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BACKGROUND: Acute myeloid leukemia (AML) is characterized by high heterogeneity, poor long-term survival, and a propensity for relapse. Exceptional efficacy in treating recurrent or refractory B-lymphoid malignancies has been demonstrated by Chimeric antigen receptor T cells (CAR-T cells). Given the therapeutic potential of targeting both CD33 and C-type lectin-like molecule-1 (CLL1) in AML, the development of a dual-targeting CD33-CLL1 CAR-T cells assumes significant importance. MATERIALS AND METHODS: The expressions of CD33 and CLL-1 antigens in peripheral blood cells and bone marrow cells from AML patients was assessed. Subsequently, a Chimeric Antigen Receptor (CAR) incorporating a dual-specific single-chain variable fragment targeting CLL1 and CD33 (CD33-CLL1-CAR-T) was engineered. The anti-tumor efficacy and potential side effects of CD33-CLL1-CAR-T cells were comprehensively investigated in both in vitro and in vivo settings. RESULTS: The constructed tandem CD33-CLL1 CAR-T exhibited potent cytotoxicity against leukemia cell lines and human primary AML cells in vitro. Co-cultivation of AML blasts with CD33-CLL1-CAR-T cells resulted in effective proliferation and the secretion of substantial quantities of GM-CSF and IFN-γ. Importantly, the impact of CD33-CLL1-CAR-T cells on normal hematopoietic stem cells was minimal, ensuring safety in vivo mouse models. Notably, significant anti-leukemic activity was observed in the mouse model, with CD33-CLL1-CAR-T cells leading to tumor eradication and prolonged survival. DISCUSSION: The tandem CD33-CLL1 CAR-T cells not only efficiently eliminated AML blasts but also exhibited low cytotoxicity toward normal hematopoietic stem cells (HSCs). These findings underscore the potential clinical applicability of the tandem CD33-CLL1 CAR-T cells as an effective and safe treatment strategy for AML, representing a noteworthy advancement in the field of CAR-T cells therapy.
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Congenital thrombotic thrombocytopenic purpura (TTP) is a rare autosomal recessive genetic disorder caused by mutations in the ADAMTS13 gene. Approximately 200 mutations of the ADAMTS-13 gene have been identified, although only a few have been characterized through in vitro expression studies. We conducted an investigation on a male congenital TTP patient with reduced plasma levels of ADAMTS13 activity. DNA sequence analysis revealed two mutations on chromosome 9 (1.9q34.2) in the patient's ADAMTS13 gene. One mutation was a non-synonymous mutation (exon 5: c.A530G: p.Y177C), while the other was a nonsense mutation (exon 21: c.G2651A: p.W884X). Both mutations were found to be heterozygous. The patient's parents had no history of thrombocytopenia or neurological symptoms. DNA sequence analysis showed the patient's father was a heterozygote for the nonsense mutation of the ADAMTS13 gene (exon 21: c.G2651A: p.W884X), while the mother was a heterozygote for the non-synonymous mutation of the ADAMTS13 gene (exon 5: c.A530G: p.Y177C). To investigate the mechanism behind ADAMTS13 deficiency in this patient, wild type (WT), ADAMTS13 p.Y177C, and ADAMTS13 p.W884X were transiently expressed in 293-6E cells. Expression studies revealed a significant reduction in enzyme activity and secretion, although the protease was detected within the cells. The 3D structures of the natural and mutated ADAMTS-13 proteins were partially reconstructed using the Phyre2 web server. The mutation that replaces the tyrosine residue at amino acid position 177 with cysteine may result in decreased steric hindrance and a looser structure. This mutation affects the binding of calcium ions and the secretion of the enzyme from intracellular to extracellular compartments.
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Púrpura Trombocitopénica Trombótica , Humanos , Masculino , Proteínas ADAM/genética , Proteínas ADAM/metabolismo , Proteína ADAMTS13/genética , Codón sin Sentido , MutaciónRESUMEN
OBJECTIVE: As first-line treatments for newly diagnosed adult immune thrombocytopenia (ITP), high-dose dexamethasone (HD-DXM) and conventional-dose prednisone achieve good initial responses, but their long-term efficacy is poor. To improve the long-term outcome of newly diagnosed ITP, we explored the efficacy and safety of HD-DXM with sequential prednisone maintenance therapy. METHODS: This retrospective study in a real-world setting assessed 72 consecutive newly diagnosed ITP patients administered first-line HD-DXM with sequential prednisone maintenance therapy from 1 June 2016 to 31 December 2019. RESULTS: Seventy patients obtained response (97.2%), and 55 achieved sustained response (SR) (76.4%). Fifty-three obtained complete remission (CR) (73.6%), and 39 achieved continuous CR at 6 months (54.2%). Among 36 anti-nuclear antibody-positive patients, 100% achieved response, and 28 achieved CR (77.8%). Among 24 antithyroid antibody-positive patients, 23 (95.8%) achieved response, and 20 achieved CR (83.3%). For patients with initial response, the 12-month probability of SR was 78.6%. For patients with initial CR, the 12-month probability of continuous CR was 64.2%. At 12 months, 21.4% of patients with initial response and 11.3% of patients with initial CR showed loss of treatment response. CONCLUSIONS: HD-DXM with sequential prednisone as the first-line treatment for newly diagnosed ITP patients may achieve good clinical efficacy.
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Púrpura Trombocitopénica Idiopática , Adulto , Dexametasona/uso terapéutico , Humanos , Prednisona/uso terapéutico , Púrpura Trombocitopénica Idiopática/diagnóstico , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Primary immune thrombocytopenia (ITP) is defined as an acquired autoimmune disease characterized by isolated thrombocytopenia. This work is to further clarify the relationship between T cell immune dysfunction and the pathogenesis of ITP. METHODS: 37 adult patients with ITP were selected and were classified into newly diagnosed ITP (nITP, n = 13), persistent ITP (pITP, n = 6) and chronic ITP (cITP n = 18). The frequency of cytotoxic T lymphocytes (Tc1, Tc2, and Tc17) and helper T cells (Th1, Th2, and Th17), Tregs, and the expression of chemokine receptors and PD-1 on CD4+ T cells were investigated by flow cytometry. Plasma levels of T cell-related cytokines (IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ, IL-17) were measured by cytometric beads array (CBA). RESULTS: The percentage of Tc1 in cITP was greatly higher than nITP and healthy controls (p < 0.05, p < 0.01). The percentage of Treg in nITP and cITP groups was remarkably lower than those in healthy control group (p < 0.05, p < 0.001); and according to platelet count analysis (PLT<50x109/L or PLT>50x109/L), Treg cells in ITP group were significantly lower than those in healthy control group (p < 0.001, p < 0.05). The percentage of CD4+CXCR3+ of cITP was significantly higher than healthy controls and nITP (p < 0.01, p < 0.05). The percentage of CD4+CCR6+ in cITP was significantly higher than healthy controls and nITP (p < 0.001, p < 0.05). The expression of PD-1 in cITP patients was higher than healthy control (p < 0.05), but there was no significant difference among nITP, pITP and cITP (p = 0.25). The levels of IL-2, IFN-γ and TNFα in nITP group and cITP group were significantly higher than those in healthy control group (p < 0.01, p < 0.05; p < 0.01, p < 0.05; p < 0.05, p < 0.05), and the level of IL-10 in nITP group was significantly higher than that in pITP group (p < 0.05). CONCLUSION: Our results suggest that T lymphocyte immune dysfunction does exist in adult ITP patients and plays an important role in the pathogenesis of ITP.
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Antineoplásicos/uso terapéutico , Leucemia Promielocítica Aguda/tratamiento farmacológico , Tretinoina/uso terapéutico , Adolescente , Adulto , Anciano , Antineoplásicos/administración & dosificación , Niño , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Quimioterapia de Inducción , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Tretinoina/administración & dosificación , Adulto JovenRESUMEN
Intracranial myeloid sarcoma is a very rare disease with poor prognosis. We report a case of a 28-year-old male patient who was admitted with intense headache, vision disturbance and severe vomiting in June 2017. He had a history of neurosurgical tumor resection operation in April 2017, and the pathological diagnosis was intracranial myeloid sarcoma. Bone marrow aspirate and biopsy had been conducted in May 2017, which demonstrated 5.5% blasts expressing CD13, CD33, CD34, CD117 and MPO, and the cytogenetic analysis demonstrated t(8;21)(q22;q22), and molecular studies showed a positive RUNX1-RUNX1T1 rearrangement. The diagnosis of acute myeloid leukemia (AML) with t (8; 21) (q22; q22)/RUNX1-RUNX1T1 was made, however, the patient refused to receive any systemic chemotherapy. Emergency cranial CT demonstrated a circular hyperdense mass (54mm×37mm), which was surrounded by hypodense peritumoral edema in the left cerebellar hemisphere, and the density of the lesions was uniform and the margin was clear. Idarubicin (12mg/m2·d×3 days) combined with high-dose cytarabine (2g/m2 q12h×3 days) was initiated for emergency chemotherapy. All of the above symptoms disappeared at the end of chemotherapy. On the first day after chemotherapy, the cranial CT indicated that the cranial lesion was markedly reduced (20mm×15mm), and on the sixth day after chemotherapy, the lesion was completely disappeared. Currently, there are no clear guidelines for the treatment of intracranial myeloid sarcoma, and our treatment approaches could provide a reference for this disease with such emergency situation.
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BACKGROUND: Hyperleukocytic acute myeloid leukemia (AML) (initial white blood cell count ≥ 100 × 109/L) is a clinical emergency often accompanied by leukostasis syndrome, tumor lysis syndrome (TLS), and disseminated intravascular coagulation (DIC), with a poor clinical prognosis. The aim of this study retrospectively analyzed the clinical features of hyperleukocytic AML, focusing on high-risk factors affecting prognosis, the selection of initial induction therapy, and the impact of hematopoietic stem cell transplantation (HSCT) on prognosis. PATIENTS AND METHODS: A total of 558 AML patients at our center from January 2013 to December 2017 were diagnosed, and 52 (9.32%) patients presented with hyperleukocytosis were retrospectively reviewed. RESULTS: The 3-year overall survival (OS) rate in the 15-39 years old and 40-60 years old group was 58.8% and 25.4%, respectively; the longest survival time in patients aged >60 years was only 8 months, and the 8-month OS rate was 8.3% (p=0.002). The 3-year OS rate of the patients in the favorable risk group, intermediate risk group and high risk group, according to the 2017 ELN risk stratification, was 50%, 28.0%, and 29.5%, respectively (p=0.374). The 3-year OS rate of patients carrying CEBPA or NPM1 mutation and those with FLT3-ITD or MLL mutation was 37.5% and 30.0%, respectively (p=0.63). The 3-year OS rate of patients employing an induction regimen of a standard IA regimen was 58.4%, and of those employing a non-standard IA regimen was 22.2% (p=0.065). The 3-year OS rate of the transplantation patients reached 73.8%, while the 9-month OS rate of patients without transplantation was 11.4% (p<0.001). CONCLUSION: This study suggest that hyperleukocytosis is an independent risk factor for AML patients, regardless of the risk stratification based on cytogenetic or molecular abnormalities. Age is the main factor influencing the prognosis of hyperleukocytic AML. The use of a standard IA regimen and HSCT can significantly improve the patient's prognosis.
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BACKGROUND: Extensively drug-resistant Gram-negative bacterial (XDR-GNB) bloodstream infection (BSI) is difficult to treat and is associated with a high mortality rate in patients with hematological diseases. The aim of this study is to investigate the predisposing risk factors and the efficacy of the antibiotic treatment in these patients, including exploration of efficacy and adverse effects of high-dose tigecycline. METHODS: Between January 2013 and December 2017, 27 XDR-GNB BSI patients with hematological diseases were diagnosed and retrospectively reviewed in the current study. RESULTS: Clinical response in patients with severe complications (such as severe neutropenia >10 days, grade III-IV acute graft-versus-host disease (aGVHD), and concurrent pneumonia) was significantly lower than in patients without or with only mild complications (P=0.033). The efficacy rate was 62.5% (10/16) in patients with tigecycline-based combination therapy regimen, 77.8% (7/9) with a high-dose tigecycline regimen, and 42.9% (3/7) with a standard-dose tigecycline regimen (P=0.36). The 30-day survival rates of patients undergoing high-dose or standard-dose tigecycline treatment were 66.7% (95% CI: 28.2-87.8) and 57.1% (95% CI: 17.2-83.7), respectively, (P=0.603). Patients with mild complications were associated with superior 30-day survival rates than patients with severe complications (93.8% vs 36.4%, P=0.001), >10 days of neutropenia (90.9% vs 33.3%, P=0.012), severe aGVHD (100% vs 40%, P=0.049), and concurrent pneumonia (84.6% vs 57.1%, P=0.048). CONCLUSION: Our study indicated that XDR-GNB BSI in patients of hematological diseases with severe complications, such as long duration of neutropenia (>10 days) and severe aGVHD were associated with poor clinical response and short survival. We first indicated that these patients undergoing high-dose tigecycline treatment had an improved clinical response and an increased 30-day survival rate compared with the standard-dose group, although the differences were not statistically significant. This might be due to more severe complicated patients enrolled in high-dose group and the limited number size in our study.