Rosa roxburghii fermented juice mitigates LPS-induced acute lung injury by modulation of intestinal flora and metabolites.

Acute lung injury (ALI) is a severe pulmonary condition with high mortality and morbidity, lacking effective pharmacotherapeutic options. Rosa roxburghii Tratt, a unique fruit from southwestern China, is valued for its rich nutritional content and functional properties. Fermentation is known to enhance the nutritional value, flavor, and shelf life of foods. In this study, we investigated the effects of fermented Rosa roxburghii juice (RRFJ) on gut microbiota, metabolites, and the levels of short-chain fatty acids in the intestines, as well as its impact on lung tissue and intestine tissue injury, inflammation, and oxidative stress in murine models. The results showed that RRFJ modulated gut microbiota and metabolites, increased short-chain fatty acid levels, and consequently reduced lung tissue injury, inflammation, and oxidative stress in mice with ALI. These findings suggest that RRFJ has the potential to serve as a functional dietary adjunct in the management of acute lung injury, providing a scientific basis for its therapeutic role.

Umbilical cord blood-derived exosomes attenuate dopaminergic neuron damage of Parkinson's disease mouse model.

BACKGROUND: Umbilical cord blood (UCB) is a rich source of multifunctional stem cells characterized by low immunogenicity. Recent research in the fields of aging and regenerative medicine has revealed the potential of human umbilical cord blood-derived exosomes (UCB-Exos) in promoting wound healing, anti-aging, and regeneration. However, their role in neurodegenerative diseases, specifically Parkinson's disease (PD), remains unexplored. This study investigates the potential therapeutic effects and underlying mechanisms of UCB-Exos on PD. METHODS: Large extracellular vesicles (LEv), Exos, and soluble fractions (SF) of human UCB plasma were extracted to investigate their effects on motor dysfunction of the MPTP-induced PD mouse model and identify the key components that improve PD symptoms. UCB-Exos were administered by the caudal vein to prevent or treat the PD mouse model. The motor function and pathological markers were detected. Differentially expressed gene and KEGG enrichment pathways were screened by transcriptome sequence. MN9D and SH-SY5Y cells were cultured and evaluated for cell viability, oxidative stress, cell cycle, and aging-related indexes by qRT-PCR, western blot, immunofluorescence, and flow cytometry. The protein expression level of the MAPK p38 and ERK1/2 signaling pathway was detected by western blot. RESULTS: We observed that LEv, Exos, and SF all exhibited potential in ameliorating motor dysfunction in MPTP-induced PD model mice, with UCB-Exos demonstrating the most significant effect. UCB-Exos showed comparable efficacy in preventing and treating motor dysfunction, cognitive decline, and substantia nigra pathological damage in PD mice. Further investigations revealed that UCB-Exos could potentially alleviate oxidative damage, aging and degeneration, and energy metabolism disorders in neurons. Transcriptome sequencing results corroborated that genes differentially expressed due to UCB-Exos were primarily enriched in the neuroactive ligand-receptor interaction, Dopaminergic synapse, and MAPK signaling pathway. We also observed that UCB-Exos significantly inhibited the hyperphosphorylation of the MAPK p38 and ERK1/2 signaling pathways both in vitro and in vivo. CONCLUSIONS: Our study provides a comprehensive evaluation of UCB-Exos on the neuroprotective effects and suggests that inhibition of hyperphosphorylation of MAPK p38 and ERK 1/2 signaling pathways by regulating transcription levels of HspB1 and Ppef2 may be the key mechanism for UCB-Exos to improve PD-related pathological features.

Precise tracking of nanoparticles in plant roots.

One of the foremost challenges in nanobiotechnology is obtaining direct evidence of nanoparticles' absorption and internalization in plants. Although confocal laser scanning microscopy (CLSM) or transmission electron microscopy (TEM) are currently the most commonly used tools to characterize nanoparticles in plants, subjectivity of researchers, incorrect sample handling, inevitable fluorescence leakage and limitations of imaging instruments lead to false positives and non-reproducibility of experimental results. This protocol provides an easy-to-operate dual-step method, combining CLSM for macroscopic tissue examination and TEM for cellular-level analysis, to effectively trace single particles in plant roots with accuracy and precision. In addition, we also provide detailed methods for processing plant materials before imaging, including cleaning, and staining, to maximize the accuracy and reliability of imaging. This protocol involves currently commonly used nanomaterial types, such as metal-based and doped carbon-based materials, and enables accurate localization of nanoparticles with different sizes at the cell level in Arabidopsis thaliana root samples either through contrast or element mapping analysis. It serves as a valuable reference and benchmark for scholars in plant science, chemistry and environmental studies to understand the interaction between plant roots and nanomaterials and to detect the distribution of nanomaterials in plants. Excluding plant culture time, the protocol can be completed in 4-5 d.

Beta-alanine promotes angiogenesis in laser-induced choroidal neovascularization mice models.

AIM: To investigate the effect of ß-alanine (BA) on laser-induced choroidal neovascularization (CNV) mice models. METHODS: Laser-induced CNV mice models were established, and BA was administrated for one week and two weeks in advance, separately. Furthermore, retinal pigment epithelium (RPE)-choroid flat mounts were separated, and immunohistochemical staining was performed. The laser-induced CNV lesion areas were measured and compared. In addition, liver and kidney morphologies were observed to identify potential hepatorenal toxicity. RESULTS: Enlarged CNV lesion areas were observed in the BA treated group. No significant differences were observed in the liver and kidney sections between groups. CONCLUSION: BA treatment increase CNV lesion areas, suggesting the detrimental effects of BA as a nutritional supplement in age-related macular degeneration (AMD) population.

Preoperative OCT-Derived Nasal Perifoveal Retinal Nerve Fiber Layer Thickness Predictively Correlates Long-Term Visual Acuity Post Oil Removal Surgery.

Purpose: With the widespread application of silicone oil in vitreoretinal surgery, the purpose of this study was to determine the risk factors of long-term vision loss 12 months post oil removal in retina-detached eyes treated with vitrectomy and silicone oil tamponade. Methods: Of the 592 patients approached, eligible eyes completed the investigation up to 12 months post-oil-removal. Eligible eyes underwent pars-plana vitrectomy following oil tamponade. Oil removal was performed after 3 to 28 months in different individuals, under the condition that the retina has reattached as well as the hemorrhage and inflammation has dissolved. Postoperative best-corrected visual acuity (BCVA), age, sex, and interval between tamponade and removal were recorded, and retinal thickness was determined using optical coherence tomography (OCT). Results: Fifty eyes of 50 participants aged 31 to 83 years were enrolled. BCVA (LogMAR) 12 months post-oil-removal improved in 25 of 40 (62.5%) patients, varying from 0.05 (20/22) to 1.0 (20/200) (mean ± SD = 0.55 ± 0.32). Pre-oil-removal nasal perifoveal retinal nerve fiber layer thickness varied from 16 to 83 µm (38.40 ± 18.50), and was significantly linked with post-oil-removal BCVA (0.5%, 95% confidence interval 0.0%-1.0%; P = 0.046). Conclusions: This study demonstrates the risk factors and prognosis of visual function after long-term regeneration post vitrectomy, oil tamponade, and oil removal, thereby underscoring the need for a complete, dynamic examination of retinal structure via OCT measurement. Related studies should be conducted on a larger scale to facilitate the stratification of late-period vision damage in retina-detached eyes. Translational Relevance: This study developed OCT-based clinical markers for the postoperative visual prognosis of eyes affected by retinal detachment.

The complex link between the gut microbiome and obesity-associated metabolic disorders: Mechanisms and therapeutic opportunities.

Microbial interactions are widespread and important processes that support the link between disease and microbial ecology. The gut microbiota is a major source of microbial stimuli that can have detrimental or beneficial effects on human health. It is also an endocrine organ that maintains energy homeostasis and host immunity. Obesity is a highly and increasingly prevalent metabolic disease and the leading cause of preventable death worldwide. An imbalance in the gut microbiome is associated with several diseases including obesity-related metabolic disorders. This review summarizes the complex association between the gut microbiome and obesity-associated metabolic diseases and validates the role and mechanisms of ecological dysregulation in the gut in obesity-associated metabolic disorders. Therapies that could potentially alleviate obesity-associated metabolic diseases by modulating the gut microbiota are discussed.

Vibration compensation control strategy of composite cage rotor bearingless induction motor based on fuzzy coefficient adaptive-linear-neuron method.

To address the vibration problem induced by rotor eccentricity in a composite cage rotor bearingless induction motor(CCR-BIM), a vibration compensation control approach based on the fuzzy coefficient adaptive-linear-neuron is proposed. Firstly, the CCR-BIM mathematical model and the mechanism of unbalanced vibration are investigated, obtaining the expression of rotor displacement when the rotor is unbalanced. Afterwards, the displacement is decomposed by the fuzzy coefficient adaptive-linear-neuron algorithm to obtain the harmonic component related to vibration, and the value range of the weight coefficient is determined using stability analysis. Furthermore, through analyzing the shortcomings of the traditional PID vibration compensation method, a rotor vibration compensation method based on the fuzzy coefficient adaptive-linear-neuron is put forward to achieve high-performance vibration compensation control. Finally, the PID method and the proposed fuzzy coefficient adaptive-linear-neuron algorithm are simulated and verified by experiments. The findings demonstrate that the proposed algorithm successfully not only suppresses rotor unbalanced vibration but also exhibiting great dynamic performance.

Mechanistic study of leukopenia treatment by Qijiao shengbai Capsule via the Bcl2/Bax/CASAPSE3 pathway.

Background: Leukopenia can be caused by chemotherapy, which suppresses bone marrow function and can impact the effectiveness of cancer treatment. Qijiao Shengbai Capsule (QJSB) is commonly used to treat leukopenia, but the specific bioactive components and mechanisms of action are not well understood. Objectives and results: This study aimed to analyze the active ingredients of QJSB and its potential targets for treating leukopenia using network pharmacology and molecular docking. Through a combination of serum pharmacochemistry, multi-omics, network pharmacology, and validation experiments in a murine leukopenia model, the researchers sought to understand how QJSB improves leukopenia. The study identified 16 key components of QJSB that act in vivo to increase the number of white blood cells in leukopenic mice. Multi-omics analysis and network pharmacology revealed that the PI3K-Akt and MAPK signaling pathways are important in the treatment of leukopenia with QJSB. Five specific targets (JUN, FOS, BCl-2, CASPAS-3) were identified as key targets. Conclusion: Validation experiments confirmed that QJSB regulates genes related to cell growth and inhibits apoptosis, suggesting that apoptosis may play a crucial role in leukopenia development and that QJSB may improve immune function by regulating apoptotic proteins and increasing CD4+ T cell count in leukopenic mice.

Evaluating mechanical and biological responses of bipolymeric drug-chitosan-hydroxyapatite scaffold for wounds: Fabrication, characterization, and finite element analysis.

This study aims to explore the potential of a scaffold composed of drug-chitosan-hydroxyapatite (HA) in improving tissue treatment. The focus of the investigation lies in analyzing the physical and biological properties of the scaffold and evaluating its mechanical characteristics through finite-element analysis. To synthesize microcapsules containing dextran-diclofenac sodium, the electrospraying method was employed. The drug-chitosan-HA scaffold with varying volume fractions (VF) of the synthesized microcapsules (10, 15, and 20) was fabricated using the freeze-drying technique. Microscopic and scanning electron microscopy (SEM) images were utilized to evaluate the morphology, shape, and size of the microcapsules, as well as the porosity of the scaffolds for wound healing purposes. The mechanical properties of the synthesized microcapsules were determined via a nanoindentation test, while the mechanical behavior of the fabricated scaffolds was assessed through compression testing. Additionally, a multiscale finite-element model was developed to predict the mechanical properties of tissue scaffolds containing pharmaceutical microcapsules. The findings indicate that the incorporation of drug-chitosan-hydroxyapatite into the tissue significantly enhances both mechanical and biological responses. The mechanical evaluations demonstrate that the drug-chitosan-hydroxyapatite tissue exhibits excellent resistance to pressure, making it a suitable protective covering for skin wounds. Moreover, biological evaluations reveal that an increase in scaffold porosity leads to higher swelling behavior. The scaffold containing 20 % pharmaceutical microcapsules demonstrated the greatest swelling and desirable antibacterial properties, thereby indicating its potential as an effective wound dressing. Furthermore, a multiscale finite-element model was developed to predict the mechanical properties of tissue containing pharmaceutical microcapsules. The results indicated that the average size of the microcapsules was in the range of 170 to 180 µm, and the porosity of the prepared tissue was between 52 % and 61 %. The experimental compressive properties revealed that an increase in the volume fraction of the embedded microcapsules led to an increase in the maximum compressive stress and compressive modulus of the scaffolds by up to 54.95 % and 53.18 %, respectively, for the scaffold containing 20 % VF of pharmaceutical microcapsules compared to the specimen containing 10 % VF. In conclusion, the developed scaffold has the potential to serve as an effective wound dressing, with the ability to provide structural support, facilitate controlled drug release, and promote wound healing.

Empagliflozin alleviates obesity-related cardiac dysfunction via the activation of SIRT3-mediated autophagosome formation.

BACKGROUND: Empagliflozin (EMPA) has demonstrated efficacy in providing cardiovascular benefits in metabolic diseases. However, the direct effect of EMPA on autophagy in obesity-related cardiac dysfunction remains unclear. Therefore, this study aimed to determine changes in cardiac autophagy during diet-induced obesity and clarify the exact mechanism by which EMPA regulates autophagic pathways. METHODS: Male C57BL/6J mice were fed a 12-week high-fat diet (HFD) followed by 8 weeks of EMPA treatment. Body composition analysis and echocardiography were performed to evaluate metabolic alterations and cardiac function. Histological and immunofluorescence staining was used to evaluate potential enhancements in myocardial structure and biological function. Additionally, H9c2 cells were transfected with small interfering RNA targeting sirtuin 3 (SIRT3) and further treated with palmitic acid (PA) with or without EMPA. Autophagy-related targets were analyzed by western blotting and RT‒qPCR. RESULTS: EMPA administration effectively ameliorated metabolic disorders and cardiac diastolic dysfunction in HFD-fed mice. EMPA prevented obesity-induced myocardial hypertrophy, fibrosis, and inflammation through the activation of SIRT3-mediated autophagosome formation. The upregulation of SIRT3 triggered by EMPA promoted the initiation of autophagy by activating AMP-activated protein kinase (AMPK) and Beclin1. Furthermore, activated SIRT3 contributed to the elongation of autophagosomes through autophagy-related 4B cysteine peptidase (ATG4B) and autophagy-related 5 (ATG5). CONCLUSIONS: EMPA promotes SIRT3-mediated autophagosome formation to alleviate damage to the cardiac structure and function of obese mice. Activated SIRT3 initiates autophagy through AMPK/Beclin1 and further stimulates elongation of the autophagosome membrane via ATG4B/ATG5. These results provide a new explanation for the cardioprotective benefits of EMPA in obesity.

Contribution of ferroptosis and SLC7A11 to light-induced photoreceptor degeneration.

Progressive photoreceptor cell death is one of the main pathological features of age-related macular degeneration and eventually leads to vision loss. Ferroptosis has been demonstrated to be associated with retinal degenerative diseases. However, the molecular mechanisms underlying ferroptosis and photoreceptor cell death in age-related macular degeneration remain largely unexplored. Bioinformatics and biochemical analyses in this study revealed xC-, solute carrier family 7 member 11-regulated ferroptosis as the predominant pathological process of photoreceptor cell degeneration in a light-induced dry age-related macular degeneration mouse model. This process involves the nuclear factor-erythroid factor 2-related factor 2-solute carrier family 7 member 11-glutathione peroxidase 4 signaling pathway, through which cystine depletion, iron ion accumulation, and enhanced lipid peroxidation ultimately lead to photoreceptor cell death and subsequent visual function impairment. We demonstrated that solute carrier family 7 member 11 overexpression blocked this process by inhibiting oxidative stress in vitro and in vivo. Conversely, solute carrier family 7 member 11 knockdown or the solute carrier family 7 member 11 inhibitor sulfasalazine and ferroptosis-inducing agent erastin aggravated H2O2-induced ferroptosis of 661W cells. These findings indicate solute carrier family 7 member 11 may be a potential therapeutic target for patients with retinal degenerative diseases including age-related macular degeneration.

Multimodal Eye Imaging, Retina Characteristics, and Psychological Assessment Dataset.

The eyes provide insights into psychology, potentially offering a distinctive perspective for psychological health profiles. However, there exist a notable deficiency in datasets that simultaneously encompass eye features and psychological assessments. To address this gap, our study presents a dataset that included Fundus Photography, Psychological Assessment, Retina Characteristics, and Multimodal Imaging (FPRM). FPRM dataset comprise fundus images at different wavelengths (548 nm and 605 nm), image of oxygen saturation for the retina and 8 specific retinal vessels, videos of retinal blood flow and pupillary light reflex, along with 61 items of multimodal quantitative measurement from 384 participants. Additionally, it features psychological assessments across five dimensions (geriatric depression, generalized anxiety disorder, insomnia, activities of daily living, and deterioration), accompanied by fundus photographs and 6 items of retina characteristics from 1683 participants. FPRM dataset is the first to integrate multimodal ophthalmic data and psychological assessments, not only advancing the development of machine learning applications but also facilitating in-depth research into the relationship between eye health and psychological health profiles.

Sestrin2 knockout exacerbates high-fat diet induced metabolic disorders and complications in female mice.

BACKGROUND: Obesity and its associated complications raise significant public concern, revealing gender disparities in the susceptibility to metabolic disorders, with females often displaying greater resistance to obesity-related metabolic disorder than males. Sestrin2 is a crucial protein involved in metabolism and energy balance. This study seeks to explore whether Sesn2 knockout (KO) exacerbates high-fat diet (HFD) induced obesity in female mice. METHODS: Female mice with wild-type (WT) and Sesn2 KO were subjected to a 12-week regimen of normal diet or HFD. Using a Body Composition Analyzer, body composition was gauged. Biochemical assays encompassed glucose, lipid, and liver function measurements, alongside 24-hour urine albumin excretion. Echocardiographic evaluation assessed cardiac function. Histopathological analysis of key metabolic tissues (liver, kidney, and heart tissues) were conducted. Western blotting or qRT-PCR evaluated key proteins and genes linked to inflammation, mitochondrial, and lipid metabolism in adipose tissues. RESULTS: In comparison to mice fed a regular diet, those on a HFD exhibited significant increases in body weight and fat mass. Notably, Sesn2 KO further aggravated obesity, showcasing the most pronounced metabolic anomalies: elevated body weight, fat mass, impaired glucose tolerance, and insulin sensitivity, alongside heightened levels of free fatty acids and triglycerides. Additionally, KO-HFD mice displayed exacerbated multi-tissue impairments, including elevated hepatic enzymes, increased urinary albumin excretion, compromised cardiac function, and accumulation of lipids in the liver, kidney, and heart. Moreover, adipose tissue showcased altered lipid dynamics and function, characterized by enhanced triglyceride breakdown and modified adipokine levels. Browning was diminished, along with decreased Pgc1α and Sirt1 in KO-HFD mice. CONCLUSION: Sesn2 KO exacerbates HFD-induced obesity and metabolic disorders in female mice. These findings underscore Sestrin2's novel role as a regulator of obesity in female mice.

Publication trends of Leber congenital amaurosis researches: a bibliometric study during 2002-2022.

AIM: To analyze the changes in scientific output relating to Leber congenital amaurosis (LCA) and forecast the study trends in this field. METHODS: All of the publications in the field of LCA from 2002 to 2022 were collected from Web of Science (WOS) database. We analyzed the quantity (number of publications), quality (citation and H-index) and development trends (relative research interest, RRI) of published LCA research over the last two decades. Moreover, VOSviewer software was applied to define the co-occurrence network of keywords in this field. RESULTS: A total of 2158 publications were ultimately examined. We found that the focus on LCA kept rising and peaked in 2015 and 2018, which is consistent with the development trend of gene therapy. The USA has contributed most to this field with 1162 publications, 56 674 citations and the highest H-index value (116). The keywords analysis was divided into five clusters to show the hotspots in the field of LCA, namely mechanism-related, genotype-related, local phenotype-related, system phenotype-related, and therapy-related. We also identified gene therapy and anti-retinal degeneration therapy as a major focus in recent years. CONCLUSION: Our study illustrates historical research process and future development trends in LCA field. This may help to guide the orientation for further clinical diagnosis, treatment and scientific research.

Robust Edge States of Quasi-1D Material Ta2NiSe7 and Applications in Saturable Absorbers.

The helical edge states (ESs) protected by underlying Z2 topology in two-dimensional topological insulators (TIs) arouse upsurges in saturable absorptions thanks to the strong photon-electron coupling in ESs. However, limited TIs demonstrate clear signatures of topological ESs at liquid nitrogen temperatures, hindering the applications of such exotic quantum states. Here, we demonstrate the existence of one-dimensional (1D) ESs at the step edge of the quasi-1D material Ta2NiSe7 at 78 K by scanning tunneling microscopy. Such ESs are rather robust against the irregularity of the edges, suggesting a possible topological origin. The exfoliated Ta2NiSe7 flakes were used as saturable absorbers (SAs) in an Er-doped fiber laser, hosting a mode-locked pulse with a modulation depth of up to 52.6% and a short pulse duration of 225 fs, far outstripping existing TI-based SAs. This work demonstrates the existence of robust 1D ESs and the superior SA performance of Ta2NiSe7.

Comprehensive assessment of the impact of intravitreal faricimab on retinal diseases: A systematic review, meta-analysis, and trial sequential analysis.

BACKGROUND: Faricimab stands as the inaugural and sole bispecific antibody approved by the US Food and Drug Administration (FDA) for intravitreal injection. Nonetheless, the efficacy and safety of intravitreal faricimab remained uncertain. OBJECTIVES: The purpose of this study was to evaluate faricimab. METHODS: This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (CRD42023398320). Five databases (Pubmed, Embase, Web of science, Cochrane Library, ClinicalTrials gov) were searched. We calculated pooled standard mean difference or odds ratio with 95 % confident interval under a random-effect model or fixed-effect model. Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) was employed to ascertain the reliability of the analyses. Trial sequential analysis was performed to gauge the statistical reliability of the data in the cumulative meta-analysis. RESULTS: 8 studies (3975 participants) were included. The use of faricimab was associated with central subfield thickness (CST) change, but no difference was found in other primary efficacy outcomes. Apart from that, a correlation was observed between the use of faricimab and the risk of vitreous floaters. Based on TSA, strong evidence indicates that compared to the control group, faricimab aided in reducing CST but increasing the risk of vitreous floaters. CONCLUSIONS: In this study, a correlation existed between the use of faricimab and a reduction in CST, indicating a superior therapeutic effect. Moreover, participants treated with faricimab demonstrated a higher risk of vitreous floaters. More randomized controlled trials are essential to further explore the efficacy and safety of faricimab.

Cost-Effectiveness of Varicella Vaccination for 1-4-Year-Olds in Shanghai, China.

INTRODUCTION: Varicella has not yet been included in the National Immunization Program (NIP) in China, and varicella vaccination strategies vary by region. To determine the optimal varicella vaccination strategy in Shanghai, China, the cost-effectiveness and 5-year costs of 5 immunization scenarios were analyzed. METHODS: A static decision tree-Markov model was developed in 2022 to assess the cost-effectiveness and 5-year costs of voluntary and routine varicella vaccination programs in the 2019 birth cohort in Shanghai from a societal perspective. Parameters were collected in 2022 from the varicella surveillance system, a questionnaire survey of 414 guardians of patients with childhood varicella, and semi-structured interviews with 20 experts on varicella outbreaks from different institutions in Shanghai. The outcomes included varicella cases avoided, quality-adjusted life year (QALY) loss, and incremental costs per QALY (ICER). The 5-year costs were compared with local medical expenditures. RESULTS: Among the 5 scenarios, one dose of routine varicella vaccination was the most cost-saving (USD 70.2) and cost-effective (Dominant) with a 5-year immunization expenditure of USD 9.9 million. Two doses of routine varicella vaccination had the highest QALY (29.9), and its ICER (USD 791.9/QALY) was below the willingness-to-pay threshold (USD 5,203-23,767/QALY). The 5-year immunization expenditure was USD 19.8 million. The effectiveness and price of vaccines, vaccination coverage, and per capita income are the 4 main factors that affect ICERs. CONCLUSIONS: In Shanghai, the 2 doses of routine varicella vaccination strategy for 1- and 4-year-olds with a 95% coverage rate was found to be the optimal varicella immunization strategy.

Efficacy and safety of efdamrofusp alfa versus aflibercept in participants with neovascular age-related macular degeneration: a randomized, double-masked, active-controlled, non-inferiority, phase 2 trial.

PURPOSE: To evaluate efficacy and safety of efdamrofusp alfa compared with aflibercept in neovascular age-related macular degeneration (nAMD). DESIGN: Randomized, double-masked, multicenter, active-controlled, non-inferiority phase 2 study PARTICIPANTS: A total of 231 treatment-naïve and previously treated participants with active choroidal neovascularization secondary to nAMD were enrolled. METHODS: Eligible participants were randomized (1:1:1) to 2 mg efdamrofusp alfa, 4 mg efdamrofusp alfa or 2 mg aflibercept groups. Participants in all groups received three initial monthly loading doses, followed by treatment every 8 weeks with assessment every 4 weeks up to week 52. MAIN OUTCOME MEASURES: The primary endpoint was the mean BCVA change from baseline to week 36. The pre-specified noninferiority margin was set as -5 letters (80% CI). RESULTS: Each treatment group included 77 participants. The mean BCVA changes from baseline to week 36 for 2 mg efdamrofusp alfa, 4 mg efdamrofusp alfa and aflibercept groups were +10.6, +11.4, +12.0 letters, respectively; Least Squares (LS) mean difference were -1.4 (80% CI: -3.5 to 0.7) between 2 mg efdamrofusp alfa and aflibercept, and -0.6 (80% CI: -2.7 to 1.6) between 4 mg efdamrofusp alfa and aflibercept. Mean central retinal thickness changes were consistent across groups. Adverse event rate was comparable among the groups. CONCLUSIONS: Efdamrofusp alfa demonstrated noninferiority to aflibercept in BCVA improvement, accompanied by a similar safety profile.

Donor and recipient hematopoietic stem and progenitor cells mobilization in liver transplantation patients.

BACKGROUND: Hematopoietic stem and progenitor cells (HSPCs) mobilize from bone marrow to peripheral blood in response to stress. The impact of alloresponse-induced stress on HSPCs mobilization in human liver transplantation (LTx) recipients remains under-investigated. METHODS: Peripheral blood mononuclear cell (PBMC) samples were longitudinally collected from pre- to post-LTx for one year from 36 recipients with acute rejection (AR), 74 recipients without rejection (NR), and 5 recipients with graft-versus-host disease (GVHD). 28 PBMC samples from age-matched healthy donors were collected as healthy control (HC). Multi-color flow cytometry (MCFC) was used to immunophenotype HSPCs and their subpopulations. Donor recipient-distinguishable major histocompatibility complex (MHC) antibodies determined cell origin. RESULTS: Before LTx, patients who developed AR after transplant contained more HSPCs in PBMC samples than HC, while the NR group patients contained fewer HSPCs than HC. After LTx, the HSPC ratio in the AR group sharply decreased and became less than HC within six months, and dropped to a comparable NR level afterward. During the one-year follow-up period, myeloid progenitors (MPs) biased differentiation was observed in all LTx recipients who were under tacrolimus-based immunosuppressive treatment. During both AR and GVHD episodes, the recipient-derived and donor-derived HSPCs mobilized into the recipient's blood-circulation and migrated to the target tissue, respectively. The HSPCs percentage in blood reduced after the disease was cured. CONCLUSIONS: A preoperative high HSPC ratio in blood characterizes recipients who developed AR after LTx. Recipients exhibited a decline in blood-circulating HSPCs after transplant, the cells mobilized into the blood and migrated to target tissue during alloresponse.