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Background: T lymphocytes in tumor microenvironment play a pivotal role in the anti-tumor immunity, and the memory of T cells contributes to the long-term protection against tumor antigens. Compared to solid tumors, studies focusing on the T-cell differentiation in the acute myeloid leukemia (AML) bone marrow (BM) microenvironment remain limited. Patients and methods: Fresh BM specimens collected from 103 adult AML patients at diagnosis and 12 healthy donors (HDs) were tested T-cell differentiation subsets by multi-parameter flow cytometry. Results: CD4 and CD8 T-cell compartments had different constituted profiles of T-cell differentiated subsets, which was similar between AML patients and HDs. Compared to HDs, AML patients as a whole had a significantly higher proportion of CD8 effector T cells (Teff, P = 0.048). Moreover, the T-cell compartment of AML patients with no DNMT3A mutations skewed toward terminal differentiation at the expense of memory T cells (CD4 Teff: P = 0.034; CD8 Teff: P = 0.030; CD8 memory T: P = 0.017), whereas those with mutated DNMT3A had a decrease in CD8 naïve T (Tn) and CD4 effector memory T cells (Tem) as well as an increase in CD4 central memory T cells (Tcm) (P = 0.037, 0.053 and 0.053). Adverse ELN genetic risk correlated with a lower proportion of CD8 Tn. In addition, the low proportions of CD4 Tem and CD8 Tn independently predicted poorer relapse-free survival (RFS, HR [95%CI]: 5.7 (1.4-22.2), P = 0.017 and 4.8 [1.3-17.4], P = 0.013) and event-free survival (EFS, HR [95% CI]: 3.3 (1.1-9.5), P = 0.029; 4.0 (1.4-11.5), P = 0.010), respectively. Conclusions: AML patients had abnormal profiles of BM T-cell differentiation subsets at diagnosis, which was related to DNMT3A mutations. The low proportions of CD4 Tem and CD8 Tn predicted poor outcomes.
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Diferenciação Celular , Leucemia Mieloide Aguda , Subpopulações de Linfócitos T , Humanos , Leucemia Mieloide Aguda/imunologia , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/mortalidade , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Diferenciação Celular/imunologia , Prognóstico , Idoso , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Adulto Jovem , Linfócitos T CD8-Positivos/imunologia , Mutação , Microambiente Tumoral/imunologia , Células T de Memória/imunologia , Linfócitos T CD4-Positivos/imunologia , DNA Metiltransferase 3A , Idoso de 80 Anos ou mais , AdolescenteRESUMO
INTRODUCTION: Central nervous system leukemia (CNSL) remains a serious complication in patients with acute myeloid leukemia (AML) and an ambiguous prognostic factor for those receiving allo-geneic hematopoiesis stem cell transplantation (allo-HSCT). It is unknown whether using more sensitive tools, such as multiparameter flow cytometry (MFC), to detect blasts in the cerebrospinal fluid (CSF) would have an impact on outcome. METHODS: We retrospectively analyzed the clinical outcomes of 1472 AML patients with or without cytology or MFC positivity in the CSF before transplantation. Abnormal CSF (CSF+) was detected via conventional cytology and MFC in 44 patients at any time after diagnosis. A control group of 175 CSF-normal (CSF-) patients was generated via propensity score matching (PSM) analyses according to sex, age at transplant, and white blood cell count at diagnosis. RESULTS: Compared to those in the CSF-negative group, the conventional cytology positive and MFC+ groups had comparable 8-year nonrelapse mortality (NRM) (4%, 4%, and 6%, p = 0.82), higher cumulative incidence of relapse (CIR) (14%, 31%, and 32%, p = 0.007), lower leukemia-free survival (LFS) (79%, 63%, and 64%, p = 0.024), and overall survival (OS) (83%, 63%, and 68%, p = 0.021), with no significant differences between the conventional cytology positive and MFC+ groups. Furthermore, multivariate analysis confirmed that CSF involvement was an independent factor affecting OS and LFS. CONCLUSION: Our results indicate that pretransplant CSF abnormalities are adverse factors independently affecting OS and LFS after allotransplantation in AML patients.
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Citometria de Fluxo , Transplante de Células-Tronco Hematopoéticas , Leucemia Mieloide Aguda , Transplante Homólogo , Humanos , Feminino , Masculino , Leucemia Mieloide Aguda/terapia , Leucemia Mieloide Aguda/líquido cefalorraquidiano , Leucemia Mieloide Aguda/mortalidade , Estudos Retrospectivos , Adulto , Prognóstico , Pessoa de Meia-Idade , Seguimentos , Adolescente , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Taxa de Sobrevida , Adulto Jovem , Doença Enxerto-Hospedeiro/etiologia , Doença Enxerto-Hospedeiro/líquido cefalorraquidiano , Doença Enxerto-Hospedeiro/diagnóstico , Doença Enxerto-Hospedeiro/mortalidade , Idoso , Criança , CitologiaRESUMO
Background: Impact of B-cell depletion following treatment with Bruton tyrosine kinase-inhibitors (BTKi) on the outcome of SARS-CoV-2 infection in chronic lymphocytic leukemia (CLL) patients remain controversial. We investigated the impact of BTKi on susceptibility and the severity of COVID-19 in Chinese patients with CLL during the first wave of COVID-19 (Omicron variant). Methods: CLL patients (n=171) visiting the Institute of Hematology, Peoples' Hospital, China (November 15, 2022- January 20, 2023) were included in the study. Seventeen patients receiving BTKi and venetoclax with or without obinutuzumab were excluded. Data from 117 patients receiving treatment with BTKi were collected using a standardized questionnaire through telephone interviews. Thirty-four patients without CLL-specific treatment served as controls. The data was analysed using IBM SPSS Software version 21 and a P value of <0.05 was considered statistically significant. Results: The median age of patients was 67 years and majority were males (n=100). Treatment with BTKi was not associated with higher incidence of COVID-19 (74% [95% Confidence Interval (CI) 60%, 92%]) versus 74% (CI 48%, 100%) without any treatment (P=0.92). Hypoxemia was reported by 45% (32%, 61%) and 16% (4%, 41%) (P=0.01). BTKi was the only independent risk factor of hypoxemia (Hazard Ratio [HR], 4.22 [1.32, 13.50]; P = 0.02). Five (5.7%) patients with COVID-19 under BTKi required ICU admission; 4 of them died. No ICU admissions/deaths were observed in the control group. Conclusion: In Chinese patients with CLL and treated with BTKi experienced more severe lung disease and ICU admissions due to COVID-19 than patients without CLL therapy. Frequency of infections with SARS-CoV-2, however, was not different in patients with or without BTKi treatment.
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The treatment of primary central nervous system tumors is challenging due to the blood-brain barrier and complex mutational profiles, which is associated with low survival rates. However, recent studies have identified common mutations in gliomas [isocitrate dehydrogenase (IDH)-wild-type and mutant, WHO grades II-IV; with grade IV tumors referred to as glioblastomas (GBM)]. These mutations drive epigenetic changes, leading to promoter methylation at the nicotinic acid phosphoribosyl transferase (NAPRT) gene locus, which encodes an enzyme involved in generating NAD+. Importantly, NAPRT silencing introduces a therapeutic vulnerability to inhibitors targeting another NAD+ biogenesis enzyme, nicotinamide phosphoribosyl transferase (NAMPT), rationalizing a treatment for these malignancies. Multiple systemically administered NAMPT inhibitors (NAMPTi) have been developed and tested in clinical trials, but dose-limiting toxicities-including bone marrow suppression and retinal toxicity-have limited their efficacy. Here, we report a novel approach for the treatment of NAPRT-silenced GBMs using nanoparticle (NP)-encapsulated NAMPTis administered by convection-enhanced delivery (CED). We demonstrate that GMX1778 (a NAMPTi) can be formulated in degradable polymer NPs with retention of potency for NAMPT inhibition and anticancer activity in vitro, plus sustained drug release in vitro and in vivo. Direct injection of these drugs via CED into the brain is associated with reduced retinal toxicity compared with systemic administration. Finally, we show that CED of NP-encapsulated GMX1778 to NAPRT-silenced intracranial GBM xenografts in mice exhibit significant tumor growth delay and extends survival. These data support an approach to treat gliomas harboring defects in NAD+ metabolism using CED of NP-encapsulated NAMPTis to greatly improve the therapeutic index and treatment efficacy for this class of drugs.
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Glioma , Nanopartículas , Nicotinamida Fosforribosiltransferase , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Humanos , Animais , Camundongos , Nanopartículas/química , Glioma/tratamento farmacológico , Glioma/patologia , Citocinas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Linhagem Celular Tumoral , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologiaRESUMO
This study introduces a distributed electrified heating approach that is able to innovate chemical engineering involving endothermic reactions. It enables rapid and uniform heating of gaseous reactants, facilitating efficient conversion and high product selectivity at specific equilibrium. Demonstrated in catalyst-free CH4 pyrolysis, this approach achieves stable production of H2 (530 g h-1 L reactor -1) and carbon nanotube/fibers through 100% conversion of high-throughput CH4 at 1150 °C, surpassing the results obtained from many complex metal catalysts and high-temperature technologies. Additionally, in catalytic CH4 dry reforming, the distributed electrified heating using metallic monolith with unmodified Ni/MgO catalyst washcoat showcased excellent CH4 and CO2 conversion rates, and syngas production capacity. This innovative heating approach eliminates the need for elongated reactor tubes and external furnaces, promising an energy-concentrated and ultra-compact reactor design significantly smaller than traditional industrial systems, marking a significant advance towards more sustainable and efficient chemical engineering society.
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Thrombocythemia (ET), polycythemia vera (PV), primary myelofibrosis (PMF), prefibrotic/early (pre-PMF), and overt fibrotic PMF (overt PMF) are classical Philadelphia-Negative (Ph-negative) myeloproliferative neoplasms (MPNs). Differentiating between these types based on morphology and molecular markers is challenging. This study aims to clarify the application of flow cytometry in the diagnosis and differential diagnosis of classical MPNs. This study retrospectively analyzed the immunophenotypes, clinical characteristics, and laboratory findings of 211 Ph-negative MPN patients, including ET, PV, pre-PMF, overt PMF, and 47 controls. Compared to ET and PV, PMF differed in white blood cells, hemoglobin, blast cells in the peripheral blood, abnormal karyotype, and WT1 gene expression. PMF also differed from controls in CD34+ cells, granulocyte phenotype, monocyte phenotype, percentage of plasma cells, and dendritic cells. Notably, the PMF group had a significantly lower plasma cell percentage compared with other groups. A lasso and random forest model select five variables (CD34+CD19+cells and CD34+CD38- cells on CD34+cells, CD13dim+CD11b- cells in granulocytes, CD38str+CD19+/-plasma, and CD123+HLA-DR-basophils), which identify PMF with a sensitivity and specificity of 90%. Simultaneously, a classification and regression tree model was constructed using the percentage of CD34+CD38- on CD34+ cells and platelet counts to distinguish between ET and pre-PMF, with accuracies of 94.3% and 83.9%, respectively. Flow immunophenotyping aids in diagnosing PMF and differentiating between ET and PV. It also helps distinguish pre-PMF from ET and guides treatment decisions.
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Citometria de Fluxo , Imunofenotipagem , Mielofibrose Primária , Humanos , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/patologia , Mielofibrose Primária/sangue , Mielofibrose Primária/genética , Citometria de Fluxo/métodos , Pessoa de Meia-Idade , Imunofenotipagem/métodos , Feminino , Masculino , Idoso , Adulto , Estudos Retrospectivos , Policitemia Vera/diagnóstico , Policitemia Vera/patologia , Policitemia Vera/genética , Policitemia Vera/sangue , Idoso de 80 Anos ou mais , Diagnóstico Diferencial , Algoritmo Florestas AleatóriasRESUMO
The rapid expansion of the drone industry has resulted in a substantial increase in the number of low-altitude drones, giving rise to concerns regarding collision avoidance and countermeasure strategies among these unmanned aerial vehicles. These challenges underscore the urgent need for air-to-air drone target detection. An effective target detection model must exhibit high accuracy, real-time capabilities, and a lightweight network architecture to achieve a balance between precision and speed when deployed on embedded devices. In response to these requirements, we initially curated a dataset comprising over 10,000 images of low-altitude operating drones. This dataset encompasses diverse and intricate backgrounds, significantly enhancing the model's training capacity. Subsequently, a series of enhancements were applied to the YOLOv5 algorithm to realize lightweight object detection. A novel feature extraction network, CF2-MC, streamlined the feature extraction process, while an innovative module, MG, in the feature fusion section aimed to improve detection accuracy and reduce model complexity. Concurrently, the original CIoU loss function was replaced with the EIoU loss function to further augment the model's accuracy. Experimental results demonstrate an enhancement in the accuracy of drone target detection, achieving mAP values of 95.4% on the UAVfly dataset and 82.2% on the Det-Fly dataset. Finally, real-world testing conducted on the Jetson TX2 revealed that the YOLOv5s-ngn model achieved an average inference speed of 14.5 milliseconds per image. The code utilized in this paper can be accessed via https://github.com/lucien22588/yolov5-ngn.git .
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INTRODUCTION: Immune microenvironment plays an important role in the occurrence and development of acute myeloid leukemia (AML). Studies assessing the prognostic significance of bone marrow (BM) lymphocyte subsets' frequencies at diagnosis in patients with AML were limited. METHODS: Fresh BM samples collected from 97 adult AML patients at diagnosis were tested for lymphocyte, T, CD4+ T, CD8+ T, γδT, NK, and B cell frequencies using multi-parameter flow cytometry. RESULTS: Low frequencies of lymphocytes, T, CD4+ T, and CD8+ T cells were associated with significantly lower rates of one-course complete remission (CR) (all p < 0.05). Moreover, the frequency of CD4+ T cells independently predicted one-course CR achievement (p = 0.021). Low frequencies of T and CD8+ T cells were significantly associated with lower relapse-free survival (RFS) rates (p = 0.032; 0.034), respectively, and a low frequency of CD8+ T cells was associated with a significantly lower overall survival (OS) rate (p = 0.028). Combination of frequency of CD8+ T cells and ELN risk stratification showed that patients with ELN-intermediate/adverse risk + high CD8+ T cell frequency had a similar RFS rate to those with ELN-favorable risk + high CD8+ T cell frequency and those with ELN-favorable risk + low CD8+ T cell frequency (p = 0.88; 0.76), respectively. The RFS rate of patients with ELN intermediate/adverse risk + low CD8+ T cell frequency was significantly lower than that of all aforementioned patients (p = 0.021; 0.0007; 0.028), respectively. CONCLUSION: The frequencies of BM lymphocyte subsets at diagnosis predicted clinical outcomes and could help improve risk stratification in AML.
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Medula Óssea , Leucemia Mieloide Aguda , Adulto , Humanos , Prognóstico , Linfócitos T CD8-Positivos , Leucemia Mieloide Aguda/diagnóstico , Subpopulações de Linfócitos , Microambiente TumoralRESUMO
BACKGROUND: Autism spectrum disorder (ASD) includes a range of multifactorial neurodevelopmental disabilities characterized by a variable set of neuropsychiatric symptoms. Immunological abnormalities have been considered to play important roles in the pathogenesis of ASD, but it is still unknown which abnormalities are more prominent. METHODS: A total of 105 children with ASD and 105 age and gender-matched typically developing (TD) children were recruited. An eating and mealtime behavior questionnaire, dietary habits, and the Bristol Stool Scale were investigated. The immune cell profiles in peripheral blood were analyzed by flow cytometry, and cytokines (IFN-γ, IL-8, IL-10, IL-17A, and TNF-α) in plasma were examined by Luminex assay. The obtained results were further validated using an external validation cohort including 82 children with ASD and 51 TD children. RESULTS: Compared to TD children, children with ASD had significant eating and mealtime behavioral changes and gastrointestinal symptoms characterized by increased food fussiness and emotional eating, decreased fruit and vegetable consumption, and increased stool astriction. The proportion of γδT cells was significantly higher in children with ASD than TD children (ß: 0.156; 95% CI: 0.888 â¼ 2.135, p < 0.001) even after adjusting for gender, eating and mealtime behaviors, and dietary habits. In addition, the increased γδT cells were evident in all age groups (age < 48 months: ß: 0.288; 95% CI: 0.420 â¼ 4.899, p = 0.020; age ≥ 48 months: ß: 0.458; 95% CI: 0.694 â¼ 9.352, p = 0.024), as well as in boys (ß: 0.174; 95% CI: 0.834 â¼ 2.625, p < 0.001) but not in girls. These findings were also confirmed by an external validation cohort. Furthermore, IL-17, but not IFN-γ, secretion by the circulating γδT cells was increased in ASD children. Machine learning revealed that the area under the curve in nomogram plots for increased γδT cells combined with eating behavior/dietary factors was 0.905, which held true in both boys and girls and in all the age groups of ASD children. The decision curves showed that children can receive significantly higher diagnostic benefit within the threshold probability range from 0 to 1.0 in the nomogram model. CONCLUSIONS: Children with ASD present with divergent eating and mealtime behaviors and dietary habits as well as gastrointestinal symptoms. In peripheral blood, γδT cells but not αßT cells are associated with ASD. The increased γδT cells combined with eating and mealtime behavior/dietary factors have a high value for assisting in the diagnosis of ASD.
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Transtorno do Espectro Autista , Masculino , Feminino , Humanos , Criança , Pré-Escolar , Inquéritos e Questionários , CitocinasRESUMO
Glioblastoma (GBM) is one of the most lethal malignancies with poor survival and high recurrence rates. Here, we aimed to simultaneously target oncomiRs 10b and 21, reported to drive GBM progression and invasiveness. We designed short (8-mer) γ-modified peptide nucleic acids (sγPNAs), targeting the seed region of oncomiRs 10b and 21. We entrapped these anti-miR sγPNAs in nanoparticles (NPs) formed from a block copolymer of poly(lactic acid) and hyperbranched polyglycerol (PLA-HPG). The surface of the NPs was functionalized with aldehydes to produce bioadhesive NPs (BNPs) with superior transfection efficiency and tropism for tumor cells. When combined with temozolomide, sγPNA BNPs administered via convection-enhanced delivery (CED) markedly increased the survival (>120 days) of two orthotopic (intracranial) mouse models of GBM. Hence, we established that BNPs loaded with anti-seed sγPNAs targeting multiple oncomiRs are a promising approach to improve the treatment of GBM, with a potential to personalize treatment based on tumor-specific oncomiRs.
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Neoplasias Encefálicas , Glioblastoma , Nanopartículas , Ácidos Nucleicos Peptídicos , Camundongos , Animais , Ácidos Nucleicos Peptídicos/farmacologia , Encéfalo/patologia , Glioblastoma/patologia , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Temozolomida , Linhagem Celular TumoralRESUMO
Tremendous progress has been made in the field of nanomedicine for cancer treatment. However, most of the research to date has been focused on inhibiting primary tumor growth with comparatively less efforts directed towards managing tumor metastasis. Here, we introduce a polymeric conjugate P-DOX-iRGD that not only significantly suppressed primary tumor growth but also substantially inhibited pulmonary metastasis in an orthotopic mouse model of breast cancer. In addition, treatment with P-DOX-iRGD markedly reduced breast cancer-induced splenomegaly and liver hematopoiesis. Interestingly, contrasting results were seen for the free form and polymeric form of DOX in vitro and in vivo, which may be attributed to the enhanced permeability and retention (EPR) effect.
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Background: Acute myeloid leukemia (AML) with t(8;21) needs to be further stratified. In addition to leukemia cells, immune cells in tumor microenvironment participate in tumor initiation, growth and progression. Interleukins (ILs)/interleukin receptors (ILRs) interaction plays important roles in the antitumor immune response. IL7R is reported to be relevant to prognosis in solid tumor and acute lymphoblastic leukemia. However, the prognostic significance of IL7R in t(8;21) AML remains to be clarified. Methods: Bone marrows collected from 156 newly diagnosed t(8;21) AML patients were used for testing IL7R transcript level by TaqMan-based real-time quantitative PCR (RQ-PCR), and RNAseq were performed in 15 of them. Moreover, IL7R expression at diagnosis were measured by RQ-PCR and flow cytometry (FCM) simultaneously in other 13 t(8;21) AML patients. Results: t(8;21) AML patients had varied IL7R transcript levels and were categorized into low-expression (IL7R-L) and high-expression (IL7R-H) groups; IL7R-L was significantly associated with a lower relapse-free survival (RFS) rate (P=0.0027) and KITD816/D820 mutation (P=0.0010). Furthermore, IL7R-L was associated with a lower RFS rate in KITD816/D820 group (P=0.013) and IL7R-H/KITD816/D820 patients had similar RFS to KITN822/e8/WT patients (P=0.35). GO analysis enrichment showed that down-regulated genes were predominantly involved in the regulation of T cell and leukocyte activation, proliferation and differentiation in IL7R-L group. IL7R-L had significantly lower levels of Granzymes A/B, CCR7, CD28 and CD27 than IL7R-H group (all P<0.05). FCM analysis showed IL7R protein was primarily expressed in CD4+ T and CD8+ T cell subset. A significant association was found between the transcript level of IL7R and the percentage of CD8+ T cells in nucleated cells (P=0.015) but not CD4+ T cells (P=0.47). Conclusion: Low IL7R transcript level of bone marrow at diagnosis predicted relapse in t(8;21) AML, which might be caused by the difference in the amount, status and function of T cells.
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Antígenos CD/genética , Antígenos de Diferenciação Mielomonocítica/genética , Linfócitos T CD8-Positivos , Leucemia Mieloide Aguda , Adulto , Linfócitos T CD8-Positivos/metabolismo , Humanos , Subunidade alfa de Receptor de Interleucina-7/genética , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Mutação , Prognóstico , Regiões Promotoras Genéticas , Recidiva , Microambiente TumoralRESUMO
BACKGROUND: ZNF384 rearrangement has been recently identified as a new subtype of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, comprehensive studies clarifying immunophenotypic features and discriminating them from non-ZNF384 in adult BCP-ALL remain scarce to date. METHODS: Flow cytometric assessments were retrospectively performed in 43 patients with ZNF384 rearrangement, 45 with BCR-ABL1, 29 with KMT2A rearrangement and 44 with other BCP-ALL in the analysis cohort. RESULTS: CD33- and CD13-positive frequencies were significantly higher in patients with ZNF384 rearrangement than in those with non-ZNF384; however, no significant difference was observed in CD10- and CD123-positive frequencies. Analysis of antigen-positive cell proportion and median fluorescence intensity (MFI) further indicated that patients with ZNF384 rearrangement had significantly lower CD10 and higher CD33, CD13, and CD123 proportion and MFI. However, compared with KMT2A rearrangement, the CD10 expression in patients with ZNF384 rearrangement was higher, with the median percentage and MFI of 36.16 (3.63-94.79)% versus 4.53 (0.03-21.00)%, and 4.50 (0.86-32.26) versus 2.06 (0.87-4.04), respectively (p < 0.0001). Furthermore, compared with BCR-ABL1 and other BCP-ALL, ZNF384 rearrangement had significantly higher CD33 and CD13 proportion and MFI (p < 0.0001 and p < 0.05, respectively). In addition, higher CD123 proportion and MFI in ZNF384 rearrangement than those in the other three groups were reported for the first time (p < 0.01). A flow cytometry scoring system, including CD10%, CD33MFI, CD13%, and CD123MFI, was proposed and verified to predict ZNF384 rearrangement with high sensitivity and specificity, that is, 76.74% and 91.53% in the analysis and 87.50% and 91.30% in the validation cohort. CONCLUSIONS: The multiparameter immunophenotypic scoring system could suggest ZNF384 rearrangement.
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Linfoma de Burkitt , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Aberrações Cromossômicas , Citometria de Fluxo , Humanos , Imunofenotipagem , Subunidade alfa de Receptor de Interleucina-3 , Neprilisina , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Estudos Retrospectivos , Transativadores/genética , Transativadores/metabolismo , Fatores de Transcrição/genéticaRESUMO
BACKGROUND: Poor graft function (PGF) or prolonged isolated thrombocytopenia (PT), which are characterized by pancytopenia or thrombocytopenia, have become serious complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our previous single-arm trial suggests that N-acetyl-L-cysteine (NAC) prophylaxis reduced PGF or PT after allo-HSCT. Therefore, an open-label, randomized, phase 3 trial was performed to investigate the efficacy and tolerability of NAC prophylaxis to reduce PGF or PT after allo-HSCT. METHODS: A phase 3, open-label randomized trial was performed. Based on the percentage of CD34+VEGFR2 (CD309)+ endothelial cells (ECs) in bone marrow (BM) detected by flow cytometry at 14 days before conditioning, patients aged 15 to 60 years with acute leukemia undergoing haploidentical HSCT were categorized as low-risk (EC ≥ 0.1%) or high-risk (EC < 0.1%); patients at high risk were randomly assigned (2:1) to receive NAC prophylaxis or nonprophylaxis. The primary endpoint was PGF and PT incidence at +60 days post-HSCT. RESULTS: Between April 18, 2019, and June 24, 2021, 120 patients with BM EC <0.1% were randomly assigned for NAC (group A, N = 80) or nonprophylaxis (group B, N = 40), and 105 patients with EC≥0.1% (group C) were also analyzed. The +60 days incidence of PGF and PT was 7.5% (95% CI, 1.7 to 13.3%) and 22.5% (95% CI, 9.1 to 35.9%) in group A and group B (hazard ratio, 0.317; 95% CI, 0.113 to 0.890; P = 0.021) and 11.4% (95% CI, 5.2 to 17.6%) in group C (hazard ratio, 0.643; 95% CI, 0.242 to 1.715; P = 0.373). Consistently, NAC prophylaxis gradually improved BM ECs and CD34+ cells in group A, whereas reduced their reactive oxygen species (ROS) levels post-HSCT. Within 60 days post-HSCT, the most common grade 3 to 5 adverse events for the NAC and control groups were infections (19/80 [24%] vs. 10/40 [25%]) and gastrointestinal adverse events (16/80 [20%] vs. 7/40 [18%]). There were no treatment-related deaths. CONCLUSIONS: N-Acetyl-L-cysteine prophylaxis can prevent the occurrence of poor hematopoietic function and is well tolerated in haploidentical HSCT. It may offer a potential pathogenesis-oriented therapeutic approach for patients with poor hematopoietic function. TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov as #NCT03967665.
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Transplante de Células-Tronco Hematopoéticas , Trombocitopenia , Humanos , Acetilcisteína/uso terapêutico , Células Endoteliais , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Trombocitopenia/etiologiaRESUMO
Acute myeloid leukemia (AML) with t(8;21) is a heterogeneous disease and needs to be stratified. Both, cancer cells and immune cells participate in tumor initiation, growth and progression and might affect clinical outcomes. TIM-3 (T cell immunoglobulin and mucin domain-containing protein 3), an immune checkpoint molecule, is expressed not only on immune cells but also on leukemic stem cells (LSCs) in AML. This prompted us to investigate the prognostic significance of TIM-3 in t(8;21) AML. A total of 47 t(8;21) AML patients were tested for TIM-3 expression by multi-parameter flow cytometry at diagnosis. 35 of these, who received chemotherapy alone or along with allogeneic hematopoietic stem cell transplantation were followed up. The expression pattern of TIM-3 on T-cells and NK (natural killer) cells as a whole (T + NK) and LSCs were evaluated independently. High percentage of T + NK - TIM-3+ and CD34+CD38-TIM-3+ cells were significantly associated with a high 2-year cumulative incidence of relapse (CIR) (p = 0.028, 0.016). Further, concurrent high frequencies of T + NK-TIM-3+ and CD34+CD38-TIM-3+ cells at diagnosis were significantly associated with a high 2-year CIR (p < 0.0001) and this together with c-KIT D816 mutation were the independent adverse prognostic factors for relapse (hazard ratio (HR)=2.5, [95% confidence interval (CI), 1.1-6.0], p = 0.04; HR = 46.5, [95% CI, 2.7-811.5], p = 0.009). In conclusion, the expression pattern of TIM-3 on both T and NK cells and LSCs at diagnosis had prognostic significance in t (8;21) AML.
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Receptor Celular 2 do Vírus da Hepatite A , Leucemia Mieloide Aguda , Antígenos CD34/metabolismo , Citometria de Fluxo , Receptor Celular 2 do Vírus da Hepatite A/genética , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Receptor Celular 2 do Vírus da Hepatite A/uso terapêutico , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/terapia , Células-Tronco Neoplásicas/metabolismo , PrognósticoRESUMO
Elderly individuals exhibit unbalanced bone marrow (BM) effector T cell subset differentiation, such as increased T helper type 1 (Th1) and T cytotoxic type 1 (Tc1) cell frequencies, but the underlying mechanism is still unclear. Endothelial cells (ECs), which are instructive components of the BM microenvironment, exhibit the phenotype of semi-professional antigen-presenting cells and regulate T cell recruitment and activation. Thus, we compared the frequency and function of BM ECs, especially their capacity to regulate effector T cell subsets, between young and elderly healthy individuals, and explored the underlying mechanism of this immunomodulatory discrepancy. Although the young and elderly EC percentages were comparable, young ECs showed fewer reactive oxygen species and better migratory and tube-forming abilities than elderly ECs. Notably, increased T cell activation molecules and inflammatory cytokines were found in elderly ECs which regulated T cells to differentiate into more proinflammatory T cells, including Th1 and Tc1 cells, than young ECs.
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Células da Medula Óssea/imunologia , Diferenciação Celular/imunologia , Células Endoteliais/imunologia , Linfócitos T Citotóxicos/imunologia , Células Th1/imunologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Achieving high spinning speed is critical to the production efficiency and viable application of fiber species. Graphene fiber (GF) has recently emerged as a carbonaceous fiber with excellent functionality. However, the extremely low wet spinning speed of GF has limited its applications. We realized high-speed blow spinning of neat GF and fabric by modulating the rheological properties of the graphene oxide (GO) dispersion. We achieved a speed of 556 m min-1, 2 orders of magnitude faster than that for wet spinning. We chose ultrahigh molecular weight polymers as transient additives to circumvent the intrinsic barrier effect of GO and achieve high spinning dope stretchability at low polymer percentages-down to 25 wt %. Minimizing the polymer additive content ensures the high electrical/thermal conductivity of the blow-spun fiber and fabric. This work provides insight into the unique flow properties of 2D sheets and will promote the efficient production of graphene-based fibrous materials.
Assuntos
Grafite , Polímeros , TêxteisRESUMO
We performed a retrospective analysis to investigate dynamic peri-hematopoietic stem cell transplantation (HSCT) minimal/measurable residual disease (MRD) on outcomes in patients with T-cell acute lymphoblastic leukemia (T-ALL). A total of 271 patients were enrolled and classified into three groups: unchanged negative MRD pre- and post-HSCT group (group A), post-MRD non-increase group (group B), and post-MRD increase group (group C). The patients in group B and group C experienced a higher cumulative incidence of relapse (CIR) (42% vs. 71% vs. 16%, P<0.001) and lower leukemia-free survival (LFS) (46% vs. 21% vs. 70%, P<0.001) and overall survival (OS) (50% vs. 28% vs. 72%, P<0.001) than in group A, but there was no significant difference in non-relapse mortality (NRM) among three groups (14% vs. 12% vs. 8%, P=0.752). Multivariate analysis showed that dynamic peri-HSCT MRD was associated with CIR (HR=2.392, 95% CI, 1.816-3.151, P<0.001), LFS (HR=1.964, 95% CI, 1.546-2.496, P<0.001) and OS (HR=1.731, 95% CI, 1.348-2.222, P<0.001). We also established a risk scoring system based on dynamic peri-HSCT MRD combined with remission status pre-HSCT and onset of chronic graft-versus-host disease (GVHD). This risk scoring system could better distinguish CIR (c=0.730) than that for pre-HSCT MRD (c=0.562), post-HSCT MRD (c=0.616) and pre- and post-MRD dynamics (c=0.648). Our results confirm the outcome predictive value of dynamic peri-HSCT MRD either alone or in combination with other variables for patients with T-ALL.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Neoplasia Residual/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Linfócitos T/metabolismo , Adolescente , Adulto , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Citometria de Fluxo , Fator Estimulador de Colônias de Granulócitos/genética , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasia Residual/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Prognóstico , Recidiva , Linfócitos T/patologia , Adulto JovemRESUMO
SETD2 encodes an important protein for epigenetic modification of histones which plays an essential role in early development. Variants in SETD2 have been reported in neurodevelopmental disorders including autism spectrum disorder (ASD). However, most de novo SETD2 variants were reported in different large-cohort sequencing studies, mutation pattern and comprehensive genotype-phenotype correlations for SETD2 are still lacking. We have applied target sequencing to identify rare, clinical-relevant SETD2 variants and detected two novel de novo SETD2 variants, including a de novo splicing variant (NM_014159: c.4715+1G>A) and a de novo missense variant (c.3185C>T: p.P1062L) in two individuals with a diagnosis of ASD. To analyze the correlations between SETD2 mutations and corresponding phenotypes, we systematically review the reported individuals with de novo SETD2 variants, classify the pathogenicity, and analyze the detailed phenotypes. We subsequently manually curate 17 SETD2 de novo variants in 17 individuals from published literature. Individuals with de novo SETD2 variants present common phenotypes including speech and motor delay, intellectual disability, macrocephaly, ASD, overgrowth and recurrent otitis media. Our study reveals new SETD2 mutations and provided a relatively homozygous phenotype spectrum of SETD2-related neurodevelopmental disorders which will be beneficial for disease classification and diagnosis in clinical practice.
Assuntos
Histona-Lisina N-Metiltransferase/genética , Mutação , Transtornos do Neurodesenvolvimento/genética , Fenótipo , Pré-Escolar , Feminino , Humanos , Masculino , Transtornos do Neurodesenvolvimento/patologia , Splicing de RNARESUMO
OBJECTIVE: To investigate the predict significance of the high aldehyde dehydrogenase activity (ALDH+) propitiation to the relapse of t(8;21) acute myeloid leukemia(AML) patients before and after treatment. METHODS: Bone marrow samples of 23 t(8;21) AML patients diagnosis and achieved complete remission in our hospital from April 2015 to June 2016 were collected, then flow cytometry method was used to detect the activity of ALDH, relationship between it and relapse was analyzed. RESULTS: All the patients were followed up for a median of 32 (2-52) months. The median percentage of CD34+CD38- and CD34+CD38-ALDH+ cells among nucleated cells were 2.7 (0.36-35.7)% and 0.017 (0.0013-0.62)% at diagnosis, respectively. Among the bone marrow samples in patients achieved CR, the median percentage of CD34+CD38- cells was 0.035 (0.0064-0.66)%, and it was significantly decreased as compared with the percentage at diagnosis (P<0.001); The median percentage of CD34+CD38-ALDH+ cells was 0.014 (0.0019-0.24)%, and it showed no different as compared with the percentage at diagnosis (P=0.45). Survival analysis showed that patients with higher percentage of CD34+CD38- and CD34+CD38-ALDH+ cells at diagnosis tended to the lower 3-year relapse-free survival (RFS) (P=0.27 and 0.21). Furthermore, patients with higher percentage of CD34+CD38- and CD34+CD38-ALDH+ cells when achieved CR had a significant lower 3-year RFS rates (P=0.010 and 0.0044) as compared with those with lower percentage of CD34+CD38- and CD34+CD38-ALDH+ cells. Multivariate analysis showed that higher percentage of CD34+CD38-ALDH+ cells when achieved CR was an independent factor affecting RFS of the patients. CONCLUSION: The percentage of CD34+CD38-ALDH+ cells at CR in t(8;21) AML patients could predicts relapse, and had more profound predictive significance for relapse than the percentage of CD34+CD38- cells.