ABO incompatibility haploidentical peripheral blood stem cell transplantation combined with a single cord blood unit for severe aplastic anemia patients.

Objective: To observe the efficacy of haploidentcial peripheral blood stem cell transplantation combined with a single unrelated cord blood unit for severe aplastic anemia patients with donor-recipient ABO incompatibility. Methods: This was a retrospective cohort study and data of 57 severe aplastic anemia patients underwent haploidentical stem cell transplantation from August 1, 2018 to February 28, 2022 in the First Affiliated Hospital of Xi'an Jiaotong University was retrospectively analyzed. All patients were divided into two groups, the donor-recipient ABO matched group (bone marrow+peripheral blood group) using haploidentical bone marrow and peripheral blood stem cells as grafts, and donor-recipient ABO mismatched group (cord blood+peripheral blood group), using unrelated cord blood and haploidentical peripheral blood stem cells as grafts. The differences of hematopoietic reconstitution, acute and chronic graft-versus-host disease, Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) infection, and overall survival between the two groups were compared. Results: There were 30 cases in cord blood+peripheral blood group and 27 cases in bone marrow+peripheral blood group. One patient in bone marrow+peripheral blood group had primary graft failure, while other patients were successfully implanted. There were no significant differences of neutrophil and platelet recovery rates between two groups. The erythrocyte recovery time of cord blood+peripheral blood group was slower than that of bone marrow+peripheral blood group (p < 0.05). There was no significant difference of the incidence of graft-versus-host disease, CMV, EB virus infection and post-transplant lymphoproliferative disorders between two groups (p > 0.05). The incidence of grade III-IV acute graft-versus-host disease in cord blood+peripheral blood group was higher than that of bone marrow+peripheral blood group (p < 0.05). The incidence of intestinal graft-versus-host disease was higher in minor ABO-mismatched transplantation than that in major ABO-mismatched transplantation (p < 0.05). There was no significant difference of overall survival between two groups (p > 0.05). Conclusion: These findings suggest that haploidentical peripheral blood stem cell transplantation combined with a single cord blood unit may be an alternative option for severe aplastic anemia patients with donor-recipient ABO incompatibility.

Exploring natural killer cell-related biomarkers in multiple myeloma: a novel nature killer cell-related model predicting prognosis and immunotherapy response using single-cell study.

BACKGROUND: Natural killer cells (NKs) may be involved in multiple myeloma (MM) progression. The present study elucidated the correlation between NKs and the progression of MM using single-cell binding transcriptome probes to identify NK cell-related biomarkers. METHODS: Single-cell analysis was performed including cell and subtype annotation, cell communication, and pseudotime analysis. Hallmark pathway enrichment analysis of NKs and NKs-related differentially expressed genes (DEGs) were conducted using Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and protein-protein interaction (PPI) networks. Then, a risk model was structured based on biomarkers identified through univariate Cox regression analysis and least absolute shrinkage and selection operator regression analysis and subsequently validated. Additionally, correlation of clinical characteristics, gene set enrichment analysis, immune analysis, regulatory network, and drug forecasting were explored. RESULTS: A total of 13 cell clusters were obtained and annotated, including 8 cell populations that consisted of NKs. Utilizing 123 PPI network node genes, 8 NK-related DEGs were selected to construct a prognostic model. Immune cell infiltration results suggested that 11 immune cells exhibited marked differences in the high and low-risk groups. Finally, the model was used to screen potential drug targets to enhance immunotherapy efficacy. CONCLUSION: A new prognostic model for MM associated with NKs was constructed and validated. This model provides a fresh perspective for predicting patient outcomes, immunotherapeutic response, and candidate drugs.

Relationship Between Urinary Iodine Concentration and the Prevalence of Thyroid Nodules and Subclinical Hypothyroidism.

The aim of the study was to investigate the iodine intake in the resident population in Xi'an and analyze the relationship between iodine nutritional status and the prevalence of subclinical hypothyroidism and thyroid nodules (TNs). A total of 2507 people were enrolled in Xi'an. Venous serum thyroid stimulating hormone (TSH), thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb), urinary iodine concentration (UIC), and thyroid ultrasonography were collected. Patients with abnormal TSH were checked for free thyroxine (FT4) and triiodothyronine (FT3). Adults in Xi'an had median UICs of 220.80 µg/L and 178.56 µg/l, respectively. A sum of 16.78% of people had subclinical hypothyroidism. Both iodine excess and iodine deficit increased the frequency of subclinical hypothyroidism. The lowest was around 15.09% in females with urine iodine levels between 200 and 299 µg/l. With a rate of 10.69%, the lowest prevalence range for males was 100-199 µg/l. In Xi'an, 11.37% of people have TNs. In comparison to other UIC categories, TN occurrences were higher in females (18.5%) and males (12%) when UIC were below 100 µg/l. In conclusion, iodine intake was sufficient in the Xi'an area, while the adults' UIC remains slightly higher than the criteria. Iodine excess or deficiency can lead to an increase in the prevalence of subclinical hypothyroidism. Patients with iodine deficiency are more likely to develop TNs.

Efficacy and safety of TCMs with anti-inflammatory effect in patients with rheumatoid arthritis: A network meta-analysis.

Background: Traditional Chinese medicines (TCMs), such as Tripterygium wilfordii Hook F (TwHF), Glycyrrhiza uralensis, Caulis sinomenii and others have anti-inflammatory effects. They are widely used in China to treat rheumatoid arthritis (RA), but proof of their use as an evidence-based medicine is little. The aim of this network meta-analysis (NMA) was to evaluate the efficacy and safety of TCMs. Methods: By searching online databases and using a manual retrieval method, randomized controlled trials (RCTs) that met specific selection criteria were included in the meta-analysis. The search included papers that were published between the establishment of the databases and November 10, 2022. Analyses were performed using Stata software (version 14) and Review Manager (version 5.3). Results: 61 papers with 6316 subjects were included in the current NMA. For ACR20, MTX plus SIN therapy (94.30%) may be a significant choice. For ACR50 and ACR70, MTX plus IGU therapy (95.10%, 75.90% respectively) performed better than other therapies. IGU plus SIN therapy (94.80%) may be the most promising way to reduce DAS-28, followed by MTX plus IGU therapy (92.80%) and TwHF plus IGU therapy (83.80%). In the analysis of the incidence of adverse events, MTX plus XF therapy (92.50%) had the least potential, while LEF therapy (22.10%) may cause more adverse events. At the same time, TwHF therapy, KX therapy, XF therapy and ZQFTN therapy were not inferior to MTX therapy. Conclusions: TCMs with anti-inflammatory effect were not inferior to MTX therapy in the treatment of RA patients. Combining with TCMs can improve the clinic efficacy and reduce the possibility of adverse events of DMARDs, which may be a promising regimen. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022313569.

ADAR1 improved Treg cell function through the miR-21b/Foxp3 axis and inhibits the progression of acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

Th17/Treg equilibrium towards the pro-inflammatory Th17 side contributes greatly to the rejection during allogeneic hematopoietic stem cell transplantation (allo-HSCT). Forkhead box P3 (Foxp3) is important in the pathogenic conversion between Th17 and Treg cells. However, how Foxp3 expression was regulated is largely unknown. Here, we investigated the role of RNA-editing enzyme ADAR1 in Foxp3-mediated Th17/Treg imbalance and progression of acute graft-versus-host disease (aGVHD), a most serious complication in patients received allo-HSCT. Th1, Th17 and Treg cells were respectively isolated from peripheral blood CD4 + T cells of allo-HSCT patients, and we found that proportions of Th1 and Th17 were markedly increased, while Treg proportion was significantly decreased in aGVHD patients post transplantation compared with non-aGVHD patients, accompanied by decreased ADAR1 and increased miR-21b levels. RNA-immunoprecipitation (RIP) combined with gain- and loss-of-function experiments demonstrated that ADAR1 improved Treg cell functions and negatively regulated the production of miR-21b, a Foxp3-targeting miRNA. Inhibition of miR-21b improved Treg functions, and Foxp3 knockdown could eliminate the effect of miR-21b inhibition or ADAR1 overexpression on Treg function. Finally, an aGVHD mouse model was established and Ad-O/E-ADAR1 was injected into aGVHD mice to verify the effect of ADAR1 on aGVHD progression in vivo. The results showed that ADAR1 overexpression decreased Th17 proportion and increased Treg proportion in aGVHD mice and obviously improved tissue necrosis and reticular structure of aGVHD liver and lung in vivo. Collectively, ADAR1 suppresses miR-21b production and improves Foxp3-mediated Treg cell function to inhibit the progression of aGVHD after allo-HSCT.

Integrative Analysis of Bulk RNA-Seq and Single-Cell RNA-Seq Unveils Novel Prognostic Biomarkers in Multiple Myeloma.

Molecular heterogeneity has great significance in the disease biology of multiple myeloma (MM). Thus, the analysis combined single-cell RNA-seq (scRNA-seq) and bulk RNA-seq data were performed to investigate the clonal evolution characteristics and to find novel prognostic targets in MM. The scRNA-seq data were analyzed by the Seurat pipeline and Monocle 2 to identify MM cell branches with different differentiation states. Marker genes in each branch were uploaded to the STRING database to construct the Protein-Protein Interaction (PPI) network, followed by the detection of hub genes by Cytoscape software. Using bulk RNA-seq data, Kaplan-Meier (K-M) survival analysis was then carried out to determine prognostic biomarkers in MM. A total of 342 marker genes in two branches with different differentiation states were identified, and the top 20 marker genes with the highest scores in the network calculated by the MCC algorithm were selected as hub genes in MM. Furthermore, K-M survival analysis revealed that higher NDUFB8, COX6C, NDUFA6, USMG5, and COX5B expression correlated closely with a worse prognosis in MM patients. Moreover, ssGSEA and Pearson analyses showed that their expression had a significant negative correlation with the proportion of Tcm (central memory cell) immune cells. Our findings identified NDUFB8, COX6C, NDUFA6, USMG5, and COX5B as novel prognostic biomarkers in MM, and also revealed the significance of genetic heterogeneity during cell differentiation in MM prognosis.

A Systematic Review and Network Meta-Analysis about the Efficacy and Safety of Tripterygium wilfordii Hook F in Rheumatoid Arthritis.

Objective: This study aims to evaluate the efficacy of various conventional synthetic DMARDs, including Tripterygium wilfordii Hook F (TwHF) for treating rheumatoid arthritis (RA) by network meta-analysis. Methods: We retrieved the related literature from online databases and supplemented it by using a manual retrieval method. Data was extracted from the literature and analyzed with STATA software. Results: A total of 21 trials (5,039 participants) were identified. Assessment of ACR20 response found that TwHF combined with methotrexate (MTX) had the greatest probability for being the best treatment option among the treatments involved, while TwHF used singly was second only to TwHF combined with MTX. Assessment of ACR50 response found that TwHF combined with MTX ranked second in all treatment options after cyclosporine A (CsA) combined with leflunomide (LEF) and TwHF alone, followed by TwHF combined with MTX. Assessment of ACR70 response found that CsA combined with LEF ranked first, TwHF combined with LEF ranked second, TwHF combined with MTX ranked third, and TwHF used singly ranked fourth. In the safety analysis, TwHF had the least probability of adverse event occurrence, followed by TwHF combined with MTX, which ranked first and second, respectively. Conclusion: Compared with the current csDMARDs for treating RA, the efficacy of TwHF was clear, and TwHF combined with MTX performed well under various endpoints. In the future, large, rigorous, and high-quality RCTs are still needed to confirm the benefits of TwHF therapy on RA.

Role of cofilin­1 in arsenic trioxide­induced apoptosis of NB4­R1 cells.

All­trans retinoic acid (ATRA) and arsenic trioxide (As2O3) are currently first­line treatments for acute promyelocytic leukemia (APL). However, a number of patients with APL are resistant to ATRA but still sensitive to As2O3, and the underlying mechanisms of this remain unclear. In the present study, two­dimensional gel electrophoresis, mass spectrometry and other proteomic methods were applied to screen and identify the differentially expressed proteins between the retinoic acid­sensitive cell lines and drug­resistant cell lines. The results demonstrated that in retinoic acid­resistant NB4­R1 cells, the protein expression of cofilin­1 was markedly increased compared with that in the drug­sensitive NB4 cells. Subsequently, the effects of cofilin­1 on As2O3­induced apoptosis in NB4­R1 cells were further investigated. The results revealed that cell viability was markedly suppressed and apoptosis was increased in the As2O3­treated NB4­R1 cells, with increased expression levels of cleaved­poly (ADP­ribose) polymerase and cleaved­caspase 12. Cofilin­1 expression was significantly decreased at both the mRNA and protein levels in the As2O3­treated group compared with the control. Western blotting further revealed that As2O3 treatment decreased the cytoplasmic cofilin­1 level but increased its expression in the mitochondrion. However, the opposite effects of As2O3 on the cytochrome C distribution were found in NB4­R1 cells. This suggested that As2O3 can induce the transfer of cofilin­1 from the cytoplasm to mitochondria and trigger the release of mitochondrial cytochrome C in NB4­R1 cells. Moreover, cofilin­1 knockdown by its specific short hairpin RNA significantly suppressed As2O3­induced NB4­R1 cell apoptosis and inhibited the release of mitochondrial cytochrome C. Whereas, overexpression of cofilin­1 using a plasmid vector carrying cofilin­1 increased the release of cytochrome C into the cytoplasm from the mitochondria in As2O3­treated NB4­R1 cells. In conclusion, cofilin­1 played a role in As2O3­induced NB4­R1 cell apoptosis and it might be a novel target for APL treatment.

Toxic epidermal necrolysis syndrome induced by tigecycline: a case report.

A 56-year-old man diagnosed with non-Hodgkin's lymphoma underwent autologous bone marrow transplantation. He was subsequently admitted to the hospital with fever, and his symptoms were initially controlled by multiple antibiotics, including tigecycline. He then developed a generalized body rash that improved after treatment with anti-allergy drugs and steroids. Furthermore, tigecycline treatment for a second time resulted in a severe skin reaction with systemic symptoms, suggesting toxic epidermal necrolysis syndrome (TEN). The patient was shown to have the slow-metabolizing cytochrome P450 2C19 allele, denoted CYP2C19*2. He was transferred to a laminar flow ward and given strict mucosal care, together with corticosteroids and intravenous immunoglobulin. He recovered after 3 weeks of treatment. Tigecycline-induced Stevens-Johnson syndrome (SJS)/TEN has rarely been reported in the Chinese population. However, our experience suggests that Asians are more likely to have adverse reactions to drugs metabolized by the cytochrome P450 enzyme. Early identification of drug reactions and immediate cessation of the suspected drug is essential. Additionally, a combined therapy scheme and a clean laminar flow environment may improve the cure rate of SJS/TEN.