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Background: Peripheral T-cell lymphoma (PTCL) is a heterogeneous disease with dismal outcomes. We conducted an open-label, phase 2 nonrandomised, externally controlled study to evaluate the efficacy and safety of targeted agents plus CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) (CHOPX) for PTCL in the front-line setting. Methods: Eligible patients were ≥18 years of age and newly diagnosed PTCL. Patients in the CHOPX group received standard CHOP at Cycle 1. Specific targeted agents were added from Cycle 2, decitabine if TP53 mut, azacytidine if TET2/KMT2D mut, tucidinostat if CREBBP/EP300 mut, and lenalidomide if without mutations above. Patients in the CHOP group received CHOP for 6 cycles. The primary endpoint was the complete response rate (CRR) at the end of treatment (EOT). Secondary endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety. The study was registered with ClinicalTrials.gov, NCT04480099. Findings: Between July 29, 2020, and Sep 22, 2022, 96 patients were enrolled and included for efficacy and safety analysis with 48 in each group. The study met its primary endpoint. CRR at EOT in the CHOPX group was superior to the CHOP group (64.6% vs. 33.3%, OR 0.27, 95%CI 0.12-0.64; p = 0.004). At a median follow-up of 24.3 months (IQR 12.0-26.7), improved median PFS was observed in the CHOPX group (25.5 vs. 9.0 months; HR 0.57, 95%CI 0.34-0.98; p = 0.041). The median OS was similar between two groups (not reached vs. 30.9 months; HR 0.55, 95%CI 0.28-1.10; p = 0.088). The most common grade 3-4 hematological and non-hematological adverse events in the CHOPX group were neutropenia (31, 65%) and infection (5, 10%). Interpretation: Targeted agents combined with CHOP demonstrated effective and safe as first-line treatment in PTCL. Biomarker-driven therapeutic strategy is feasible and may lead to promising efficacy specifically toward molecular features in PTCL. Funding: This study was supported by the National Key Research and Development Program (2022YFC2502600) and the General Program of the Shanghai Municipal Health Commission (202040400).
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Histone methyltransferase KMT2D is one of the most frequently mutated genes in diffuse large B-cell lymphoma (DLBCL) and has been identified as an important pathogenic factor and prognostic marker. However, the biological relevance of KMT2D mutations on tumor microenvironment remains to be determined. KMT2D mutations were assessed by whole-genome/exome sequencing (WGS/WES) in 334 patients and by targeted sequencing in 427 patients with newly diagnosed DLBCL. Among all 761 DLBCL patients, somatic mutations in KMT2D were observed in 143 (18.79%) patients and significantly associated with advanced Ann Arbor stage and MYC expression ≥ 40%, as well as inferior progression-free survival and overall survival. In B-lymphoma cells, the mutation or knockdown of KMT2D inhibited methylation of lysine 4 on histone H3 (H3K4), downregulated FBXW7 expression, activated NOTCH signaling pathway and downstream MYC/TGF-ß1, resulting in alterations of tumor-induced regulatory T cell trafficking. In B-lymphoma murine models established with subcutaneous injection of SU-DHL-4 cells, xenografted tumors bearing KMT2D mutation presented lower H3K4 methylation, higher regulatory T cell recruitment, thereby provoking rapid tumor growth compared with wild-type KMT2D via FBXW7-NOTCH-MYC/TGF-ß1 axis.
Assuntos
Proteína 7 com Repetições F-Box-WD , Linfoma Difuso de Grandes Células B , Mutação , Proteínas Proto-Oncogênicas c-myc , Linfócitos T Reguladores , Humanos , Proteína 7 com Repetições F-Box-WD/metabolismo , Proteína 7 com Repetições F-Box-WD/genética , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/metabolismo , Linfoma Difuso de Grandes Células B/patologia , Animais , Camundongos , Feminino , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Masculino , Linfócitos T Reguladores/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Receptores Notch/metabolismo , Pessoa de Meia-Idade , Linhagem Celular Tumoral , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/genética , Transdução de Sinais , Adulto , Progressão da Doença , IdosoRESUMO
Peripheral T cell lymphoma (PTCL) is a heterogeneous group of non-Hodgkin's lymphomas varying in clinical, phenotypic, and genetic features. The molecular pathogenesis and the role of the tumor microenvironment in PTCL are poorly understood, with limited biomarkers available for genetic subtyping and targeted therapies. Through an integrated genomic and transcriptomic study of 221 PTCL patients, we delineate the genetic landscape of PTCL, enabling molecular and microenvironment classification. According to the mutational status of RHOA, TET2, histone-modifying, and immune-related genes, PTCL is divided into 4 molecular subtypes with discrete patterns of gene expression, biological aberrations, and vulnerabilities to targeted agents. We also perform an unsupervised clustering on the microenvironment transcriptional signatures and categorize PTCL into 4 lymphoma microenvironment subtypes based on characteristic activation of oncogenic pathways and composition of immune communities. Our findings highlight the potential clinical rationale of future precision medicine strategies that target both molecular and microenvironment alterations in PTCL.
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Linfoma de Células T Periférico , Humanos , Linfoma de Células T Periférico/genética , Linfoma de Células T Periférico/metabolismo , Perfilação da Expressão Gênica , Genômica , Mutação , Microambiente Tumoral/genéticaRESUMO
Sulfide-containing wastewater, characterized by its foul odor, corrosiveness, and toxicity, can endanger human health. Fluidized-bed homogeneous crystallization (FBHC) avoids the excessive sludge production commonly associated with conventional chemical precipitation methods. In this study, FBHC is used to treat sulfur-containing synthetic wastewater. Furthermore, nickel-containing wastewater was utilized as a precipitant in the system, hence the advantage of simultaneous sulfur and nickel removal from the wastewater. The operating parameters, including pH, a precipitant dosage of [Ni2+]0/[S2-]0, and cross-sectional surface loading (LS, kg/m2h) are optimized. The optimum operating conditions of pH 9.8 ± 0.3, [Ni2+]0/[S2-]0 = 0.8, and LS = 1.5 kg/m2h results in total sulfur removal (TR) of 95.7% and crystallization ratio (CR) of 94.8%. The effect of organic compounds (acetic acid, oxalic acid, EDTA, and citric acid) and inorganic ions (NO3-, CO32-, PO43-, F-, and Cl-) on the nickel sulfide granulation process was discussed.
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Decitabina/farmacologia , Linfoma Difuso de Grandes Células B/genética , Resultado do Tratamento , Microambiente Tumoral/fisiologia , Idoso , Biomarcadores/análise , Decitabina/metabolismo , Feminino , Humanos , Linfoma Difuso de Grandes Células B/diagnóstico , Linfoma Difuso de Grandes Células B/fisiopatologia , Masculino , Pessoa de Meia-IdadeRESUMO
Epigenetic alterations play an important role in tumor progression of diffuse large B-cell lymphoma (DLBCL). However, the biological relevance of epigenetic gene mutations on tumor microenvironment remains to be determined. The core set of genes relating to histone methylation (KMT2D, KMT2C, EZH2), histone acetylation (CREBBP, EP300), DNA methylation (TET2), and chromatin remodeling (ARID1A) were detected in the training cohort of 316 patients by whole-genome/exome sequencing (WGS/WES) and in the validation cohort of 303 patients with newly diagnosed DLBCL by targeted sequencing. Their correlation with peripheral blood immune cells and clinical outcomes were assessed. Underlying mechanisms on tumor microenvironment were investigated both in vitro and in vivo. Among all 619 DLBCL patients, somatic mutations in KMT2D (19.5%) were most frequently observed, followed by mutations in ARID1A (8.7%), CREBBP (8.4%), KMT2C (8.2%), TET2 (7.8%), EP300 (6.8%), and EZH2 (2.9%). Among them, CREBBP/EP300 mutations were significantly associated with decreased peripheral blood absolute lymphocyte-to-monocyte ratios, as well as inferior progression-free and overall survival. In B-lymphoma cells, the mutation or knockdown of CREBBP or EP300 inhibited H3K27 acetylation, downregulated FBXW7 expression, activated the NOTCH pathway, and downstream CCL2/CSF1 expression, resulting in tumor-associated macrophage polarization to M2 phenotype and tumor cell proliferation. In B-lymphoma murine models, xenografted tumors bearing CREBBP/EP300 mutation presented lower H3K27 acetylation, higher M2 macrophage recruitment, and more rapid tumor growth than those with CREBBP/EP300 wild-type control via FBXW7-NOTCH-CCL2/CSF1 axis. Our work thus contributed to the understanding of aberrant histone acetylation regulation on tumor microenvironment as an alternative mechanism of tumor progression in DLBCL.
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Linfoma Difuso de Grandes Células B/imunologia , Proteínas de Neoplasias/imunologia , Transdução de Sinais/imunologia , Macrófagos Associados a Tumor/imunologia , Animais , Proteína de Ligação a CREB/genética , Proteína de Ligação a CREB/imunologia , Quimiocina CCL2/genética , Quimiocina CCL2/imunologia , Proteína p300 Associada a E1A/genética , Proteína p300 Associada a E1A/imunologia , Proteína 7 com Repetições F-Box-WD/genética , Proteína 7 com Repetições F-Box-WD/imunologia , Feminino , Humanos , Linfoma Difuso de Grandes Células B/genética , Fator Estimulador de Colônias de Macrófagos/genética , Fator Estimulador de Colônias de Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Proteínas de Neoplasias/genética , Receptores Notch/genética , Receptores Notch/imunologia , Transdução de Sinais/genética , Células THP-1RESUMO
BACKGROUND: Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)/CHOP-like chemotherapy is widely used in peripheral T cell lymphoma (PTCL). Here we conducted a phase 2, multicenter, randomized, controlled trial, comparing the efficacy and safety of CEOP/IVE/GDP alternating regimen with CEOP in newly diagnosed PTCL. METHODS: PTCL patients, except for anaplastic large cell lymphoma-anaplastic lymphoma kinase positive, were 1:1 randomly assigned to receive CEOP/IVE/GDP (CEOP, cyclophosphamide 750 mg/m2, epirubicin 70 mg/m2, vincristine 1.4 mg/m2 [maximum 2 mg] on day 1, and prednisone 60 mg/m2 [maximum 100 mg] on days 1-5 every 21 days, at the first and fourth cycle; IVE, ifosfamide 2000 mg/m2 on days 1-3, epirubicin 70 mg/m2 on day 1, and etoposide 100 mg/m2 on days 1-3 every 21 days, at the second and fifth cycle; and GDP, gemcitabine 1000 mg/m2 on days 1 and 8, cisplatin 25 mg/m2 on days 1-3, and dexamethasone 40 mg on days 1-4 every 21 days, at the third and sixth cycle) and CEOP (every 21 days for 6 cycles). Analysis of efficacy and safety was of the intent-to-treatment population. The primary endpoint was a complete response rate at the end of treatment. Meanwhile, whole exome sequencing and targeted sequencing were performed in 62 patients with available tumor samples to explore prognostic biomarkers in this cohort as an exploratory post hoc analysis. RESULTS: Among 106 patients, 53 each were enrolled to CEOP/IVE/GDP and CEOP. With 51 evaluable patients each in two groups, a complete response rate of the CEOP/IVE/GDP group was similar to that of the CEOP group (37.3% vs. 31.4%, p = 0.532). There was no difference in median progression-free survival (PFS; 15.4 months vs. 9.2 months, p = 0.122) or overall survival (OS; 24.3 months vs. 21.9 months, p = 0.178). Grade 3-4 hematological and non-hematological adverse events were comparable. Histone modification genes were most frequently mutated (25/62, 40.3%), namely KMT2D, KMT2A, SETD2, EP300, and CREBBP. Multivariate analysis indicated that CREBBP and IDH2 mutations were independent factors predicting poor PFS and OS (all p < 0.001), while KMT2D predicting poor PFS (p = 0.002). CONCLUSIONS: CEOP/IVE/GDP alternating regimen showed no remission or survival advantage to standard chemotherapy. Future clinical trials should aim to develop alternative regimen targeting disease biology as demonstrated by recurrent mutations in epigenetic factors. TRIAL REGISTRATION: The study was registered on ClinicalTrial.gov (NCT02533700) on August 27, 2015.
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Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Desoxicitidina/análogos & derivados , Linfoma de Células T Periférico/tratamento farmacológico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Esquema de Medicação , Epirubicina/administração & dosagem , Epirubicina/efeitos adversos , Etoposídeo/administração & dosagem , Etoposídeo/efeitos adversos , Feminino , Humanos , Ifosfamida/administração & dosagem , Ifosfamida/efeitos adversos , Linfoma de Células T Periférico/genética , Masculino , Pessoa de Meia-Idade , Prednisona/administração & dosagem , Prednisona/efeitos adversos , Prognóstico , Vincristina/administração & dosagem , Vincristina/efeitos adversos , Sequenciamento do ExomaRESUMO
Activated carbon (AC), prepared from dried loofah sponge, was supported on nickel foam to fabricate AC/Ni electrodes. The characteristics of ammonium electrosorption on AC/Ni electrodes was studied. Results showed that AC prepared in one-step activation (without pre-pyrolysis), i.e., OAC, had relatively low crystallinity, high mesoporosity, and high specific capacitance compared to those made in two-step carbonation followed by activation. Adsorption and desorption density of NH4+ were measured at constant potential of -1.0 V (vs. Hg/HgO) and +0.1 V (vs. Hg/HgO), respectively. Non-faradaic charging contributed to the electrochemical storage and adsorption of ammonium ions on the AC surface with a maximal charge efficiency of 80%, at an applied potential of -1.0 V (vs. Hg/HgO). Multiple-layer adsorption isotherm better described the electrosorption of ammonium ion on OAC/Ni electrodes yielding a maximum adsorption capacity of 6 mg-N g-1, which was comparable with other similar systems. Overall, results clearly demonstrated the effect of synthesis strategy on the capacitive charging behaviors of AC/Ni electrodes and its relationship to NH4+ electrosorption.
Assuntos
Compostos de Amônio/análise , Carvão Vegetal/química , Luffa/química , Níquel/química , Poluentes Químicos da Água/análise , Purificação da Água/métodos , Adsorção , Capacitância Elétrica , Eletrodos , Íons , Modelos Teóricos , Propriedades de SuperfícieRESUMO
BACKGROUND: Anthracycline dose optimisation in the treatment of diffuse large B-cell lymphoma has rarely been tested. We aimed to find out whether R-CEOP70 was non-inferior to R-CHOP50 with less cardiotoxicity, and whether R-CEOP90 had a superior efficacy to R-CHOP50 or R-CEOP70 with acceptable toxic effects. METHODS: In this multicentre, phase 3, randomised, controlled study (NHL-001), patients with newly diagnosed diffuse large B-cell lymphoma or follicular lymphoma grade 3B were enrolled from 20 centres of the Multicenter Hematology-Oncology Programs Evaluation System in China. Young patients (16-60 years) were randomly assigned 1:1:1 (block size of six) to six courses of R-CHOP50, R-CEOP70, or R-CEOP90, and older patients (61-80 years) were assigned 1:1 (block size of four) to R-CHOP50 or R-CEOP70. Patients were randomly assigned using computer-assisted permuted-block randomisation. Investigators and patients were not masked to treatment assignment. In the R-CHOP50 group, patients were given rituximab 375 mg/m2 intravenously on day 0, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 (maximum dose 2 mg) intravenously on day 1, and prednisone 60 mg/m2 (maximum dose 100 mg) orally from day 1-5; in the R-CEOP70 group, epirubicin 70 mg/m2 replaced doxorubicin; and in the R-CEOP90 group, high dose epirubicin 90 mg/m2 replaced doxorubicin. All patients received two additional courses of rituximab 375 mg/m2 intravenously every 21 days. Consolidation radiotherapy was given to patients with bulky disease at diagnosis or residual disease at the end of treatment. The primary endpoint was 2-year progression-free survival. The non-inferiority margin for R-CEOP70 versus R-CHOP50 was defined by hazard ratio [HR] as the upper limit of its 95% CI being no greater than 1·50. Analysis of efficacy and safety were of the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01852435. FINDINGS: From May 15, 2013, to March 16, 2016, a total of 648 patients were enrolled, including 404 (62%) young patients (R-CHOP50 [n=135], R-CEOP70 [n=134], or R-CEOP90 [n=135]), and 244 (38%) older patients (R-CHOP50 [n=122] or R-CEOP70 [n=122]). Four patients were excluded from the study for consent withdrawal and one patient for misdiagnosis before treatment. The 2-year progression-free survival in the R-CHOP50 group was 72·5% (95% CI 66·6-77·6) and in the R-CEOP70 group was 72·4% ([66·5-77·5]; HR 1·00 [0·73-1·38]; p=0·99). The non-inferiority was met and adverse events were similar between the two groups. Fewer patients in the R-CEOP70 group (14 [13%] of 110) presented with over 10% decrease in left ventricular ejection fraction (LVEF) than those in the R-CHOP50 group (31 [29%] of 108) at 3 years after remission. For young patients, the 2-year progression-free survival in the R-CEOP90 group was 88·8% (82·1-93·1) and was significantly improved compared with the R-CHOP50 group (75·9% [67·7-82·3]; 0·44 [0·25-0·76]; p=0·0047) and the R-CEOP70 group (77·4% [69·4-83·7%]; 0·49 [0·27-0·86]; p=0·017). Grade 3-4 neutropenia occurred more frequently in the R-CEOP90 group (97 [72%] of 134) than in the R-CHOP50 group (87 [65%] of 133) and R-CEOP70 group (84 [63%] of 133) in young patients but without further increase of clinically significant infections. Fewer patients in the R-CEOP70 group (7 [11%] of 66) and in the R-CEOP90 group (10 [13%] of 79) presented with more than 10% decrease in LVEF than those in the R-CHOP50 group (17 [26%] of 66) at 3 years after remission. INTERPRETATION: R-CEOP70 could serve as an alternative regimen to R-CHOP50 with mild long-term cardiotoxicity. Young patients with diffuse large B-cell lymphoma might benefit from high-dose epirubicin. Epirubicin is an alternative drug to doxorubicin in regular R-CHOP with mild long-term cardiotoxicity. FUNDING: National Natural Science Foundation of China, National Key Research and Development Program, Shanghai Commission of Science and Technology, Shanghai Municipal Education Commission Gaofeng Clinical Medicine Grant Support, Multicenter Clinical Research Project by Shanghai Jiao Tong University School of Medicine, Clinical Research Plan of Shanghai Hospital Development Center, and Chang Jiang Scholars Program.
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Antraciclinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antraciclinas/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ciclofosfamida/administração & dosagem , Feminino , Humanos , Linfoma Difuso de Grandes Células B/mortalidade , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Neutropenia/etiologia , Modelos de Riscos Proporcionais , Rituximab/administração & dosagem , Taxa de Sobrevida , Resultado do Tratamento , Vincristina/administração & dosagem , Adulto JovemRESUMO
An electrode made of loofah sponge derived activated carbon supported on nickel foam (AC/Ni) was successfully fabricated and used to remove ammonium ion (NH4+) from aqueous solution. A multilayer adsorption isotherm was used to describe ammonium electro-sorption on AC/Ni electrodes at different temperature, initial NH4+ concentration, and electrical field. The cyclic voltammetry (CV) results suggested that the electrical capacitance of AC/Ni electrodes, with the AC being prepared without preheating (OAC) or with low temperature heating (i.e., 300â¯AC), were higher than those prepared at high preheating temperature (i.e., 400â¯AC and 500â¯AC). Increasing the electro-sorption temperature from 10 to 50⯰C decreased the monolayer NH4+ adsorption capacity from 5 to ca. 2-3â¯mg-Nâ¯g-1, respectively. Background electrolyte, namely, sodium sulfate, exhibited significant competitive effect on the adsorption of ammonium ion at sodium ion concentrationâ¯>â¯10-2â¯M. The activation energy and heat of adsorption were 9-23.2â¯kJâ¯mol-1 and -3.7--10.7â¯kJâ¯mol-1, respectively, indicating a physisorption and exothermic adsorption characteristics. Based on the kinetics and thermodynamics analysis, there was slight increase in the activation energy with elevating preheating temperature, which increased the quantity of micro-pores and surface heterogeneity of the AC materials. Overall, results clearly demonstrated that carbon pyrolysis played a role on the capacitive charging behaviors of electrodes and the efficiency of NH4+ electro-sorption on the AC/Ni electrodes.
Assuntos
Compostos de Amônio/química , Carvão Vegetal/química , Luffa/química , Níquel/química , Poluentes Químicos da Água/química , Adsorção , Compostos de Amônio/análise , Eletrodos , Concentração de Íons de Hidrogênio , Cinética , Modelos Químicos , Temperatura , Termodinâmica , Poluentes Químicos da Água/análiseRESUMO
Tetrafluoroborate anion (BF4-) is found in the streams of flue-gas desulfurization and borosilicate glasses etching which deteriorates water quality through slow hydrolysis into boric acid and fluoride. Decomposition and electrocoagulation (EC) of BF4- were studied using metallic aluminum as the sacrificial electrode. The dissolved Al(III) from the anode could efficiently decompose BF4- in forms of fluoroaluminate complexes, and the derived boric acid and fluoride ion were removed by sweep flocculation. Major variables were investigated to optimize EC, including the reaction pH, initial concentration of BF4-, current density and electrolyte type. The mechanism of EC process was elucidated with the kinetics of consecutive reactions. Experimental results suggested that the removal of BF4- and total fluoride were less influenced by pH, and that of total boron reached a maximum at pH 8 which favored the surface complexation between borate species and EC precipitates. Under the conditions: [BF4-]0â¯=â¯9.3â¯mM, [NaCl]â¯=â¯10â¯mM, pHâ¯=â¯8.0, current densityâ¯=â¯5â¯mA/cm2, 98.3% of BF4- was decomposed and the removal of total fluoride and boron attained 98.2% and 74.1%, respectively within 3â¯h. EC using the Al electrode outperformed the conventional chemical coagulation and reduced the levels of BF4, B(OH)3 and F- in aqueous solution synergically.
Assuntos
Poluentes Químicos da Água , Purificação da Água , Alumínio , Boro , Eletrocoagulação , Eletrodos , Fluoretos , Flúor , Concentração de Íons de HidrogênioRESUMO
Due to heterogeneous morphological and immunophenotypic features, approximately 50% of peripheral T-cell lymphomas are unclassifiable and categorized as peripheral T-cell lymphomas, not otherwise specified. These conditions have an aggressive course and poor clinical outcome. Identification of actionable biomarkers is urgently needed to develop better therapeutic strategies. Epigenetic alterations play a crucial role in tumor progression. Histone modifications, particularly methylation and acetylation, are generally involved in chromatin state regulation. Here we screened the core set of genes related to histone methylation (KMT2D, SETD2, KMT2A, KDM6A) and acetylation (EP300, CREBBP) and identified 59 somatic mutations in 45 of 125 (36.0%) patients with peripheral T-cell lymphomas, not otherwise specified. Histone modifier gene mutations were associated with inferior progression-free survival time of the patients, irrespective of chemotherapy regimens, but an increased response to the histone deacetylase inhibitor chidamide. In vitro, chidamide significantly inhibited the growth of EP300-mutated T-lymphoma cells and KMT2D-mutated T-lymphoma cells when combined with the hypomethylating agent decitabine. Mechanistically, decitabine acted synergistically with chidamide to enhance the interaction of KMT2D with transcription factor PU.1, regulated H3K4me-associated signaling pathways, and sensitized T-lymphoma cells to chidamide. In a xenograft KMT2D-mutated T-lymphoma model, dual treatment with chidamide and decitabine significantly retarded tumor growth and induced cell apoptosis through modulation of the KMT2D/H3K4me axis. Our work thus contributes to the understanding of aberrant histone modification in peripheral T-cell lymphomas, not otherwise specified and the stratification of a biological subset that can benefit from epigenetic treatment.
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Proteínas de Ligação a DNA/metabolismo , Genes Modificadores/genética , Histonas/metabolismo , Linfoma de Células T Periférico/tratamento farmacológico , Linfoma de Células T Periférico/genética , Mutação , Proteínas de Neoplasias/metabolismo , Acetilação , Aminopiridinas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Benzamidas/farmacologia , Linhagem Celular Tumoral , Análise Mutacional de DNA , Decitabina/farmacologia , Xenoenxertos , Histonas/genética , Humanos , Linfoma de Células T Periférico/mortalidade , Metilação , Camundongos , Prognóstico , Análise de Sobrevida , Células Tumorais CultivadasRESUMO
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous subtype of non-Hodgkin lymphoma. In addition to clinical and immunophenotypic characteristics, recurrent gene mutations have recently been identified in patients with DLBCL using next-generation sequencing technologies. The aim of this study is to investigate the clinical relevance of B-cell function gene mutations in DLBCL. Clinical analysis was performed on 680 Chinese DLBCL patients (146 non-CR and 534 CR cases) treated with six cycles of 21-day R-CHOP (Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), alone or followed by two additional doses of rituximab consolidation on patients' own intention. Somatic mutations of B-cell function genes were further screened on 275 (71 non-CR and 204 CR) cases with available tumor samples by targeted sequencing, including genes involved in B-cell receptors (BCRs) pathway (CARD11, LYN, CD79A, and CD79B), Toll-like receptors (TLRs) pathway (MYD88), and tumor necrotic factor receptor (TNFR) pathway (TRAF2 and TNFAIP3). B-cell function gene mutations occurred in 44.0% (121/275) of DLBCL patients. The TLRs and TNFR related gene mutations were more frequently observed in non-CR patients (p=0.019 and p=0.032, respectively). BCRs related gene mutations, as well as revised IPI (R-IPI) and double BCL-2/MYC expression, were independently related to short progression-free survival in DLBCL after CR. The adverse prognostic effect of BCRs related gene mutations could be overcome by two additional doses of rituximab consolidation. These results highlight the molecular heterogeneity of DLBCL and identify a significant role of B-cell function gene mutations on lymphoma progression and response to rituximab in DLBCL.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos B/metabolismo , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/genética , Mutação , Sequência de Aminoácidos , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Esquema de Medicação , Feminino , Humanos , Linfoma Difuso de Grandes Células B/patologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Fator 88 de Diferenciação Mieloide/genética , Prednisona/administração & dosagem , Prognóstico , Indução de Remissão , Estudos Retrospectivos , Rituximab/administração & dosagem , Homologia de Sequência de Aminoácidos , Resultado do Tratamento , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Vincristina/administração & dosagemRESUMO
The electrocoagulation (EC) using metallic Ni foam as electrodes was studied for the removal of boron from solution. The electrolytic parameters were pH (4-12), current density (0.6-2.5 mA cm-2), and initial concentration of boron (10-100 mg L-1). Experimental results revealed that removal efficiency was maximized at pH 8-9, and decreased as the pH increased beyond that range. At particular onset potentials (0.5-0.8 V vs. Hg/HgO), the micro-granular nickel oxide that was created on the surface of the nickel metal substrate depended on pH, as determined by cyclic voltammetry. Most of the crystallites of the precipitates comprised a mixed phase of ß-Ni(OH)2, a theophrastite phase, and NiOOH, as revealed by XRD and SEM analyses. A current density of 1.25 mA cm-2 was effective in the EC of boron, and increasing the concentration of boric acid from 10 to 100 mg L-1 did not greatly impair removal efficiency. A kinetic investigation revealed that the reaction followed a pseudo-second order rate model. The optimal conditions under which 99.2% of boron was removed from treated wastewater with 10 mg L-1-B, leaving less than 0.1 mg L-1-B in the electrolyte, were pH 8 and 1.25 mA cm-2 for 120 min.
Assuntos
Boro/química , Boro/isolamento & purificação , Eletroquímica/instrumentação , Níquel/química , Poluentes Químicos da Água/química , Poluentes Químicos da Água/isolamento & purificação , Eletrodos , Concentração de Íons de Hidrogênio , Cinética , Oxirredução , Águas Residuárias/químicaRESUMO
Heavy metal removal is a significant task that protects our water resources. Fluidized-bed homogeneous granulation process (FBHGP) was used to treat nickel containing wastewaters by recovering nickel in the form of nickel carbonate hydroxide granules with low moisture content rather than soft sludge. This study investigated nickel removal and recovery through HFBGP by determining the effects of varying influent nickel concentrations, [CO32-: Ni2+] molar ratios, and pH of the precipitant. This was conducted in a continuous process using a laboratory scale fluidized-bed reactor that determined the effects driven by supersaturation. The best operating conditions that resulted in a 98.8% nickel removal and 97.8% granulation efficiency were 200 mg L-1 influent nickel concentration, 2.0 M R of [CO3-2:Ni+2], and 10.7 pH of precipitant. Based on SEM analysis, the granules formed have sizes between 0.50 mm and 0.15 mm. EDS results showed that the atomic percentages of nickel carbon, and hydrogen were â¼50%, â¼9-12%, and â¼35% respectively, representing the nickel carbonate compound. The XRD results showed the low symmetry of the granules formed that confirmed the characteristics of nullaginite mineral of Ni2(CO3)(OH)2.
Assuntos
Reatores Biológicos/microbiologia , Níquel/análise , Poluentes Químicos da Água/análise , Purificação da Água/métodos , Precipitação Química , Hidróxidos/análise , Modelos Teóricos , Níquel/química , Esgotos/química , Solubilidade , Águas Residuárias/química , Poluentes Químicos da Água/químicaRESUMO
The heterogeneous oxidation of azo dye Reactive Black B (RBB) by the photo-Fenton system catalyzed with an immobilized iron oxide, B1 (supported with SiO2 grain), was investigated. Reactive Black B oxidation was carried out in an expended-bed reactor in which the effect of B1 dosage on the decolorization and degradation of RBB was examined. Through pseudo-first-order kinetic studies, decolorization was found to be faster than degradation with a fixed rate constant ratio. By determining the iron dissolution from B1, RBB oxidation was supposed to mainly occur on the B1 surface, which catalyzed the generation of hydroxyl radicals in the photo-Fenton reaction. Accordingly, the efficiency of photo-Fenton could reach 100% and 91.2% of decolorization and degradation, respectively, in 300 minutes.
Assuntos
Compostos Férricos/química , Naftalenossulfonatos/química , Catálise , Cinética , Oxirredução , Poluentes Químicos da Água/químicaRESUMO
2,2,3,3-Tetrafluoro-1-propanol (TFP, C3H4F4O, M.W. = 132.06) is extensively used as the solvent in CD-R and DVD-R fabrication. Since it has a fluorinated alky-chain configuration and is non-biodegradable, its treatment by conventional oxidation methods is typically very inefficient. In this work, novel three-phase fluidized bed reactor (3P-FBR, 7.5 cm in diameter, 50 cm high) that combines photo oxidation (UV/H2O2, one of AOPs (Advanced Oxidation Process) and adsorption (BT5 iron oxide as adsorbent) processes is designed for mineralizing and defluorinizing TFP wastewater. The experimental results reveal that TFP can be efficiently mineralized, and the BT5 that is circulated by aeration in the 3P-FBR system can remove the released fluoride ions in the reaction period. Irradiation with 254 nm UV and a 10 mM H2O2 dose yield a TOC removal of TFP (1.39 mM, equivalent to an initial TOC of 50 ppm) of over 99.95% in 2 h, and 99% of fluoride was removed by BT5 with an adsorption capacity of 24.1 mg-F g(-1).
Assuntos
Reatores Biológicos , Fluoretos/química , Fluorocarbonos/química , Minerais/química , Propanóis/química , Raios Ultravioleta , Adsorção/efeitos da radiação , Biodegradação Ambiental/efeitos da radiação , Compostos Férricos/química , Peróxido de Hidrogênio/química , Concentração de Íons de Hidrogênio/efeitos da radiação , Microscopia Eletrônica de Varredura , Oxirredução/efeitos da radiaçãoRESUMO
This work demonstrates the combination of UV/persulfate and adsorption processes for treating 2,2,3,3-tetrafluoro-1-propanol (TFP) wastewater. Under the optimum conditions, 20mM persulfate (S(2)O(8)(2-)), 254 nm UV-C, and pH 3, 99.7% of TOC removal from an initial TFP solution of 1.39 mM was achieved. The photolysis of persulfate (S(2)O(8)(2-)) by UV irradiation yielded the sulfate radical (SO(4)(-)) with high activity, which mineralized most of the TFP in 2h. The released fluoride ions were then removed by using a waste iron oxide, BT-4 adsorbent. 20 g L(-1) BT-4 adsorbed 95% of the fluoride that was produced by mineralization of 1.39 mM TFP. The kinetics and isotherms of adsorption were examined to determine the fluoride removal efficiency of BT-4 which co-existed with the sulfate ions from the consumed sulfate radicals. Accordingly, the kinetics of adsorption was described by a pseudo-second-order rate model, while the adsorption isotherms were well fitted with the Langmuir model. BT-4 had a high adsorption capacity of 26.4 mg g(-1) (25°C) in removing the fluoride from TFP mineralization, suggesting that the co-existing sulfate ions never significantly affected the fluoride removal efficiency.
Assuntos
Fluoretos/química , Fluorocarbonos/química , Propanóis/química , Eliminação de Resíduos Líquidos/métodos , Águas Residuárias/química , Poluentes Químicos da Água/química , Adsorção , Fluoretos/análise , Fluorocarbonos/análise , Cinética , Oxirredução , Fotólise , Propanóis/análise , Raios Ultravioleta , Poluentes Químicos da Água/análiseRESUMO
This work demonstrates the synthesis of a novel KMnO(4)-modified form of iron oxide, MnBT-4, using a fluidized bed reactor (FBR) for the adsorptive removal of arsenic (III)/(V). Characterization by XRD, BET, and SEM indicated that the BT-4 support was poorly crystallized goethite (α-FeOOH) with a specific surface area of 229 m(2) g(-1). In FBR experiments of synthesizing MnBT-4, the Fe and Mn salts were found to have an optimal dosage ratio of less than 4, which maximized the KMnO(4) immobilization efficiency. The immobilized Mn compounds on MnBT-4 underwent an additional oxidation step of As (III), promoting arsenic adsorption. When applied MnBT-4 for As (III) removal from solution, the sorption isotherm was accurately fitted with Langmuir and Freundlich models, while the maximum adsorption capacity of 27.4 mg g(-1) exceeded those of other adsorbents in the literature. Batch experimental results revealed that both raw BT-4 and MnBT-4 could take up a large amount of As (V). However, the MnBT-4 provided a substantially higher As (III) removal efficiency than BT-4.