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The biological neural network is a highly efficient in-memory computing system that integrates memory and logical computing functions within synapses. Moreover, reconfiguration by environmental chemical signals endows biological neural networks with dynamic multifunctions and enhanced efficiency. Nanofluidic memristors have emerged as promising candidates for mimicking synaptic functions, owing to their similarity to synapses in the underlying mechanisms of ion signaling in ion channels. However, realizing chemical signal-modulated logic functions in nanofluidic memristors, which is the basis for brain-like computing applications, remains unachieved. Here, we report a single-pore nanofluidic logic memristor with reconfigurable logic functions. Based on the different degrees of protonation and deprotonation of functional groups on the inner surface of the single pore, the modulation of the memristors and the reconfiguration of logic functions are realized. More noteworthy, this single-pore nanofluidic memristor can not only avoid the average effects in multipore but also act as a fundamental component in constructing complex neural networks through series and parallel circuits, which lays the groundwork for future artificial nanofluidic neural networks. The implementation of dynamic synaptic functions, modulation of logic gates by chemical signals, and diverse combinations in single-pore nanofluidic memristors opens up new possibilities for their applications in brain-inspired computing.
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BACKGROUND: Patients with relapsed or refractory acute myeloid leukemia (R/R AML) and FLT3-internal tandem duplication (FLT3-ITD) respond infrequently to salvage chemotherapy. OBJECTIVE: To investigate the efficacy of sorafenib plus triplet therapy with venetoclax, azacitidine, and homoharringtonine (VAH) as a salvage therapy in this population. METHODS: This multicenter, single-arm, phase 2 study was conducted at 12 hospitals across China. Eligible patients had R/R AML with FLT3-ITD (aged 18-65 years) who were treated with VAH. The primary endpoint was composite complete remission (CRc) after two cycles. Secondary outcomes included the overall response rate (ORR), safety, and survival. RESULTS: Between July 9, 2020, and March 19, 2022, 58 patients were assessed for eligibility, 51 of whom were enrolled. The median patient age was 47 years (interquartile range [IQR] 31-57). CRc was 76.5% with ORR of 82.4%. At a median follow-up of 17.7 months (IQR, 8.7-24.7), the median duration of CRc was not reached (NR), overall survival was 18.1 months (95% confidence interval [CI], 11.8-NR) and event-free survival was 11.4 months (95% CI, 5.6-NR). Grade 3 or 4 adverse events occurring in ≥10% of patients included neutropenia in 47 (92.2%), thrombocytopenia in 41 (80.4%), anemia in 35 (68.6%), febrile neutropenia in 29 (56.9%), pneumonia in 13 (25.5%), and sepsis in 6 (11.8%) patients. Treatment-related death occurred in two (3.9%) patients. CONCLUSIONS: The sorafenib plus VAH regimen was well tolerated and highly active against R/R AML with FLT3-ITD. This regimen may be a suitable therapeutic option for this population, but larger population trials are needed to be explored. TRIAL REGISTRATION: Clinical Trials Registry: NCT04424147.
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Azacitidina , Compostos Bicíclicos Heterocíclicos com Pontes , Leucemia Mieloide Aguda , Sulfonamidas , Humanos , Azacitidina/uso terapêutico , Tirosina Quinase 3 Semelhante a fms/genética , Tirosina Quinase 3 Semelhante a fms/uso terapêutico , Mepesuccinato de Omacetaxina/uso terapêutico , Leucemia Mieloide Aguda/terapia , Resposta Patológica Completa , Sorafenibe/efeitos adversos , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , IdosoRESUMO
The mining and smelting site soils in South China present excessive Cd pollution. However, the transport behavior of Cd in the highly weathered acidic soil layer at the lead-zinc smelting site remains unclear. Here, under different conditions of simulated infiltration, the migration behavior of Cd2+ in acid smelting site soils at different depths was examined. The remodeling effect of Cd2+ migration behavior on microbial community structure and the dominant microorganisms in lead-zinc sites soils was analyzed using high-throughput sequencing of 16S rRNA gene amplicons. The results revealed a specific flow rate in the range of 0.3-0.5 mL/min that the convection and dispersion have no obvious effect on Cd2+ migration. The variation of packing porosity could only influence the migration behavior by changing the average pore velocity, but cannot change the adsorption efficiency of soil particles. The Cd has stronger migration capacity under the reactivation of acidic seepage fluid. However, in the alkaline solution, the physical properties of soil, especially pores, intercept the Cd compounds, further affecting their migration capacity. The acid-site soil with high content of SOM, amorphous Fe oxides, crystalline Fe/Mn/Al oxides, goethite, and hematite has stronger ability to adsorb and retain Cd2+. However, higher content of kaolinite in acidic soil will increase the potential migration of Cd2+. Besides, the migration behavior of Cd2+ results in simplified soil microbial communities. Under Cd stress, Cd-tolerant genera (Bacteroides, Sphingomonas, Bradyrhizobium, and Corynebacterium) and bacteria with both acid-Cd tolerance (WCHB 1-84) were distinguished. The Ralstonia showed a high enrichment degree in alkaline Cd2+ infiltration solution (pH 10.0). Compared to the influence of Cd2+ stress, soil pH had a stronger ability to shape the microbial community in the soil during the process of Cd2+ migration.
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Microbiota , Poluentes do Solo , Solo/química , Cádmio/toxicidade , RNA Ribossômico 16S , Poluentes do Solo/toxicidade , Poluentes do Solo/análise , Zinco/análise , ÓxidosRESUMO
BACKGROUND: The heterogeneity of relapsed or refractory (R/R) acute myeloid leukemia (AML) leads to no response to venetoclax (VEN)-based therapy in more than half of the patients. Genetic characteristics are considered important predictors for response to treatment in adults with AML. However, the association of genetic characteristics with outcomes receiving VEN-based therapy is incompletely understood in R/R AML. OBJECTIVE: To evaluate the efficacy of VEN combined with hypomethylating agents (HMA) and identify the potential genetic predictors of response in R/R AML. METHODS: A total of 150 R/R AML patients treated with VEN combined with HMA were enrolled in this retrospective study. Outcomes of the response and overall survival (OS) were analyzed. The predictors of response and OS were analyzed by logistic regression or Cox proportional hazards model. RESULTS: With a median of two (range, 1-4) cycles of therapy, the overall response rate was 56.2%, including 22.0% complete remission (CR), 21.3% CR with incomplete hematologic recovery, 2.0% morphologic leukemia-free state, and 10.7% partial remission, in which 25 patients achieved measurable residual disease (MRD)-negative response. With a median follow-up of 11.2 [95% confidence interval (CI), 7.2-14.8] months, 1- and 2-year OS were 46.9% (95% CI, 37.8%-58.1%) and 38.9% (95% CI, 28.7%-52.9%), respectively. Adverse cytogenetics and European Leukemia Net (ELN) risk predicted inferior response to VEN-based therapy. Mutations in IDH1/2, NPM1, ASXL1, and chromatin-cohesin genes predicted superior response to VEN-based therapy, whereas mutations in active signaling genes such as FLT3-ITD and K/NRAS predicted inferior response. CONCLUSION: VEN combined with HMA was effective with R/R AML patients, and the response to treatment was associated with genetic characteristics.
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Compostos Bicíclicos Heterocíclicos com Pontes , Leucemia Mieloide Aguda , Adulto , Humanos , Estudos Retrospectivos , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Sulfonamidas/uso terapêutico , Sulfonamidas/efeitos adversos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Venetoclax (VEN)-based regimens are the standard of care for elderly or unfit patients with newly diagnosed (ND) acute myeloid leukemia (AML). Some single-arm studies have implied that hypomethylating agents (HMAs) plus priming regimens may potentially provide an alternative therapeutic approach, owing to encouraging efficacy seen. However, no comparative data exists yet regarding these two treatment approaches. In this retrospective multi-center cohort study, we enrolled 294 ND AML patients, allocating 167 to the HMA + priming group and 127 to the VEN-based group. Treatment response and overall survival (OS) were compared between groups. Molecular subgroup analyses were also conducted. With a median of two cycles for HMA + priming group, the overall response (ORR) was 65.3%, including 55.1% complete remission (CR), 9.6% CR with incomplete hematologic recovery (CRi) and 0.6% morphologic leukemia-free state (MLFS). With a median of two cycles for VEN-based group, the ORR was 70.9%, including 46.5% CR, 18.9% CRi, and 5.5% MLFS. Response differences (ORR or CR/CRi) between groups were not significant (p > 0.05). With a median follow-up of 10.1 months, median OSs were similar between groups (20.9 vs 16.3 months, p = 0.41). However, VEN regimens demonstrated superior CR/CRi for patients with mutations in FLT3, IDH1/2, and NPM1 compared to HMA + priming (80.0% vs 35.0%, p = 0.01; 90.9% vs 65.5%, p = 0.02; 90.9% and 65.5%, p = 0.02, respectively). In conclusion, HMAs plus modified priming regimens might be a potential alternative therapeutic approach for patients with ND AML, but VEN-based regimens presented predominance in specific molecular subgroups. Molecular characteristics contribute to guiding choice of treatment.
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Leucemia Mieloide Aguda , Humanos , Idoso , Estudos de Coortes , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Sulfonamidas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Estudos RetrospectivosRESUMO
The investigation of chemical speciation of primary toxic metal(loid)s (Cd, Pb, and As) in soil profile in nonferrous metal smelting site is a key to the assessment of their mobility characteristics and formulation of subsequent remediation strategy. In this study, 74 soil samples were collected at 12 different soil profiles; soil physio-chemical properties and total content of Cd, Pb and As and corresponding chemical speciation were also determined. The results showed that the mean total concentration followed the order of Pb > As > Cd. A large proportion of Pb, Cd and As were accumulated in upper soil profiles (depth < 3 m). Heavy pollution of Pb, Cd and As were observed in the whole soil profile at the area of fuel oil storage tank (ZY6) and lead smelting area (ZY8). The dominant fraction of Cd was exchangeable fraction (F1); Pb was dominant in Fe/Mn oxides-bound fraction (F3) in most cases; Crystallized Fe/Al hydrous oxides bound fraction (F4) generally accounted for a large proportion of As. Mobility factor (MF) followed the order Cd > As > Pb, indicating that Cd was the most mobile element in soil profiles. Pearson correlation analysis found that MFCd was significantly positively correlated to soil silt; the F4 fraction percentage of As was significantly positively correlated to soil redox potential (Eh). Additionally, MFCd/Pb was found to be positively correlated to crystalline iron (Fec), while negatively correlated to amorphous iron (Feo). The findings reported in this study, on the basis of distribution characteristics of chemical speciation could provide a new solution for future soil remediation at the site. Long-term solutions to metal(loid)s pollution might be offered by microbial-assisted soil washing technique that promotes the transformation of Fe/Mn oxides-bound fraction and organic/sulfide-bound fraction.
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Arsênio , Metais Pesados , Poluentes do Solo , Arsênio/análise , Cádmio/análise , China , Monitoramento Ambiental/métodos , Ferro/análise , Chumbo/análise , Metais Pesados/análise , Óxidos/análise , Solo/química , Poluentes do Solo/análiseRESUMO
Emerging evidence shows that histone modification and its related regulators are involved in the progression and chemoresistance of multiple tumors including acute myeloid leukemia cells (AML). Our present study found that the expression of histone lysine demethylase Jumonji domain containing-3 (JMJD3) was increased in AML cells as compared with that in human primary bone marrow (HPBM) cells. Knockdown of JMJD3 can decrease the proliferation of AML cells and increase the chemosensitivity of daunorubicin (DNR) and cytarabine (Ara-C). By screening the expression of cytokines involved in AML progression, we found that knockdown of JMJD3 can inhibit the expression of interleukin-6 (IL-6). Recombinant IL-6 (rIL-6) can attenuate si-JMJD3-suppressed proliferation of AML cells. Mechanistically, JMJD3 can positively regulate the promoter activity and transcription of IL-6 mRNA, while had no effect on its mRNA stability. Further, JMJD3 can regulate the expression of p65, which can directly bind with promoter of IL-6 to increase its transcription. Over expression of p65 significantly attenuated si-JMJD3-suppressed expression of IL-6. Collectively, we revealed that JMJD3 can regulate the proliferation and chemosensitivity of AML cells via upregulation of IL-6. It suggested that JMJD3 might be a potential therapy target for AML treatment.
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Interleucina-6/genética , Histona Desmetilases com o Domínio Jumonji/metabolismo , Leucemia Mieloide Aguda/metabolismo , Proliferação de Células , Humanos , Interleucina-6/metabolismo , Histona Desmetilases com o Domínio Jumonji/genética , Leucemia Mieloide Aguda/patologia , Células Tumorais CultivadasRESUMO
To explore features and impacts on the prognosis of common gene mutations in acute myeloid leukemia (AML), we assessed mutation status as well as variant allele frequency (VAF) of 24 genes in 81 AML patients by next-generation sequencing (NGS) technology. Eighty-six percentages of patients showed at least one mutation. Mutation in BCOR was associated with lower complete remission (CR) rate, whereas double mutation in CEBPA was associated with a favorable odds ratio for CR achievement. TP53 mutation was associated with inferior overall survival (OS) in univariate analysis. Multivariate analysis confirmed the negative effect of adverse cytogenetic abnormalities on survival. Mutation in RUNX1 and ZRSR2 had negative impacts on OS in patients with wild-type TP53. VAF of SRSF2 mutation was observed negatively correlated with OS. In conclusion, our study suggested that mutations in BCOR and spliceosomes might predict worse outcomes, and VAF of gene mutations may play a crucial role in outcomes of AML patients.
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Leucemia Mieloide Aguda , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Leucemia Mieloide Aguda/genética , Mutação , Prognóstico , Indução de RemissãoRESUMO
Over the past few decades, nonferrous mining has produced numerous waste rock and part of the waste that has not been properly treated was generally dumped at roadsides and hill slopes. However, the vertical distributions of toxic metal(loid)s and composition of microbial communities in waste heap and the under-laid pristine soil are rarely studied. In this work, the fraction-related distributions of toxic metal(loid)s were investigated at a waste heap profile and the indigenous microbial assemblages were also analyzed by Illumina sequencing of 16 s rRNA genes. Results showed that compared to the under-laid pristine soil, content of toxic metal(loid)s, especially Cd, As and Pb, in waste rock layer were higher. Most of As in subsoil existed as non-specifically sorbed and specifically-sorbed fractions, which could be ascribed to the migration from the upper layer. The mobility was significantly correlated with Eh, EC, clay content, CEC and the total content of metal(loid)s. Phyla Proteobacteria, Acidobacteria and Firmicutes dominated the microbial communities. The microbial community compositions at the genus level were similar, but their relative abundances were mainly influenced by pH, CEC, Eh, SOM, and bioavailability content of toxic metal(loid)s. Besides, microbial functions of elements (S, Fe, Mn and As) oxidation/reduction and metabolites (siderophore, biosurfactant, organic acid, phosphatase and urease) potentially were used for pollutants bioremediation.
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Central nervous system leukemia (CNSL) relapse is relatively common among Philadelphia chromosome-positive (Ph+) leukemia patients who undergo allogeneic hematopoietic stem cell transplantation (allo-HSCT). The prognosis of patients is dismal for those with a BCR-ABL T315I mutation, which is resistant to TKIs including second-generation drugs. We assessed ponatinib for nine patients with recurrent Ph+ CNSL and a T315I mutation after allo-HSCT, including five patients with Ph+ acute lymphoblastic leukemia and four with chronic myelogenous leukemia. Five patients experienced isolated CNSL relapse, and four experienced CNSL with hematologic relapse. All patients received ponatinib combined with intrathecal chemotherapy, and four patients with hematologic relapse received systemic chemotherapy and/or donor lymphocyte infusion. All patients achieved a deep molecular response and central nervous system remission (CNSR) at a median time of 1.5 (range: 0.7-3) months after ponatinib treatment. Two patients experienced a second CNSL relapse due to ponatinib reduction, but they achieved CNSR again after an increase to the standard dosage. Six patients developed graft versus host disease. By April 1, 2019, eight patients were alive, and one died of pneumonia. The median time of survival after the first CNSL relapse posttransplantation was 18 (range: 11.2-48.5) months. Our data from a small number of samples suggests that ponatinib is effective for recurrent Ph+ CNSL patients with a BCR-ABL T315I mutation after allo-HSCT and warrants broader clinical evaluation.
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Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Proteínas de Fusão bcr-abl/genética , Transplante de Células-Tronco Hematopoéticas/métodos , Imidazóis/uso terapêutico , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Piridazinas/uso terapêutico , Adulto , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/terapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Prognóstico , Inibidores de Proteínas Quinases/uso terapêutico , Recidiva , Estudos Retrospectivos , Resultado do TratamentoRESUMO
In recent years, many studies have been devoted to investigate the application of microbial induced phosphate precipitation (MIPP) process for potentially toxic element polluted soil remediation. MIPP biomineralization technique exhibits a great potential to efficiently remediate polluted soil considering its low cost, green and ecofriendly process, and simple in operation. This paper represented a review on the state of the art of polluted soil remediation based on MIPP technique. Briefly, certain defined criteria on targeted microbe selection was discussed; an overall review on the utilization of MIPP process for toxic ions biomineralization in soil was provided; influencing factors reported in the literature, such as pH, temperature, humic substances, coexisting ions, effective microbial population, and enzyme activity, were then comprehensively reviewed; finally; a special emphasis was given to enhance MIPP remediation performance in soil in future research.
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Microbiologia do Solo , Poluentes do Solo/química , Biomineralização , Precipitação Química , Recuperação e Remediação Ambiental , Íons , Fosfatos/química , Solo/química , Poluentes do Solo/metabolismoRESUMO
We present a first prototype of a wideband microwave tomography system with potential application to medical imaging. The system relies on a compact and robust printed monopole antenna which can operate in the 1.0â»3.0 GHz range when fully immersed in commonly used coupling liquids, such as glycerineâ»water solutions. By simulating the proposed imaging setup in CST Microwave Studio, we study the signal transmission levels and array sensitivity for different target and coupling liquid media. We then present the experimental prototype design and data acquisition process, and show good agreement between experimentally measured data and results from the CST simulations. We assess imaging performance by applying our previously proposed two-dimensional (2-D) DBIM TwIST-algorithm to both simulated and experimental datasets, and demonstrate that the system can reconstruct simple cylindrical targets at multiple frequencies.
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Algoritmos , Processamento de Imagem Assistida por Computador/métodos , Tomografia/instrumentação , Tomografia/métodos , Desenho de Equipamento , Micro-OndasRESUMO
Microbial induced carbonate precipitation (MICP) can immobilize metals and reduce their bioavailability. However, little is known about the immobilization mechanism of Cd in the presence of soil cations and the triggered gene expression and metabolic pathways in paddy soil. Thus, microcosmic experiments were conducted to study the fractionation transformation of Cd and metatranscriptome analysis. Results showed that bioavailable Cd decreased from 0.62 to 0.29 mg/kg after 330 d due to the MICP immobilization. This was ascribed to the increase in carbonate bound, Fe-Mn oxides bound, and residual Cd. The underlying immobilization mechanisms could be attributed to the formation of insoluble Cd-containing precipitates, the complexation and lattice substitution with carbonate and Fe, Mn and Al (hydr)oxides, and the adsorption on functional group on extracellular polymers of cell. During the MICP immobilization process, up-regulated differential expression urease genes were significantly enriched in the paddy soil, corresponding to the arginine biosynthesis, purine metabolism and atrazine degradation. The metabolic pathway of bacterial chemotaxis, flagellum assembly, and peptidoglycan biosynthesis and the expression of cadA gene related to Cd excretion enhanced Cd resistance of soil microbiome. Therefore, this study provided new insights into the immobilization mechanisms of Cd in paddy soils through ureolysis-based MICP process.
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Oryza , Poluentes do Solo , Solo , Cádmio/metabolismo , Poluentes do Solo/análise , Carbonatos/análise , Cátions , Óxidos/análise , Oryza/metabolismo , Carbonato de Cálcio/metabolismoRESUMO
BACKGROUND: Acute myeloid leukemia (AML) is a heterogeneous disease, and its heterogeneity is associated with treatment response. Despite the demonstrated success of venetoclax (VEN)-based therapy for AML, the effect of FLT3 mutations on the efficacy of the therapy is poorly understood. We aimed to compare the efficacy of VEN-based therapy between FLT3-mutated (FLT3mut ) and FLT3 wild-type (FLT3wt ) patients and identify the predictors of efficacy in FLT3mut patients. METHODS: A total of 266 AML patients (127 newly diagnosed [ND] and 139 refractory/relapsed [R/R]) receiving VEN-based regimens were enrolled in this study. A retrospective analysis was performed, and the treatment responses and overall survival (OS) of FLT3mut and FLT3wt patients were compared. Logistic regression and Cox proportional hazards model were applied to examine the clinical and genetic predictors of outcomes. RESULTS: With a median of two cycles of VEN-based therapy, for the ND AML cohort, the FLT3mut group had a comparable composite complete remission (CRc) rate with the FLT3wt group (79.3% vs. 61.2%, p = 0.072). For the R/R AML cohort, the FLT3mut group exhibited a lower CRc rate than the FLT3wt group. With a median follow-up of 8.6 months (95% confidence interval [CI], 8.0-10), the median OS observed in the FLT3mut and FLT3wt groups for both cohorts were close (14.0 vs. 19.9 months, p = 0.356; 10.0 vs. 11.9 months, p = 0.680). For the ND AML cohort, in FLT3mut patients, MRD-positive and RNA-splicing mutation predicted inferior survival (hazard ratio [HR], 10.3; 95% CI: 2.0-53.8; p = 0.006; HR 11.3; 95% CI: 1.2-109.3; p = 0.036, respectively). For the R/R AML cohort, in FLT3mut patients, adverse ELN risk was associated with an inferior response (odds ratio [OR], 0.2; 95% CI: 0.1-0.8; p = 0.025), whereas NPM1 co-mutation was associated with a superior response (57.1%; OR, 6.7; 95% CI: 1.5-30.1; p = 0.014). CR/CRi predicted a better survival (HR 0.2; 95% CI: 0.1-0.8; p = 0.029), while DNMT3A mutation predicted an inferior survival (HR, 4.6; 95% CI: 1.4-14.9; p = 0.011). CONCLUSIONS: FLT3 mutations may influence response to VEN-based therapy in R/R AML patients but not in ND AML patients. Furthermore, clinical and genetic characteristics could predict outcomes of FLT3mut patients receiving VEN-based therapy.
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Compostos Bicíclicos Heterocíclicos com Pontes , Leucemia Mieloide Aguda , Nucleofosmina , Sulfonamidas , Humanos , Estudos Retrospectivos , Mutação , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
PURPOSE: T(8;21)(q22;q22.1)/AML1-ETO positive acute myeloid leukemia (AE-AML) is sensitive to conventional chemotherapy with a favorable prognosis. However, recent small case reports suggest the limited effectiveness of venetoclax (VEN) and hypomethylating agents (HMA) in treating AE-AML. The aim of this retrospective study was to evaluate the effectiveness of VEN plus AZA (VA) in AE-AML and explore whether adding homoharringtonine (HHT) to VA (VAH) could improve the response. METHODS: Patients who received VEN plus AZA and HHT (VAH) or VEN plus AZA (VA) regimens were included in this retrospective study. The endpoints of this study were to evaluate the rate of composite complete remission (CRc), measurable residual disease (MRD), event-free survival (EFS), overall survival (OS), and relapse between VAH and VA groups. RESULTS: A total of 32 AE-AML patients who underwent VA or VAH treatments (newly diagnosed with VA, ND-VA, n = 8; relapsed/refractory with VA, R/R-VA, n = 10; relapsed/refractory with VAH, R/R-VAH, n = 14) were included. The CR (complete remission) /CRi (CR with incomplete count recovery) rate of ND-VA, R/R-VA and R/R-VAH were 25%, 10%, and 64.3%, respectively. Measurable residual disease (MRD) negative was observed in 66.7% of R/R-VAH and none of VA-R/R patients. Co-occurring methylation mutations are associated with poor outcomes with VA but exhibit a more favorable response with VAH treatment. Additionally, patients with c-kit mutation presented inferior outcomes with both VEN-based regimens. All regimens were tolerated well by all patients. CONCLUSION: Our data confirmed the poor response of VA in AE-AML, whether used as frontline or salvage therapy. Adding HHT to VA may improve outcomes and enhance the efficacy of VEN in this population.
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Protocolos de Quimioterapia Combinada Antineoplásica , Azacitidina , Compostos Bicíclicos Heterocíclicos com Pontes , Subunidade alfa 2 de Fator de Ligação ao Core , Mepesuccinato de Omacetaxina , Leucemia Mieloide Aguda , Proteína 1 Parceira de Translocação de RUNX1 , Sulfonamidas , Humanos , Mepesuccinato de Omacetaxina/administração & dosagem , Mepesuccinato de Omacetaxina/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Feminino , Estudos Retrospectivos , Azacitidina/administração & dosagem , Sulfonamidas/administração & dosagem , Idoso , Adulto , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Proteína 1 Parceira de Translocação de RUNX1/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Proteínas de Fusão Oncogênica/genética , Adulto JovemRESUMO
Diffuse hemangiomatosis of the liver and spleen is rare. Currently, few studies are available on diffuse hepatic and splenic hemangiomatosis accompanied by Kasabach-Merritt syndrome (KMS). The conserved telomere maintenance component 1 (CTC1) gene contributes to telomere maintenance and replication by forming the telomeric capping complex. Herein, we report a case of diffuse hemangiomatosis in the liver and spleen accompanied by KMS in a 59-year-old woman who carried two novel heterozygous CTC1 variants: c.435+9A>C and c.3074C>T (p.Ala1025Val). Using next-generation sequencing, we detected mutations in the CTC1 gene in our patient, who had chief complaints of fatigue and abdominal distension complicated by severe thrombocytopenia and consumptive coagulopathy. Clinical symptoms, laboratory tests, and imaging findings led to the diagnosis of diffuse hepatic and splenic hemangiomatosis accompanied by KMS. The patient was treated with prednisone, thalidomide, and sirolimus, and her general condition was ameliorated at the 4-month follow-up with improved platelet count and coagulation function. A CTC1 gene mutation may be involved in the pathological process of vascular diseases. A combination treatment regimen of prednisone, thalidomide, and sirolimus may be effective for KMS.
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At present, the pollution of arsenic (As) and lead (Pb) is becoming increasingly serious. The pollution caused by the release of As and Pb from lead-zinc mines has seriously affected the water and soil environment and threatened human health. It is necessary to reveal the release characteristics of As and Pb. The actual scene of mine drainage (MD) and rainwater (RW) leaching waste rocks is the one of the main reasons for the release of As and Pb. However, the leaching behavior of As and Pb in these waste rocks under MD and RW suffered from a lack of in-depth research. In this study, we investigated the occurrence of As and Pb in waste rocks (S1-S6) by using X-ray diffraction (XRD) and time-of-flight secondary ion mass spectrometry (TOF-SIMS), and then, the changes in As and Pb concentration and the hydrochemical parameter in leaching solution were systematically studied. Furthermore, the correlation between the release of As and Pb and mineral composition was also evaluated. Results showed that these waste rocks were mainly composed of carbonate and sulfide minerals. As and Pb were mainly bounded or associated with sulfide minerals such as arsenopyrite, pyrite, chalcopyrite, and galena in these waste rocks, and small parts of As and Pb were absorbed or encased by clay minerals such as kaolinite and chlorite. Under MD and RW leaching, the pH, redox potential (Eh), and electric conductivity (EC) of each waste rock tended to be consistent due to their buffering ability; the leachate pH of waste rocks with more carbonate minerals was higher than that of sulfide minerals. Both As and Pb were released most under MD leaching in comparison to RW, reaching 6.57 and 60.32 mg/kg, respectively, due to MD's low pH and high Eh value. However, As in waste rock released more under alkaline conditions because part of the arsenic was in the form of arsenate. As and Pb release were mainly positively correlated with the proportions of sulfide minerals in these waste rocks. MD leaching significantly promoted the release of As and Pb from waste rocks, which would cause a great threat to the surrounding environment, and control measures were imperative. This paper not only reveals the As and Pb pollution mechanism around the lead-zinc mining area but also provides a theoretical basis for the prevention and control of As and Pb pollution in the future.
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Phosphorus recovery from water and the subsequent reuse of its products can solve both water eutrophication and phosphorus resource waste issues. However, the potential use of the final recovered products as crop phosphorus fertilizers and the transformation of phosphorus fractions in soils have rarely been analyzed. In this study, the effects of a phosphorus recovery product (w-HC/CSH/P) obtained from our previous phosphorus recovery study on pepper growth were investigated. The association between soil phosphorus fraction transformation and the microbial co-occurrence network was investigated using high-throughput sequencing. The results showed that amendment with w-HC/CSH/P could promote the growth and chlorophyll content of pepper, which exhibited high phosphorus fertilizer efficiency. In addition, applying w-HC/CSH/P in soils could increase the microbial alpha-diversity during pepper cultivation and induce changes in the microbial community, leading to an increase in the relative abundance of Povalibacter, Lysobacter, and GP10 and a decrease in GP17. The proportion of Resin-P and NaHCO3-Po decreased, whereas that of NaOH-Po increased during pepper cultivation. psOTU331 (g_Latescibacteria), psOTU377 (g_Lysobacter), and psOTU461 (g_Pseudoxanthomonas) were the key microorganisms driving the transformation of phosphorus fractionation in the microbial co-occurrence network. Latescibacteria and Lysobacter were closely correlated with the transformation of NaHCO3-Po to NaOH-Po, and Pseudoxanthomonas was significantly correlated with a decrease in Resin-P. These observations highlight the potential of phosphorus recovery products as fertilizer for pepper and provide new insights into the transformation of phosphorus fractions corresponding to the microbiome in soils.
Assuntos
Fósforo , Solo , Fertilizantes , Hidróxido de Sódio , Bactérias , Microbiologia do Solo , ÁguaRESUMO
Xixin-Ganjiang Herb Pair (XGHP), a classic combination treatment to warm the lungs and dissolve phlegm, is widely used in the treatment of various pulmonary diseases. Chronic obstructive pulmonary disease (COPD) refers to a group of chronic obstructive airway diseases that can seriously harm human health. However, the effective components, targets, and pathways that underlie XGHP in the treatment of COPD remain unclear. Therefore, this study initially identified the effective components of XGHP through the use of UPLC-MS/MS and pharmacologic methods of traditional Chinese medicine. Secondly, transcriptomic analysis of the lung tissues of rats revealed the pharmacodynamic transcripts of each group, and metabolomics analysis revealed the differential metabolites associated with XGHP treatment. Finally, molecular docking of effective components with transcriptome genes was performed and western blotting was performed in order to determine the expression of related proteins in rat lung tissue. Overall, 30 effective components of XGHP were identified, including L-asarinin, 6-gingerol, sesamin, kaempferol, and quercetin. Transcriptomic studies demonstrated that expression of 386 genes recovered after XGHP treatment, and that they were mainly enriched in the oxidative phosphorylation and AMPK signaling pathways. According to the metabolomics studies, expression of eight metabolites differed between the COPD and the XGHP groups. These metabolites were mainly involved the biosynthesis of unsaturated fatty acids. Finally, the transcriptomic and metabolomics data were integrated. FASN and SCD in AMPK signaling pathway were directly linked to certain metabolites, including linoleic acid, palmitic acid, and oleic acid. These results indicate that XGHP can inhibit pAMPK expression and negatively regulate FASN and SCD expression during treatment of COPD in order to enhance the biosynthesis of unsaturated fatty acids and maintain energy homeostasis.
Assuntos
Medicamentos de Ervas Chinesas , Doença Pulmonar Obstrutiva Crônica , Ratos , Humanos , Animais , Transcriptoma , Proteínas Quinases Ativadas por AMP/metabolismo , Cromatografia Líquida , Simulação de Acoplamento Molecular , Espectrometria de Massas em Tandem , Pulmão/metabolismo , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Doença Pulmonar Obstrutiva Crônica/metabolismo , Metabolômica/métodos , Medicamentos de Ervas Chinesas/metabolismoRESUMO
PURPOSE: The busulfan plus fludarabine (BuFlu) conditioning regimen has lower transplant-related mortality (TRM) than busulfan plus cyclophosphamide (BuCy) in HLA-matched transplantation. We aimed to compare outcomes of the BuFlu regimen with those of the BuCy regimen in HLA-haploidentical hematopoietic cell transplantation (haplo-HCT). METHODS: We performed an open-label, randomized phase III trial at 12 hospitals in China. Eligible patients with AML (18-65 years) were randomly assigned 1:1 to receive BuFlu (busulfan 0.8 mg/kg four times per day on days -6 to -3; fludarabine 30 mg/m2 once daily on days -7 to -3) or BuCy (same dose of busulfan; cyclophosphamide 60 mg/kg once daily on days -3 and -2). The primary end point was 1-year TRM in the intention-to-treat population and safety in the per-protocol population. This trial is registered with ClinicalTrials.gov (identifier: NCT02487069) and is complete. RESULTS: From November 20, 2015, to September 30, 2019, 386 patients were randomly assigned to receive the BuFlu (n = 194) or BuCy (n = 192) regimen. The median follow-up was 55.0 (IQR, 46.5-69.0) months after random assignment. The 1-year TRM was 7.2% (95% CI, 4.1 to 11.4) and 14.1% (95% CI, 9.6 to 19.4; hazard ratio [HR], 0.51; 95% CI, 0.27 to 0.97; P = .041), the 5-year relapse was 17.9% (95% CI, 9.6 to 28.3) and 14.2% (95% CI, 9.1 to 20.5; HR, 1.12; 95% CI, 0.65 to 1.95; P = .670), and the 5-year overall survival was 72.5% (95% CI, 62.2 to 80.4) and 68.2% (95% CI, 58.9 to 75.9; HR, 0.84; 95% CI, 0.56 to 1.26; P = .465) in two groups, respectively. Grade 3 regimen-related toxicity (RRT) was reported for 0 of 191 patients following the BuFlu regimen and 9 (4.7%) of 190 patients following the BuCy regimen (P = .002). At least one type of grade 3-5 adverse event was reported for 130 (68.1%) of the 191 patients and 147 (77.4%) of the 190 patients in two groups, respectively (P = .041). CONCLUSION: The BuFlu regimen has a lower TRM and RRT and similar relapse for patients with AML undergoing haplo-HCT compared with the BuCy regimen.