A Novel Anti-CD38 Monoclonal Antibody for Treating Immune Thrombocytopenia.

BACKGROUND: Immune thrombocytopenia (ITP) is an autoimmune disease characterized by autoantibody-mediated platelet destruction. Treatment with CM313, a novel anti-CD38 monoclonal antibody, can result in targeted clearance of CD38-positive cells, including plasma cells. METHODS: We conducted a phase 1-2, open-label study to evaluate the safety and efficacy of CM313 in adult patients with ITP. CM313 was administered intravenously at a dose of 16 mg per kilogram of body weight every week for 8 weeks, followed by a 16-week follow-up period. The primary outcomes were adverse events and documentation of two or more consecutive platelet counts of at least 50×109 per liter within 8 weeks after the first dose of CM313. The status of peripheral-blood immune cells in patients and changes in the mononuclear phagocytic system in passive mouse models of ITP receiving anti-CD38 therapy were monitored. RESULTS: Of the 22 patients included in the study, 21 (95%) had two consecutive platelet counts of at least 50×109 per liter during the treatment period, with a median cumulative response duration of 23 weeks (interquartile range, 17 to 24). The median time to the first platelet count of at least 50×109 per liter was 1 week (range, 1 to 3). The most common adverse events that occurred during the study were infusion-related reaction (in 32% of the patients) and upper respiratory tract infection (in 32%). After CD38-targeted therapy, the percentage of CD56dimCD16+ natural killer cells, the expression of CD32b on monocytes in peripheral blood, and the number of macrophages in the spleen of the passive mouse models of ITP all decreased. CONCLUSIONS: In this study, anti-CD38 targeted therapy rapidly boosted platelet levels by inhibiting antibody-dependent cell-mediated cytotoxicity on platelets, maintained long-term efficacy by clearing plasma cells, and was associated with mainly low-grade toxic effects. (Funded by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences and others; ClinicalTrials.gov number, NCT05694767).

Metabolomics profile and machine learning prediction of treatment responses in immune thrombocytopenia: A prospective cohort study.

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by antibody-mediated platelet destruction and impaired platelet production. The mechanisms underlying ITP and biomarkers predicting the response of drug treatments are elusive. We performed a metabolomic profiling of bone marrow biopsy samples collected from ITP patients admission in a prospective study of the National Longitudinal Cohort of Hematological Diseases. Machine learning algorithms were conducted to discover novel biomarkers to predict ITP patient treatment responses. From the bone marrow biopsies of 91 ITP patients, we quantified a total of 4494 metabolites, including 1456 metabolites in the positive mode and 3038 metabolites in the negative mode. Metabolic patterns varied significantly between groups of newly diagnosed and chronic ITP, with a total of 876 differential metabolites involved in 181 unique metabolic pathways. Enrichment factors and p-values revealed the top metabolically enriched pathways to be sphingolipid metabolism, the sphingolipid signalling pathway, ubiquinone and other terpenoid-quinone biosynthesis, thiamine metabolism, tryptophan metabolism and cofactors biosynthesis, the phospholipase D signalling pathway and the phosphatidylinositol signalling system. Based on patient responses to five treatment options, we screened several metabolites using the Boruta algorithm and ranked their importance using the random forest algorithm. Lipids and their metabolism, including long-chain fatty acids, oxidized lipids, glycerophospholipids, phosphatidylcholine and phosphatidylethanolamine biosynthesis, helped differentiate drug treatment responses. In conclusion, this study revealed metabolic alterations associated with ITP in bone marrow supernatants and a potential biomarker predicting the response to ITP.

Health risk assessment of heavy metals based on source analysis and Monte Carlo in the downstream basin of the Zishui.

In this study, stone coal mines in the lower reaches of the Zijiang River were adopted as the research object. To analyze the spatial distribution, sources, and health risks of heavy metals in the surrounding soil of stone coal mines, 82 topsoil samples were collected in the study area, and the contents of 8 heavy metals including Cd, Hg, As, Cr, Pb, Cu, Ni, and Zn were determined. The spatial distribution of heavy metals was analyzed using ArcGIS, and the pollution sources of heavy metals were identified using Positive matrix factorization (PMF). Then, Monte Carlo and health risk assessment models were used to evaluate the health risks of different populations. The results showed that the average content of heavy metals followed the order of Zn > Cr > Pb > Cu > Ni > As > Cd > Hg, and the contents of all heavy metals were higher than the soil background values of Hunan Province. The high-value areas of heavy metals content were mostly concentrated in the central region close to areas with a notable concentration of stone coal mines. PMF identified four pollution sources, namely, mining activities (26.9%), atmospheric deposition (18.8%), natural sources (32.8%) and agricultural sources (21.5%). The carcinogenic and non-carcinogenic risks for children were higher than those for adults, with As and Cd posing higher carcinogenic risks to children. Based on the source of health risks, it was determined that the health risks could be primarily attributed to agricultural sources, and As was the main heavy metal causing health risks. This study provides theoretical support for treating heavy metal pollution in mining basins.

Blended Tea Ameliorates T2DM via Modulation of Gut Microflora.

Increasing evidences suggest that type 2 diabetes mellitus (T2DM) is closely related to gut microflora dysbiosis, which can be improved by dietary intervention. Four natural plant products, including Cyclocarya paliurus, Fu brick tea, Ampelopsis grossedentata, and Lithocarpus litseifolius, were blended to form a blended tea product for obtaining the better flavor. The blended tea was also expected to have excellent pharmacological activity. Therefore, the ameliorative effect of blended tea on T2DM and underlying mechanisms were studied in this study. The results showed that the blended tea extract effectively attenuated the symptoms of glucose and lipid metabolism-related disorders in T2DM mice fed by high-fat and high-sucrose diet. Furthermore, blended tea extract intervention significantly attenuated gut microbiota dysbiosis, the abundance of bacteria such as Bacteroidetes and Firmicutes, which aid in the hydrolysis and utilization of carbohydrates, significantly increased, while the abundance of pathogenic bacteria such as Proteobacteria significantly decreased. Certain core microorganisms involved in energy metabolism, including Ruminococcaceae_UCG-005, Butyricimonas, Roseburia, Oscillibacter, [Eubacterium]_nodatum_group, Muribaculaceae, Prevotellaceae UCG 001, were also found to be improved by blended tea extract. Collectively, our results demonstrated that the blended tea may ameliorate T2DM through modulation of gut microflora. The blended tea may serve as novel functional drink for the treatment of T2DM and dysbiosis of gut microbiota.

Calcium Hexacyanoferrate Nanozyme Enhances Plant Stress Resistance by Oxidative Stress Alleviation and Heavy Metal Removal.

Oxidative damage, exacerbated by the excessive accumulation of reactive oxygen species (ROS), profoundly inhibits both crop growth and yield. Herein, a biocompatible nanozyme, calcium hexacyanoferrate nanoparticles (CaHCF NPs), targeting ROS is developed, to mitigate oxidative damage and sequestrate heavy metal ions during plant growth. Uniquely, CaHCF NPs feature multifaced enzyme-like activities, involving superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), glutathione peroxidase, thiol peroxidase, and ascorbate peroxidase, which enable them to neutralize excessive ROS. Furthermore, CaHCF NPs promote calcium-cadmium exchange process, diminishing the uptake of heavy metals. Importantly, 120 µg mL-1 of CaHCF NPs alleviate the inhibitory effects of hydrogen peroxide and cadmium chloride on Arabidopsis and tomato. The activities of SOD, POD, and CAT increase by 46.2%, 74.4%, and 48.3%, respectively, meanwhile the glutathione level rises by 72.4% in Arabidopsis under cadmium stress. Moreover, CaHCF NPs boost the expression of genes associated with antioxidation, heavy metal detoxification, nutrient transport, and stress resistance. These findings unveil the significant potential of nanoplatforms equipped with nanozymes in alleviating oxidative stress in plants, which not only regulate crop growth but also substantially ameliorate yield and quality, heralding a new era in agricultural nanotechnology.

Revealing the changes in signaling pathways caused by tofacitinib in patients with rheumatoid arthritis through RNA sequencing and the correlation with clinical parameters.

OBJECTIVES: The current study is to accelerate the understanding of how tofacitinib works in patients with rheumatoid arthritis (RA) due to the lack of relevant information. METHOD: We selected ten patients with active RA and obtained the expression profile for their peripheral blood mononuclear cells before and after the tofacitinib treatment by RNA sequencing. The gene set enrichment analysis was conducted, and the significantly enriched gene sets were identified. The hub gene highly correlated with clinical parameters in the gene set was selected. We constructed the weighted gene co-expression network, linked modules with clinical indicators, and screened hub genes. The expression of representative hub genes was validated by real-time quantitative PCR (qPCR). RESULTS: Gene set interferon (IFN) α and IFN ß signaling was the most significantly down-regulated after tofacitinib treatment. In this gene set, genes Oas2 and Oasl showed a significant positive correlation with morning stiffness. In co-expression network, gene Vgll3 from the violet module with the highest correlation coefficient, was positively correlated with morning stiffness. Among them, Oasl and Vgll3 have shown significant down-regulation in qPCR validation. CONCLUSIONS: Our results highlighted the role of type I IFN, mainly including IFN α and IFN ß, in the pathogenesis of RA and action for tofacitinib, and provided a new entry point for further elucidating the mechanism of morning stiffness. Key Points • Gene set IFN α and IFN ß signaling was the most significantly down-regulated after tofacitinib treatment in RA patients. • Gene Oasl and Vgll3 were correlated with morning stiffness and significantly down-regulated due to the action of tofacitinib. • Type I IFN system was highlighted in the action of tofacitinib.

2D Catalytic Nanozyme Enables Cascade Enzyodynamic Effect-Boosted and Ca2+ Overload-Induced Synergistic Ferroptosis/Apoptosis in Tumor.

The introduction of glucose oxidase, exhibiting characteristics of glucose consumption and H2O2 production, represents an emerging antineoplastic therapeutic approach that disrupts nutrient supply and promotes efficient generation of reactive oxygen species (ROS). However, the instability of natural enzymes and their low therapeutic efficacy significantly impede their broader application. In this context, 2D Ca2Mn8O16 nanosheets (CMO NSs) designed and engineered to serve as a high-performance nanozyme, enhancing the enzyodynamic effect for a ferroptosis-apoptosis synergistic tumor therapy, are presented. In addition to mimicking activities of glutathione peroxidase, catalase, oxidase, and peroxidase, the engineered CMO NSs exhibit glucose oxidase-mimicking activities. This feature contributes to their antitumor performance through cascade catalytic reactions, involving the disruption of glucose supply, self-supply of H2O2, and subsequent efficient ROS generation. The exogenous Ca2+ released from CMO NSs, along with the endogenous Ca2+ enrichment induced by ROS from the peroxidase- and oxidase-mimicking activities of CMO NSs, collectively mediate Ca2+ overload, leading to apoptosis. Importantly, the ferroptosis process is triggered synchronously through ROS output and glutathione consumption. The application of exogenous ultrasound stimulation further enhances the efficiency of ferroptosis-apoptosis synergistic tumor treatment. This work underscores the crucial role of enzyodynamic performance in ferroptosis-apoptosis synergistic therapy against tumors.

Acquired hemophilia A: a single-center study of 165 patients.

Background: Acquired hemophilia A (AHA) is a rare hemorrhagic disorder caused by factor (F)VIII inhibitors. The diagnosis and management of AHA remains challenging because of its rarity and heterogeneity. Objectives: To analyze the characteristics of AHA to enhance our understanding of this disease and identify effective treatment strategies. To analyze the characteristics of AHA to enhance our understanding of this disease and identify effective treatment strategies. Methods: Clinical features of 165 patients with AHA from a single center between July 1997 and December 2021 were retrospectively analyzed. Results: The median age of patients at diagnosis was 45 years. The median time to diagnosis was 30 days. All 165 patients experienced bleeding, with a median bleeding score (BS) of 4 (range, 2-12). Hemostatic therapy was administered to 129 (78.2%) patients. Bleeding control was achieved in 80.0% of patients who received prothrombin complex concentrate and in 92.3% of patients who were treated with recombinant activated FVII. Of the 163 patients who received immunosuppressive therapy, 80 (49.1%) received rituximab-based therapy with a 93.3% complete remission (CR) rate, 50 (30.7%) received steroids plus cyclophosphamide with an 85.0% CR rate, and 22 (13.5%) received steroids alone with an 82.4% CR rate. Six cases relapsed after a median duration of 330 days. Immunosuppressive therapy-related adverse events were reported in 17 patients. Seven deaths were recorded. FVIII inhibitor titer of ≥15 BU/mL and BS of ≥6 were identified as significantly poor prognostic factors for CR. Conclusion: Immunosuppressive therapies yield remarkably high response rates, with a CR rate exceeding 80%; notably, the regimen containing rituximab exhibits a CR rate of approximately 90%. FVIII inhibitor titer of ≥5 BU/mL and BS of ≥6 were poor predictors of CR in patients with AHA.

Catalytic Nanodots-Driven Pyroptosis Suppression in Nucleus Pulposus for Antioxidant Intervention of Intervertebral Disc Degeneration.

Low back pain resulting from intervertebral disc degeneration (IVDD) is a prevalent global concern; however, its underlying mechanism remains elusive. Single-cell sequencing analyses revealed the critical involvement of pyroptosis in IVDD. Considering the involvement of reactive oxygen species (ROS) as the primary instigator of pyroptosis and the lack of an efficient intervention approach, this study developed carbonized Mn-containing nanodots (MCDs) as ROS-scavenging catalytic biomaterials to suppress pyroptosis of nucleus pulposus (NP) cells to efficiently alleviate IVDD. Catalytic MCDs have superior efficacy in scavenging intracellular ROS and rescuing homeostasis in the NP microenvironment compared with N-acetylcysteine, a classical antioxidant. The data validates that pyroptosis plays a vital role in mediating the protective effects of catalytic MCDs against oxidative stress. Systematic in vivo assessments substantiate the effectiveness of MCDs in rescuing a puncture-induced IVDD rat model, further demonstrating their ability to suppress pyroptosis. This study highlights the potential of antioxidant catalytic nanomedicine as a pyroptosis inhibitor and mechanistically unveils an efficient strategy for the treatment of IVDD.

Discovery of a novel flavonol O-methyltransferase possessing sequential 4'- and 7-O-methyltransferase activity from Camptotheca acuminata Decne.

The biosynthetic route for flavonol in Camptotheca acuminata has been recently elucidated from a chemical point of view. However, the genes involved in flavonol methylation remain unclear. It is a critical step for fully uncovering the flavonol metabolism in this ancient plant. In this study, the multi-omics resource of this plant was utilized to perform flavonol O-methyltransferase-oriented mining and screening. Two genes, CaFOMT1 and CaFOMT2 are identified, and their recombinant CaFOMT proteins are purified to homogeneity. CaFOMT1 exhibits strict substrate and catalytic position specificity for quercetin, and selectively methylates only the 4'-OH group. CaFOMT2 possesses sequential O-methyltransferase activity for the 4'-OH and 7-OH of quercetin. These CaFOMT genes are enriched in the leaf and root tissues. The catalytic dyad and critical substrate-binding sites of the CaFOMTs are determined by molecular docking and further verified through site-mutation experiments. PHE181 and MET185 are designated as the critical sites for flavonol substrate selectivity. Genomic environment analysis indicates that CaFOMTs evolved independently and that their ancestral genes are different from that of the known Ca10OMT. This study provides molecular insights into the substrate-binding pockets of two new CaFOMTs responsible for flavonol metabolism in C. acuminata.

Multi-omics differences in the bone marrow between essential thrombocythemia and prefibrotic primary myelofibrosis.

Essential thrombocythemia (ET) and prefibrotic primary myelofibrosis (pre-PMF) are Philadelphia chromosome-negative myeloproliferative neoplasms. These conditions share overlapping clinical presentations; however, their prognoses differ significantly. Current morphological diagnostic methods lack reliability in subtype differentiation, underlining the need for improved diagnostics. The aim of this study was to investigate the multi-omics alterations in bone marrow biopsies of patients with ET and pre-PMF to improve our understanding of the nuanced diagnostic characteristics of both diseases. We performed proteomic analysis with 4D direct data-independent acquisition and microbiome analysis with 2bRAD-M sequencing technology to identify differential protein and microbe levels between untreated patients with ET and pre-PMF. Laboratory and multi-omics differences were observed between ET and pre-PMF, encompassing diverse pathways, such as lipid metabolism and immune response. The pre-PMF group showed an increased neutrophil-to-lymphocyte ratio and decreased high-density lipoprotein and cholesterol levels. Protein analysis revealed significantly higher CXCR2, CXCR4, and MX1 levels in pre-PMF, while APOC3, APOA4, FABP4, C5, and CFB levels were elevated in ET, with diagnostic accuracy indicated by AUC values ranging from 0.786 to 0.881. Microbiome assessment identified increased levels of Mycobacterium, Xanthobacter, and L1I39 in pre-PMF, whereas Sphingomonas, Brevibacillus, and Pseudomonas_E were significantly decreased, with AUCs for these genera ranging from 0.833 to 0.929. Our study provides preliminary insights into the proteomic and microbiome variations in the bone marrow of patients with ET and pre-PMF, identifying specific proteins and bacterial genera that warrant further investigation as potential diagnostic indicators. These observations contribute to our evolving understanding of the multi-omics variations and possible mechanisms underlying ET and pre-PMF.

Efficacy and safety of human umbilical cord-derived mesenchymal stem cells in the treatment of refractory immune thrombocytopenia: a prospective, single arm, phase I trial.

Patients with refractory immune thrombocytopenia (ITP) frequently encounter substantial bleeding risks and demonstrate limited responsiveness to existing therapies. Umbilical cord-derived mesenchymal stem cells (UC-MSCs) present a promising alternative, capitalizing on their low immunogenicity and potent immunomodulatory effects for treating diverse autoimmune disorders. This prospective phase I trial enrolled eighteen eligible patients to explore the safety and efficacy of UC-MSCs in treating refractory ITP. The research design included administering UC-MSCs at escalating doses of 0.5 × 106 cells/kg, 1.0 × 106 cells/kg, and 2.0 × 106 cells/kg weekly for four consecutive weeks across three cohorts during the dose-escalation phase, followed by a dose of 2.0 × 106 cells/kg weekly for the dose-expansion phase. Adverse events, platelet counts, and changes in peripheral blood immunity were monitored and recorded throughout the administration and follow-up period. Ultimately, 12 (with an addition of three patients in the 2.0 × 106 cells/kg group due to dose-limiting toxicity) and six patients were enrolled in the dose-escalation and dose-expansion phase, respectively. Thirteen patients (13/18, 72.2%) experienced one or more treatment emergent adverse events. Serious adverse events occurred in four patients (4/18, 22.2%), including gastrointestinal hemorrhage (2/4), profuse menstruation (1/4), and acute myocardial infarction (1/4). The response rates were 41.7% in the dose-escalation phase (5/12, two received 1.0 × 106 cells/kg per week, and three received 2.0 × 106 cells/kg per week) and 50.0% (3/6) in the dose-expansion phase. The overall response rate was 44.4% (8/18) among all enrolled patients. To sum up, UC-MSCs are effective and well tolerated in treating refractory ITP (ClinicalTrials.gov ID: NCT04014166).