bioequivalence and safety analysis of capecitabine tablets and Xeloda® under postprandial dosing conditions in Chinese patients with solid tumor.

OBJECTIVES: To compare the pharmacokinetic and safety of the test group capecitabine tablets (0.5 g) and the reference group capecitabine tablets (0.5 g). METHODS: This study was registered at www.chinadrugtrials.org.cn under the registration number CTR20220138. 48 subjects with solid tumor were recruited and randomized to receive either the test group or the reference group at a dose of 2 g per cycle for three cycles of the entire trial. RESULTS: The point estimate of the geometric mean ratio of Cmax for the subject and reference groups was 1.0670, which was in the range of 80.00%-125.00%. And the upper limit of 95% confidence interval was -0.0450 < 0. The statistics of geometric mean ratio of AUC0-t and AUC0-∞ (test group/reference group) and their 90% confidence intervals were in the range of 80.00%-125.00%, thus the test group was bioequivalent to the reference group under the conditions of this postprandial test. There were no major or serious adverse events. Conclusion: The pharmacokinetic profiles of capecitabine under postprandial conditions were consistent between the two groups. The two groups were bioequivalent and had a similar favorable safety profile in Chinese patients with solid tumor.

Spatial transcriptomics: recent developments and insights in respiratory research.

The respiratory system's complex cellular heterogeneity presents unique challenges to researchers in this field. Although bulk RNA sequencing and single-cell RNA sequencing (scRNA-seq) have provided insights into cell types and heterogeneity in the respiratory system, the relevant specific spatial localization and cellular interactions have not been clearly elucidated. Spatial transcriptomics (ST) has filled this gap and has been widely used in respiratory studies. This review focuses on the latest iterative technology of ST in recent years, summarizing how ST can be applied to the physiological and pathological processes of the respiratory system, with emphasis on the lungs. Finally, the current challenges and potential development directions are proposed, including high-throughput full-length transcriptome, integration of multi-omics, temporal and spatial omics, bioinformatics analysis, etc. These viewpoints are expected to advance the study of systematic mechanisms, including respiratory studies.

Oseltamivir phosphate for suspension is bioequivalent to TAMIFLU in healthy volunteers: a randomized, open-label clinical study.

PURPOSE: The study was aimed at evaluating the bioequivalence and safety of oseltamivir phosphate for suspension, provided by Shenzhen Beimei Pharmaceutical Co. Ltd. and manufactured by Hetero Labs Limited, and the reference product TAMIFLU® in healthy Chinese subjects. METHODS: A single-dose, randomized, two-phase, self-crossed model was adopted. Among 80 healthy subjects, 40 subjects in the fasting group and 40 subjects in the fed group. Subjects in the fasting group were randomized into two sequences according to the proportion of 1:1, each given 75 mg/12.5 mL of Oseltamivir Phosphate for Suspension or TAMIFLU®, and cross-administered after 7 days. Postprandial group is the same as fasting group. RESULTS: The Tmax of TAMIFLU® and Oseltamivir Phosphate for Suspension in the fasting group were 1.50 h and 1.25 h, which in the fed group were both 1.25 h. Geometrically adjusted mean ratios of the PK parameters of Oseltamivir Phosphate for Suspension along with TAMIFLU® under fasting and postprandial conditions were in the range of 80.00-125.00% at the 90% confidence interval (CI). The 90% CI of Cmax, AUC0-t, AUC0-∞ for fasting group and postprandial group were (92.39,106.50), (94.26,100.67), (94.32,100.89) and (93.61,105.83),(95.64,100.19),(96.06,102.66). Among the subjects on medication, a total of 18 subjects reported 27 adverse events, all of which were treatment-emergent adverse events (TEAEs), six of these TEAEs were rated as grade 2 in severity and the rest were as grade 1. The number of TEAEs in the test product and the reference product were 14,13 respectively. CONCLUSION: Two Oseltamivir phosphate for suspensions are safe and bioequivalent.

Mass balance, metabolic disposition, and pharmacokinetics of a novel selective inhibitor of PI3Kδ [14C] SHC014748M in healthy Chinese subjects following oral administration.

PURPOSE: SHC014748M is a potent, novel selective PI3Kδ isoform inhibitor and is proposed for the treatment of non-Hodgkin lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma. This study investigated the pharmacokinetics, mass balance, metabolism and excretion of SHC014748M in Chinese male subjects following a single oral dose of 150 mg (100 µCi) [14C] SHC014748M. METHODS: Six healthy Chinese male subjects administrated an oral suspension of 150 mg (100 µCi) [14C] SHC014748M and the samples of blood, urine and feces were collected for measuring. Liquid chromatography-tandem mass spectrometry and liquid scintillation counter were utilized to obtain mass balance and the pharmacokinetic data. RESULTS: The median Tmax for [14C]-radioactivity was 1.6 ± 0.5 h after the oral administration of [14C] SHC014748M and the mean Cmax was 3863 ± 354 ng Eq./mL in plasma, while the mean Cmax, t1/2 values and AUC0-∞ values for total radioactivity in whole blood were 2466 ± 518 ng Eq./mL, 32.2 ± 30.5 h and 66,236 ± 44,232 h * ng Eq./mL, respectively. Fecal excretion was proposed as the predominant elimination route, accounting for a mean of 90.68 ± 11.38% of the administered dose, whereas the mean urine excretion was 6.00 ± 1.48% within 336 h post-dose. The proposed major metabolic pathway of [14C] SHC014748M in the human body were as follows: (I) monooxidation, (II) glucuronide acid conjugation, and (III) monoxide-hydrogenation. CONCLUSIONS: SHC014748M was absorbed, metabolized and excreted with unchanged SHC014748M as its main circulating component in plasma following oral administration. In addition, it was speculated that fecal excretion was the principal excretion pathway; meanwhile, monohydroxy, glucuronide conjugation, oxygen, and hydrogenation were the major clearance pathways of SHC014748M through urine and/or feces. TRIAL REGISTRATION: The trial registration number: CTR20202505.

Mid-term outcomes of microfragmented adipose tissue plus arthroscopic surgery for knee osteoarthritis: A randomized, active-control, multicenter clinical trial.

BACKGROUND: Osteoarthritis (OA) is the most prevalent form of degenerative whole-joint disease. Before the final option of knee replacement, arthroscopic surgery was the most widely used joint-preserving surgical treatment. Emerging regenerative therapies, such as those involving platelet-rich plasma, mesenchymal stem cells, and microfragmented adipose tissue (MFAT), have been pushed to the forefront of treatment to prevent the progression of OA. Currently, MFAT has been successfully applied to treat different types of orthopedic diseases. AIM: To assess the efficacy and safety of MFAT with arthroscopic surgery in patients with knee OA (KOA). METHODS: A randomized, multicenter study was conducted between June 2017 and November 2022 in 10 hospitals in Zhejiang, China. Overall, 302 patients diagnosed with KOA (Kellgren-Lawrence grades 2-3) were randomized to the MFAT group (n = 151, were administered MFAT following arthroscopic surgery), or the control group (n = 151, were administered hyaluronic acid following arthroscopic surgery). The study outcomes were changes in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, the visual analog scale (VAS) score, the Lequesne index score, the Whole-Organ Magnetic Resonance Imaging Score (WORMS), and safety over a 24-mo period from baseline. RESULTS: The changes in the WOMAC score (including the three subscale scores), VAS pain score, and Lequesne index score at the 24-mo mark were significantly different in the MFAT and control groups, as well as when comparing values at the posttreatment visit and those at baseline (P < 0.001). The MFAT group consistently demonstrated significant decreases in the WOMAC pain scores and VAS scores at all follow-ups compared to the control group (P < 0.05). Furthermore, the WOMAC stiffness score, WOMAC function score, and Lequesne index score differed significantly between the groups at 12 and 24 mo (P < 0.05). However, no significant between-group differences were observed in the WORMS at 24 mo (P = 0.367). No serious adverse events occurred in both groups. CONCLUSION: The MFAT injection combined with arthroscopic surgery treatment group showed better mid-term clinical outcomes compared to the control group, suggesting its efficacy as a therapeutic approach for patients with KOA.