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Summary: A chemotherapy‐based mobilization regimen in patients who mobilize poorly, based on etoposide, cytarabine and pegfilgrastim (EAP), has recently been introduced. The aim of this prospective study was to investigate the efficacy and safety of the EAP regimen in patients with poorly mobilizing multiple myeloma (MM) or lymphoma. This single‐arm clinical trial was performed at eight public hospitals in China and was registered as a clinical trial (NCT05510089). The inclusion criteria were; (1) diagnosis of MM or lymphoma, (2) defined as a 'poor mobilizer' and (3) aged 18–75 years. The EAP regimen consisted of etoposide 75 mg/m2/day on days 1–2, cytarabine 300 mg/m2 every 12 h on days 1–2 and pegfilgrastim 6 mg on day 6. The primary endpoint of the study was the ratio of patients achieving adequate mobilization (≥2.0 × 106 CD34+ cells/kg). From 1 September 2022 to 15 August 2023, a total of 58 patients were enrolled, 53 (91.4%) achieved adequate mobilization, while 41 (70.7%) achieved optimal mobilization with a median number of cumulative collected CD34+ cells was 9.2 (range 2.1–92.7) × 106/kg and the median number of apheresis per patient of 1.2. The median time from administration of the EAP regimen to the first apheresis was 12 days. Approximately 8.6% of patients required plerixa for rescue, which was successful. Twelve (20.7%) of the 58 patients suffered grade 2–3 infections, while 25 (43.1%) required platelet transfusions. The duration of neutrophil and platelet engraftment was 11 days. In conclusion, these results suggest that the EAP mobilization regimen might be a promising option for poorly mobilizing patients with MM or lymphoma. [ABSTRACT FROM AUTHOR]

Background: Pure red cell aplasia (PRCA) following allogeneic hematopoietic stem cell transplantation (allo‐HSCT) with ABO major incompatibility is characterized by transfusion dependent anemia. No standard treatment existed for PRCA following allo‐HSCT yet. Study Design and Methods: We conducted a retrospective study, and reported our experience with the use of avatrombopag and lower dose rituximab to treat five patients with PRCA subsequent to major ABO‐incompatible allo‐HSCT. Results: Five cases of PRCA were identified from 72 patients who underwent allo‐HSCT with major or bidirectional ABO mismatch. Cumulative incidence at Day +60 was 6.9% (5/72) at our center. All donor and recipient blood groups were A+ and O+, respectively. In the first three cases we reported, patients received erythropoietin, plasma exchange, and donor lymphocyte infusion, but none of them had any effect. After 4 weeks of treatment with low dose rituximab (100 mg/week) combined with avatrombopag (40 mg/day), favorable outcomes were obtained. According to the aforementioned experience, Cases 4 and 5 were administered low‐dose rituximab and avatrombopag in 3 months after transplantation, and erythroid response was observed on 3 weeks after treatment. Our patients tolerated low‐dose rituximab and avatrombopag well and experienced rapid efficacy, with a median duration of 3 weeks. Furthermore, no severe infection or thrombocytosis necessitated a dose adjustment. Conclusion: Low‐dose rituximab and avatrombopag may be an effective treatment for patients with PRCA after major ABO‐incompatible allo‐HSCT. The patients should be treated at least 90 days post transplantation if conventional erythropoietin therapy fails. [ABSTRACT FROM AUTHOR]

Objective: Mounting evidence has linked microbiome and metabolome to systemic autoimmunity and cardiovascular diseases (CVDs). Takayasu arteritis (TAK) is a rare disease that shares features of immune‐related inflammatory diseases and CVDs, about which there is relatively limited information. This study was undertaken to characterize gut microbial dysbiosis and its crosstalk with phenotypes in TAK. Methods: To address the discriminatory signatures, we performed shotgun sequencing of fecal metagenome across a discovery cohort (n = 97) and an independent validation cohort (n = 75) including TAK patients, healthy controls, and controls with Behçet's disease (BD). Interrogation of untargeted metabolomics and lipidomics profiling of plasma and fecal samples were also used to refine features mediating associations between microorganisms and TAK phenotypes. Results: A combined model of bacterial species, including unclassified Escherichia, Veillonella parvula, Streptococcus parasanguinis, Dorea formicigenerans, Bifidobacterium adolescentis, Lachnospiraceae bacterium 7 1 58FAA, Escherichia coli, Streptococcus salivarius, Klebsiella pneumoniae, Bifidobacterium longum, and Lachnospiraceae Bacterium 5 1 63FAA, distinguished TAK patients from controls with areas under the curve (AUCs) of 87.8%, 85.9%, 81.1%, and 71.1% in training, test, and validation sets including healthy or BD controls, respectively. Diagnostic species were directly or indirectly (via metabolites or lipids) correlated with TAK phenotypes of vascular involvement, inflammation, discharge medication, and prognosis. External validation against publicly metagenomic studies (n = 184) on hypertension, atrial fibrillation, and healthy controls, confirmed the diagnostic accuracy of the model for TAK. Conclusion: This study first identifies the discriminatory gut microbes in TAK. Dysbiotic microbes are also linked to TAK phenotypes directly or indirectly via metabolic and lipid modules. Further explorations of the microbiome–metagenome interface in TAK subtype prediction and pathogenesis are suggested. [ABSTRACT FROM AUTHOR]

Background and Purpose: Hydrogen sulfide donors can block the cardiovascular injury of hyperhomocysteinemia. H2 S also lowers serum homocysteine in rats with mild hyperhomocysteinemia, but the pharmacological mechanism is unknown. The present study investigated the mechanism(s) involved.Experimental Approach: ApoE-knockout mice were fed a Paigen diet and L-methionine in drinking water for 16 weeks to create a mouse model of atherosclerosis with hyperhomocysteinemia. H2 S donors (NaHS and GYY4137) were administered by intraperitoneal injection. We also assayed the H2 S produced (by methylene blue assay and mito-HS [H2 S fluorescence probe]), cystathionine γ lyase (CSE) mRNA and protein expression, and CSE sulfhydration and nitrosylation and its activity.Key Results: H2 S donor treatment significantly lowered atherosclerotic plaque area, macrophage infiltration, and serum homocysteine level in the mouse model of atherosclerosis with co-existing hyperhomocysteinemia. mRNA and protein levels of CSE, a key enzyme catalyzing homocysteine trans-sulfuration, were down-regulated with hyperhomocysteinemia, and CSE catalytic activity was inhibited. All these effects were reversed with H2 S donor treatment. Hyperhomocysteinemia induced CSE nitrosylation, whereas H2 S sulfhydrated CSE at the same cysteine residues. Nitrosylated CSE decreased and sulfhydrated CSE increased its catalytic and binding activities towards L-homocysteine. Mutation of C252, C255, C307, and C310 residues in CSE abolished CSE nitrosylation or sulfhydration and prevented its binding to L-homocysteine.Conclusions and Implications: Sulfhydration or nitrosylation of CSE represents a yin/yang regulation of catalysis or binding to L-homocysteine. H2 S donor treatment enhanced CSE sulfhydration, thus lowering serum L-homocysteine, which contributed in part to the anti-atherosclerosis effects in ApoE-knockout mice with hyperhomocysteinemia. [ABSTRACT FROM AUTHOR]

ABSTRACT Some organophosphorus compounds can cause organophosphate-induced delayed neuropathy (OPIDN). Incidents have been documented for decades, however, little is known about which proteins contribute to the initiation, progression and development of OPIDN. In this study, 51 hens were divided into three groups. The tri-ortho-cresyl-phosphate (TOCP) group was treated with 1000 mg kg-1 TOCP whereas the control group was treated with an equivalent volume of vehicle. The PMSF + TOCP group was treated subcutaneously with 40 mg kg-1 phenylmethylsulfonyl fluoride (PMSF), followed by 1000 mg kg-1 TOCP 24 h later. Proteins in the brains of hens were separated by two-dimensional polyacrylamide gel electrophoresis on day 5 after TOCP administration. Mass spectrometry identified eight differentially expressed proteins. Among these proteins, downregulated expression of glutamine synthetase (GS) in the brains of hens after TOCP treatment was further confirmed by real time RT-PCR and ELISA. Moreover, the brains of hens exposed to TOCP exhibited increased levels of glutamate (Glu) and cytosolic calcium concentration ([Ca2+] i), and a decreased level of glutamine (Gln). However, there were no significant differences in GS expression or levels of Glu, Gln, and [Ca2+] i in the brains of hens among the groups on day 21 after TOCP administration. These results indicate that TOCP exposure downregulates GS expression in the brains of hens, and that downregulation of GS is accompanied by increased levels of Glu and [Ca2+] i in the early stage after TOCP administration. It is also suggested that the downregulated expression of GS might be associated with OPIDN through the disruption of homeostasis of the Glu-Gln cycle and [Ca2+] i. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: Culture of human hepatocarcinoma cells in three-dimensional structure or spheroid represents a unique opportunity to recapitulate aspects of cell homeostasis and to better reflect the characteristics of native hepatic tumor. In this paper, human hepatocarcinoma SMMC-7721 cells were encapsulated in alginate-poly-l-lysine-alginate (APA) microcapsules and the behavior of the cells in the restricted three-dimensional culture system was investigated. The cells were polygonal-shaped, proliferating with high viability, and formed a single multicellular spheroid in microcapsule. During the assembly of the aggregate in microcapsule, cytoskeletal reorganization and repolorization was occurred, which was absent in cells cultured in monolayer. The in vivo-like cytoarchitecture was confirmed by the phalloidin–FITC labeling of F-actin filaments. The trabecular structure revealed by scanning electron microscope (SEM), and the bile canaliculus with multiple microvilli and tight junctions revealed by transmission electron microscope (TEM) was found in microencapsulated cells, which exhibited the ultrastructural characteristics of native hepatic tissue. It suggested that microcapsule culture provides an in vivo-like model which can be used for the study of the interactions of cell–cell and cell–microenvironment, and the mechanisms of invasion, metastasis and multicellular drug resistance of tumor cells. [Copyright &y& Elsevier]