OBJECTIVES: To investigate the causal associations between autoimmune diseases and aplastic anemia (AA) using Mendelian randomization analysis. METHODS: Publicly available genome-wide association study (GWAS) data were utilized to obtain single nucleotide polymorphisms (SNPs) associated with autoimmune diseases and AA for analysis. The inverse variance weighted (IVW) method was employed as the primary analytical approach, with MR Egger, Weighted Mode, Weighted Median, and Simple Mode methods serving as complementary analyses. Heterogeneity and pleiotropy analyses were conducted using designated functions, and the robustness of Mendelian randomization results was assessed using leave-one-out analysis. RESULTS: The two-sample Mendelian randomization analysis using the IVW method revealed significant positive causal associations of rheumatoid arthritis (OR=1.094, 95% CI: 1.023-1.170, P=0.009, adjusted P=0.042), systemic lupus erythematosus (OR=1.111, 95% CI: 1.021-1.208, P=0.015, adjusted P=0.036), Hashimoto thyroiditis (OR=1.206, 95% CI: 1.049-1.387, P=0.009, adjusted P=0.029), and Sicca syndrome (OR=1.173, 95% CI: 1.054-1.306, P=0.004, adjusted P=0.035) with AA, which was supported by the results from the Weighted Median method. Sensitivity analyses indicated no evidence of pleiotropy or heterogeneity, and leave-one-out analysis confirmed the robustness of the causal relationships. No direct evidence was found linking Graves' disease, ulcerative colitis, Crohn's disease, autoimmune hepatitis, primary biliary cholangitis, or primary sclerosing cholangitis with AA (P>0.05, adjusted P>0.05), indicating a lack of causal association. Reverse Mendelian randomization results and multiple corrections indicated that AA was not an influencing factor for autoimmune diseases (adjusted P>0.05). CONCLUSIONS Our findings support at the genetic level that rheumatoid arthritis, systemic lupus erythematosus, Hashimoto thyroiditis, and Sicca syndrome are risk factors for AA, and confirm a causal association of the these 4 autoimmune diseases with an increased risk of AA.
Humans ; Mendelian Randomization Analysis ; Anemia, Aplastic/genetics* ; Autoimmune Diseases/complications* ; Polymorphism, Single Nucleotide ; Genome-Wide Association Study ; Arthritis, Rheumatoid/genetics* ; Lupus Erythematosus, Systemic/genetics* ; Genetic Predisposition to Disease

OBJECTIVE: Hepatocellular carcinoma (HCC) is sensitive to ferroptosis, a new form of programmed cell death that occurs in most tumor types. However, the mechanism through which ferroptosis modulates HCC remains unclear. This study aimed to investigate the oncogenic role and prognostic value of FANCD2 and provide novel insights into the prognostic assessment and prediction of immunotherapy. METHODS: Using clinicopathological parameters and bioinformatic techniques, we comprehensively examined the expression of FANCD2 macroscopically and microcosmically. We conducted univariate and multivariate Cox regression analyses to identify the prognostic value of FANCD2 in HCC and elucidated the detailed molecular mechanisms underlying the involvement of FANCD2 in oncogenesis by promoting iron-related death. RESULTS: FANCD2 was significantly upregulated in digestive system cancers with abundant immune infiltration. As an independent risk factor for HCC, a high FANCD2 expression level was associated with poor clinical outcomes and response to immune checkpoint blockade. Gene set enrichment analysis revealed that FANCD2 was mainly involved in the cell cycle and CYP450 metabolism. CONCLUSION To the best of our knowledge, this is the first study to comprehensively elucidate the oncogenic role of FANCD2. FANCD2 has a tumor-promoting aspect in the digestive system and acts as an independent risk factor in HCC; hence, it has recognized value for predicting tumor aggressiveness and prognosis and may be a potential biomarker for poor responsiveness to immunotherapy.
Humans ; Carcinoma, Hepatocellular/diagnosis* ; Liver Neoplasms/diagnosis* ; Immunotherapy ; Fanconi Anemia Complementation Group D2 Protein/metabolism* ; Prognosis ; Male ; Female ; Middle Aged ; Biomarkers, Tumor/metabolism*

A 4-year-old boy was admitted to the hospital with a 3-day history of rash and intermittent abdominal pain, during which abnormal results from routine blood tests were discovered. Initially, he presented with acute jaundice hepatitis and pancytopenia. The patient's condition progressed rapidly, with recurrent fever, worsening jaundice of the skin and sclera, and progressively worsening hepatosplenomegaly. Liver function impairment and bone marrow failure continued to deteriorate, while cytokine levels continued to rise. After excluding infections, autoimmune diseases, tumors, genetic metabolic disorders, and toxicities, the patient was diagnosed with hepatitis-associated aplastic anemia (HAAA) complicated by hemophagocytic lymphohistiocytosis (HLH). Following treatment with corticosteroids, plasma exchange, intravenous immunoglobulin, and liver protection therapy, the patient's symptoms partially alleviated. Aplastic anemia complicated by HLH is relatively uncommon, and HAAA complicated by HLH is even rarer, often presenting insidiously and severely. This paper presents a case of HAAA complicated by HLH and summarizes previously reported cases in the literature, providing references for the early diagnosis and treatment of this condition.
Humans ; Lymphohistiocytosis, Hemophagocytic/therapy* ; Male ; Anemia, Aplastic/complications* ; Child, Preschool ; Hepatitis/complications*

OBJECTIVES: To evaluate the clinical value of CD4⁺ cell percentage (CD4⁺%) and NK cell percentage (NK%) in predicting treatment outcomes in children with aplastic anemia (AA), providing a reference for precise diagnosis and treatment. METHODS: This retrospective study analyzed the clinical data of AA children treated with cyclosporine A at the First Affiliated Hospital of Xinjiang Medical University from January 2019 to April 2024. The study involved 48 AA children as the observation group and 50 children undergoing medical check-ups during the same period as the control group. Lymphocyte subset data were collected from both groups to analyze differences and their relationship with treatment efficacy. Based on hematological responses, the observation group was divided into an effective group of 18 patients (HR group, including complete and partial remission) and an ineffective group of 30 patients (NHR group, including non-remission). RESULTS: Univariate analysis showed that NK% in the observation group was significantly lower than that in the control group (P<0.05). The observation group was followed up for 3 months. The HR group had a lower CD4⁺% than the NHR group (P=0.018) and a higher NK% than the NHR group (P=0.029). Multivariate logistic regression analysis indicated that a high CD4⁺% was a risk factor for poor treatment efficacy (OR=1.062), whereas a high NK% was a protective factor (OR=0.820). The area under the curve for the prediction of HR in pediatric AA by combining CD4⁺% and NK% was 0.812. CONCLUSIONS A higher CD4⁺% at diagnosis is a predictor of poor treatment response, whereas a higher NK% is associated with better outcomes.
Humans ; Anemia, Aplastic/blood* ; Male ; Female ; Killer Cells, Natural ; Child ; Retrospective Studies ; Child, Preschool ; Prognosis ; Adolescent ; CD4-Positive T-Lymphocytes ; Infant

A male full-term neonate was admitted at 30 minutes of life with pallor and 10 minutes of respiratory distress. Physical examination revealed pallor, increased intercanthal distance, low-set ears, a palpable cystic mass in the neck, hepatomegaly, a pedunculated, globular appendage attached to the right thumb, and an ectopic toenail on the right second toe. Laboratory testing showed severe anemia with hemoglobin of 44 g/L. Bone marrow examination demonstrated hypoplasia. Whole-exome sequencing identified a heterozygous pathogenic variant in the RPS19 gene, c.175T>C (p.Ser59Pro), establishing the diagnosis of Diamond-Blackfan anemia. On follow-up to 2 years and 2 months of age, both hemoglobin and reticulocyte counts remained within normal ranges. This case illustrates early-onset severe anemia in a neonate with genetically confirmed Diamond-Blackfan anemia and expands the phenotypic spectrum, informing clinical recognition and management.
Humans ; Anemia, Diamond-Blackfan/diagnosis* ; Male ; Infant, Newborn ; Ribosomal Proteins/genetics*

OBJECTIVE: To analyze the factors associated with mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in children with severe aplastic anemia (SAA). METHODS: The clinical data of 90 children with SAA who received allo-HSCT in the Department of Hematology, Wuhan Children's Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology from August 2016 to July 2023 were collected. The clinical features and causes of death were analyzed retrospectively. Cox proportional hazards model was used to screen the risk factors of death. RESULTS: Only 9 children died with a median time of 6.3(2.6, 8.3) months among the 90 children with SAA after allo-HSCT. Among the 5 deaths due to infection, 3 were pulmonary infection, including 2 cases of cytomegalovirus pneumonia. One case developed septic shock due to gastrointestinal infection. One case experienced graft failure, which was complicated by bloodstream infection, and developed septic shock. Three cases died of transplantation-associated thrombotic microangiopathy (TA-TMA). One case died of gastrointestinal graft-versus-host disease (GVHD). The results of multivariate analysis showed that post-transplant +60 d PLT≤30×10⁹/L (HR=7.478, 95%CI : 1.177-47.527, P =0.033), aGVHD Ⅲ-Ⅳ (HR=7.991, 95%CI : 1.086-58.810, P =0.041), and TA-TMA occurrence (HR=13.699, 95%CI : 2.146-87.457, P =0.006) were independent risk factors for post-transplant mortality. CONCLUSION Allo-HSCT is an effective therapy for SAA in children. Post-transplant +60 d PLT≤30×10⁹/L, aGVHD Ⅲ-Ⅳ, and TA-TMA occurrence are independently associated with post-transplant mortality, which may be helpful for early detection of potential high-risk children and optimization of clinical diagnostic and treatment strategies.
Humans ; Anemia, Aplastic/therapy* ; Hematopoietic Stem Cell Transplantation/adverse effects* ; Risk Factors ; Retrospective Studies ; Child ; Transplantation, Homologous ; Male ; Female ; Graft vs Host Disease ; Child, Preschool ; Proportional Hazards Models ; Adolescent ; Infant

Ferroptosis initiates membrane oxidative damage through lipid peroxidation and iron accumulation, and accumulates reactive oxygen species (ROS) during aplastic anemia (AA). Ferroptosis induces damage and apoptosis of hematopoietic stem/progenitor cells, mesenchymal stem cells, blood cells, and T lymphocytes through various pathways, inhibits bone marrow hematopoiesis, damages bone marrow microenvironment, exacerbates immune imbalance, leading to bone marrow failure and disease progression. Therefore, further exploring the ferroptosis mechanism in AA can help clarify the pathogenesis of disease and provide new research ideas and directions for the treatment of AA.
Anemia, Aplastic/metabolism* ; Humans ; Ferroptosis ; Reactive Oxygen Species/metabolism* ; Lipid Peroxidation ; Hematopoietic Stem Cells ; Apoptosis

Humans ; Anemia, Aplastic ; Leukemia, Large Granular Lymphocytic/diagnosis* ; Immunophenotyping

A series of chemotherapeutic drugs that induce DNA damage, such as cisplatin (DDP), are standard clinical treatments for ovarian cancer, testicular cancer, and other diseases that lack effective targeted drug therapy. Drug resistance is one of the main factors limiting their application. Sensitizers can overcome the drug resistance of tumor cells, thereby enhancing the antitumor activity of chemotherapeutic drugs. In this study, we aimed to identify marketable drugs that could be potential chemotherapy sensitizers and explore the underlying mechanisms. We found that the alcohol withdrawal drug disulfiram (DSF) could significantly enhance the antitumor activity of DDP. JC-1 staining, propidium iodide (PI) staining, and western blotting confirmed that the combination of DSF and DDP could enhance the apoptosis of tumor cells. Subsequent RNA sequencing combined with Gene Set Enrichment Analysis (GSEA) pathway enrichment analysis and cell biology studies such as immunofluorescence suggested an underlying mechanism: DSF makes cells more vulnerable to DNA damage by inhibiting the Fanconi anemia (FA) repair pathway, exerting a sensitizing effect to DNA damaging agents including platinum chemotherapy drugs. Thus, our study illustrated the potential mechanism of action of DSF in enhancing the antitumor effect of DDP. This might provide an effective and safe solution for combating DDP resistance in clinical treatment.
Female ; Male ; Humans ; Cisplatin/pharmacology* ; Disulfiram/pharmacology* ; Testicular Neoplasms/drug therapy* ; Fanconi Anemia/drug therapy* ; Alcoholism/drug therapy* ; Drug Resistance, Neoplasm ; Cell Line, Tumor ; Substance Withdrawal Syndrome/drug therapy* ; Apoptosis ; Antineoplastic Agents/therapeutic use* ; Cell Proliferation

OBJECTIVE: To investigate the recovery characteristics of T cell subsets in patients with severe aplastic anemia (SAA) who received haploid hematopoietic stem cell transplantation(HSCT) and its relationship with acute graft-versus-host disease(aGVHD). METHODS: The clinical data of 29 SAA patients who received haploid hematopoietic stem cell transplantation in the department of hematology, Shanxi Bethune Hospital from June 2018 to January 2022 were retrospectively analyzed. The absolute counts of CD3⁺T, CD4⁺T, CD8⁺T lymphocytes and the ratio of CD4⁺T/CD8⁺T lymphocytes in all patients before transplantation, 14, 21, 30, 60, 90 and 120 days after transplantation were analyzed. The proportion of T lymphocytes was compared in the non-aGVHD group, the grade Ⅰ-Ⅱ aGVHD group and the grade III-IV aGVHD group. RESULTS: The counts of all T cells in 27 patients were far below the normal level at 14 and 21 days after transplantation, but there was obvious heterogeneity. There was a certain relationship between T cell immune reconstitution and conditioning regimen, age, and immunosuppressive treatment before transplantation. CD3⁺T cells showed a steady upward trend at 30, 60, 90, and 120 days after transplantation, and returned to the normal levels at 120 days after transplantation; faster recovery of CD4⁺T cells was closely related to aGVHD, which was at 30, 60, 90, 120 days after transplantation showed a slow upward trend, and which was still far below the normal level of 120 days after transplantation. CD8⁺T cell counts began to recover at 14 and 21 days after transplantation, and the recovery was earlier than the CD4⁺T cells, and its recovery speed was rapid 30 and 60 days after transptantation, which showed an upward trend and exceeded the normal levels 90 days after transplantation. Since CD8⁺ T cells reconstituted quickly, while the CD4⁺ T cells reconstitution was slowly, which made the long-term CD4⁺T/CD8⁺T cell ratio after transplantation was inverted . Compared with the non-aGVHD group, the absolute counts of CD3⁺T, CD4⁺T, and CD8⁺T cells in the aGVHD group were significantly higher than those in the non-aGVHD group at each time period after transplantation. In the aGVHD group, grade Ⅲ-Ⅳ aGVHD occurred more frequently in the early post-transplantation period (within 14-21 days), the grade Ⅰ-Ⅱ aGVHD group mostly occurred within 30-90 days after transplantation, and CD3⁺T, CD4⁺T, CD8⁺T cell counts in the grade Ⅲ-Ⅳ aGVHD group were significantly higher than those in the grade Ⅰ-Ⅱ aGVHD group; and the greater the proportion of CD4⁺T, the more severe the degree of aGVHD. CONCLUSION The speed of T cell immune reconstitution after SAA haploid transplantation is different, which is related to the conditioning regimen, age, and immunosuppressive therapy before transplantation. The rapid recovery of CD4⁺ T cells is closely related to the occurrence of aGVHD.
Humans ; Anemia, Aplastic/therapy* ; CD8-Positive T-Lymphocytes ; Retrospective Studies ; Haploidy ; Hematopoietic Stem Cell Transplantation ; Graft vs Host Disease