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1.
BMC Genomics ; 22(1): 830, 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34789157

RESUMO

BACKGROUND: Trichoderma is a genus of fungi in the family Hypocreaceae and includes species known to produce enzymes with commercial use. They are largely found in soil and terrestrial plants. Recently, Trichoderma simmonsii isolated from decaying bark and decorticated wood was newly identified in the Harzianum clade of Trichoderma. Due to a wide range of applications in agriculture and other industries, genomes of at least 12 Trichoderma spp. have been studied. Moreover, antifungal and enzymatic activities have been extensively characterized in Trichoderma spp. However, the genomic information and bioactivities of T. simmonsii from a particular marine-derived isolate remain largely unknown. While we screened for asparaginase-producing fungi, we observed that T. simmonsii GH-Sj1 strain isolated from edible kelp produced asparaginase. In this study, we report a draft genome of T. simmonsii GH-Sj1 using Illumina and Oxford Nanopore technologies. Furthermore, to facilitate biotechnological applications of this species, RNA-sequencing was performed to elucidate the transcriptional profile of T. simmonsii GH-Sj1 in response to asparaginase-rich conditions. RESULTS: We generated ~ 14 Gb of sequencing data assembled in a ~ 40 Mb genome. The T. simmonsii GH-Sj1 genome consisted of seven telomere-to-telomere scaffolds with no sequencing gaps, where the N50 length was 6.4 Mb. The total number of protein-coding genes was 13,120, constituting ~ 99% of the genome. The genome harbored 176 tRNAs, which encode a full set of 20 amino acids. In addition, it had an rRNA repeat region consisting of seven repeats of the 18S-ITS1-5.8S-ITS2-26S cluster. The T. simmonsii genome also harbored 7 putative asparaginase-encoding genes with potential medical applications. Using RNA-sequencing analysis, we found that 3 genes among the 7 putative genes were significantly upregulated under asparaginase-rich conditions. CONCLUSIONS: The genome and transcriptome of T. simmonsii GH-Sj1 established in the current work represent valuable resources for future comparative studies on fungal genomes and asparaginase production.


Assuntos
Trichoderma , Asparaginase , Genoma , Hypocreales , Telômero , Trichoderma/genética
2.
J Hematol Oncol ; 14(1): 182, 2021 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-34717720

RESUMO

Asparaginase is an important drug to treat childhood haematological malignancies. Data on the association between human leukocyte antigens (HLA) and asparaginase hypersensitivity among Chinese are lacking. We conducted a retrospective study to identify HLA alleles associated with asparaginase hypersensitivity among Chinese children with acute lymphoblastic leukaemia (ALL), mixed phenotype leukaemia and non-Hodgkin lymphoma (NHL), who received asparaginases with HLA typing performed between 2009 and 2019. 107 Chinese patients were analysed. 66.3% (71/107) developed hypersensitivity to at least one of the asparaginases. HLA-B*46:01 (OR 3.8, 95% CI 1.4-10.1, p < 0.01) and DRB1*09:01 (OR 4.3, 95% CI 1.6-11.4, p < 0.01) were significantly associated with L-asparaginase hypersensitivities, which remained significant after adjustment for age, gender and B cell ALL [HLA-B*46:01 (adjusted OR 3.5, 95% 1.3-10.5, p = 0.02) and DRB1*09:01 (OR 4.4, 95% CI 1.6-13.3, p < 0.01)].


Assuntos
Antineoplásicos/efeitos adversos , Asparaginase/efeitos adversos , Hipersensibilidade a Drogas/genética , Antígenos HLA/genética , Alelos , Antineoplásicos/uso terapêutico , Grupo com Ancestrais do Continente Asiático/genética , Asparaginase/uso terapêutico , Criança , Pré-Escolar , China/epidemiologia , Hipersensibilidade a Drogas/etiologia , Feminino , Predisposição Genética para Doença , Humanos , Linfoma não Hodgkin/tratamento farmacológico , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Estudos Retrospectivos
3.
Sheng Wu Gong Cheng Xue Bao ; 37(9): 3242-3252, 2021 Sep 25.
Artigo em Chinês | MEDLINE | ID: mdl-34622632

RESUMO

L-asparaginase hydrolyzes L-asparagine to produce L-aspartic acid and ammonia. It is widely distributed in microorganisms, plants and serum of some rodents, and has important applications in the pharmaceutical and food industries. However, the poor thermal stability, low catalytic efficiency and low yield hampered the further application of L-asparaginase. In this paper, rational design and 5' untranslated region (5'UTR) design strategies were used to increase the specific enzyme activity and protein expression of L-asparaginase derived from Rhizomucor miehei (RmAsnase). The results showed that among the six mutants constructed through homology modeling combined with sequence alignment, the specific enzyme activity of the mutant A344E was 1.5 times higher than the wild type. Subsequently, a food-safe strain Bacillus subtilis 168/pMA5-A344E was constructed, and the UTR strategy was used for the construction of recombinant strain B. subtilis 168/pMA5 UTR-A344E. The enzyme activity of B. subtilis 168/pMA5 UTR-A344E was 7.2 times higher than that of B. subtilis 168/pMA5-A344E. The recombinant strain B. subtilis 168/pMA5 UTR-A344E was scaled up in 5 L fermenter, and the final yield of L-asparaginase was 489.1 U/mL, showing great potential for industrial application.


Assuntos
Asparaginase , Rhizomucor , Asparaginase/biossíntese , Asparaginase/genética , Bacillus subtilis/genética , Microbiologia Industrial , Engenharia de Proteínas , Rhizomucor/enzimologia , Alinhamento de Sequência
4.
Sci Rep ; 11(1): 17861, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34504186

RESUMO

The enzyme L-asparaginase (L-ASNase) is used in the treatment of Acute Lymphoblastic Leukemia. The preparations of this enzyme for clinical use are derived from bacterial sources and its use is associated with serious adverse reactions. In this context, it is important to find new sources of L-ASNase. In this work, the Placket-Burman Experimental Design (PBD) was used to determine the influence of the variables on the L-ASNase production then it was followed by a 28-4 Factorial Fractional Design (FFD). The results obtained from PBD have shown a range of L-ASNase activity, from 0.47 to 1.77 U/gcell and the results obtained from FFD have showed a range of L-ASNase activity, from 1.10 to 2.36 U/gcell. L-proline and ammonium sulfate were identified as of significant positive variables on this production enzyme by Penicillium cerradense sp. nov. The precise identification of this new species was confirmed by morphological characteristics and sequence comparisons of the nuclear 18S-5.8S-28S partial nrDNA including the ITS1 and ITS2 regions, RNA polymerase II, ß-tubulin and calmodulin genomic regions. The genetic sequence coding for the L-ASNase was obtained after carrying out a full genome sequencing. The L-ASNase expressed by P. cerradense sp. nov may have promising antineoplastic properties.


Assuntos
Antineoplásicos/uso terapêutico , Asparaginase/genética , Penicillium/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Prolina/genética , Asparaginase/uso terapêutico , Humanos , Penicillium/metabolismo , Prolina/uso terapêutico , Análise de Sequência de DNA/métodos
5.
Int J Mol Sci ; 22(18)2021 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-34576056

RESUMO

L-asparaginase (L-ASNase) is a vital enzyme with a broad range of applications in medicine and food industry. Drawbacks of current commercial L-ASNases stimulate the search for better-producing sources of the enzyme, and extremophiles are especially attractive in this view. In this study, a novel L-asparaginase originating from the hyperthermophilic archaeon Thermococcus sibiricus (TsA) was expressed in Escherichia coli, purified and characterized. The enzyme is optimally active at 90 °C and pH 9.0 with a specific activity of 2164 U/mg towards L-asparagine. Kinetic parameters KM and Vmax for the enzyme are 2.8 mM and 1200 µM/min, respectively. TsA is stable in urea solutions 0-6 M and displays no significant changes of the activity in the presence of metal ions Ni2+, Cu2+, Mg2+, Zn2+ and Ca2+ and EDTA added in concentrations 1 and 10 mmol/L except for Fe3+. The enzyme retains 86% of its initial activity after 20 min incubation at 90 °C, which should be enough to reduce acrylamide formation in foods processed at elevated temperatures. TsA displays strong cytotoxic activity toward cancer cell lines K562, A549 and Sk-Br-3, while normal human fibroblasts WI-38 are almost unsensitive to it. The enzyme seems to be a promising candidate for further investigation and biotechnology application.


Assuntos
Archaea/enzimologia , Asparaginase/isolamento & purificação , Biotecnologia/tendências , Thermococcus/enzimologia , Sequência de Aminoácidos/genética , Antineoplásicos/química , Antineoplásicos/farmacologia , Asparaginase/química , Asparaginase/genética , Asparagina/metabolismo , Estabilidade Enzimática/genética , Escherichia coli/efeitos dos fármacos , Cinética , Especificidade por Substrato/genética
7.
Korean J Intern Med ; 36(6): 1471-1485, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34530526

RESUMO

BACKGROUND/AIMS: The objective of this study was to evaluate the efficacy and feasibility of the pediatric-inspired regimen of the adult acute lymphoblastic leukemia (ALL) Working Party, the Korean Society of Hematology. METHODS: Data of 99 patients with newly diagnosed ALL, who were treated with the KALLA 1406/1407 protocol, were retrospectively analyzed. All patients equally received age-adjusted daunorubicin, vincristine, and prednisolone. L-asparaginase was additionally administered to Philadelphia (Ph)-negative patients according to age, whereas Ph-positive patients received 600 mg/day of imatinib. RESULTS: A total of 99 patients were enrolled in this study, of whom 62 (62.6%) were diagnosed with Ph-negative ALL and 37 (37.3%) were diagnosed with Ph-positive ALL. The median age of patients in the Ph-negative ALL group was 46 years, and that of patients in the Ph-positive ALL group was 49 years. In patients with Ph-negative ALL, 57 (92%) patients achieved complete remission (CR) and CR with incomplete hematologic recovery (CRi). Disease-free survival (DFS) and overall survival (OS) rates at 2 years were estimated to be 42% and 63%, respectively. In patients with Ph-positive ALL, 32 (86%) patients achieved CR/CRi, and 2-year DFS and OS were 31.2% and 49.1%, respectively. Patients who were able to proceed to the allogeneic hematopoietic cell transplantation and younger patients showed significantly superior survival in both Ph-negative ALL and Ph-positive ALL. Neutropenic fever and bacterial infection were the most common and severe adverse events. CONCLUSION: The KALLA 1406/1407 protocol showed tolerable toxicities in adult ALL patients. Especially, younger patients had more survival benefits with KALLA 1406/1407 protocol.


Assuntos
Asparaginase , Leucemia-Linfoma Linfoblástico de Células Precursoras , Asparaginase/efeitos adversos , Humanos , Mesilato de Imatinib , Pessoa de Meia-Idade , Cromossomo Filadélfia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Estudos Retrospectivos
8.
Clin J Oncol Nurs ; 25(5): 511-513, 2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34533506

RESUMO

Pegaspargase, a chemotherapy drug known to improve survival outcomes in acute lymphoblastic leukemia, is associated with a risk for hypersensitivity reactions. At a children's hospital in the midwestern United States, two patients developed unusual reactions consisting of disseminated urticaria about two weeks after their second dose of pegaspargase. Both patients then proceeded to have severe anaphylaxis with the third dose of pegaspargase. These cases highlight the importance of advanced practice nurses being alert for the occurrence of unusual and delayed reactions to chemotherapy administration.


Assuntos
Anafilaxia , Hipersensibilidade a Drogas , Urticária , Anafilaxia/induzido quimicamente , Anafilaxia/diagnóstico , Asparaginase/efeitos adversos , Criança , Hipersensibilidade a Drogas/diagnóstico , Hipersensibilidade a Drogas/etiologia , Humanos , Polietilenoglicóis , Urticária/induzido quimicamente , Urticária/diagnóstico
9.
Paediatr Drugs ; 23(5): 457-463, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34351604

RESUMO

Asparaginase therapy is a vital agent in the treatment of acute lymphoblastic leukemia (ALL), with increasing evidence of its high importance in high-risk ALL populations. However, despite the clear clinical and biological benefits of asparaginase therapy, many patients experience toxicities. A well-known treatment-limiting toxicity is asparaginase-associated pancreatitis (AAP). If severe, it necessitates discontinuation of asparaginase therapy, which can lead to a higher risk of relapse in patients with ALL. New protocols for ALL therapy have increased overall total doses of asparaginase therapy in select high-risk populations and have incorporated longer half-life formulations of pegylated asparaginase. Treatment drug monitoring has also allowed assurance of adequate levels of asparagine depletion throughout treatment. It is currently unknown if these changes will increase rates of AAP. Interestingly, important pharmacogenomics data, such as single nucleotide polymorphisms, can identify patients at the highest risk for severe AAP. The incidence of AAP in recent trials, current pharmacogenomic data that could further our understanding of the disease, and the importance of cautiously re-exposing patients to further asparaginase treatment after an initial episode of AAP are discussed.


Assuntos
Antineoplásicos , Pancreatite , Leucemia-Linfoma Linfoblástico de Células Precursoras , Doença Aguda , Antineoplásicos/efeitos adversos , Asparaginase/efeitos adversos , Criança , Humanos , Pancreatite/induzido quimicamente , Pancreatite/tratamento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico
10.
Turk J Pediatr ; 63(4): 639-647, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34449146

RESUMO

BACKGROUND: Chemotherapy with high dose methotrexate is the mainstay of treatment for Burkitt lymphoma (BL), especially to manage central nervous system (CNS) disease. However, methotrexate administration requires close drug level monitoring for appropriate folinic acid rescue, which might not be readily available in all centers. In this study, we assessed the long-term treatment outcomes of a modified Non-Hodgkin lymphoma (NHL)-Berlin-Frankfurt-Munster (BFM) 90 regimen in pediatric high-risk BL without CNS involvement. METHODS: Between 1999 and 2011, 42 patients (median age: 7 years) with advanced-stage BL were treated with modified NHL-BFM 90 regimen (methotrexate at a dose of 1 g/m2). Demographic data, stage, lactate dehydrogenase (LDH) and treatment results were retrospectively evaluated. The patients were assessed for toxicity, survival and CNS recurrence. RESULTS: Thirty-six patients had Stage III and six had Stage IV disease, respectively. The median LDH level was 1,432 IU/L. Four patients died of infectious and metabolic complications. One patient had local recurrence at the 48 < sup > th < /sup > month of the follow-up and he is in the second remission for 72 months. In Kaplan-Meier analysis, the overall survival and event-free survival rates at 10 years were found as 90 % and 88 %, respectively. None of our patients died of treatment failure. CONCLUSIONS: The administration of the reduced dose of methotrexate seems to not compromise treatment success nor increase the risk of CNS recurrence in high-risk BL without CNS involvement. The limitation of the study is that it is not randomized. Our treatment scheme might be considered for centers without methotrexate measurement facility.


Assuntos
Linfoma de Burkitt , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Asparaginase , Linfoma de Burkitt/tratamento farmacológico , Criança , Daunorrubicina , Humanos , Masculino , Recidiva Local de Neoplasia , Prednisona , Estudos Retrospectivos , Resultado do Tratamento , Vincristina
11.
Pediatr Blood Cancer ; 68(11): e29295, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34398511

RESUMO

Vaccinationis a critical tool in the prevention of COVID-19 infection for individuals and for communities. The mRNA vaccines contain polyethylene glycol (PEG) as a stabilizer. Currently, in North America, only the BNT162b2 (Pfizer-BioNTech) mRNA vaccine is approved for individuals aged 12-17. Most patients treated with contemporary regimens for acute lymphoblastic leukemia receive PEG-asparaginase (PEG-ASNase) and 10%-30% will develop allergic reactions. Optimizing access and safety for vaccine administration for these patients is critical. This report describes a process developed to support COVID vaccination in a cohort of adolescents and young adults with a history of PEG-ASNase allergy.


Assuntos
Antineoplásicos/efeitos adversos , Asparaginase/efeitos adversos , Vacinas contra COVID-19/uso terapêutico , COVID-19/prevenção & controle , Hipersensibilidade a Drogas/complicações , Polietilenoglicóis/efeitos adversos , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicações , Adolescente , Adulto , COVID-19/complicações , Vacinas contra COVID-19/administração & dosagem , Vacinas contra COVID-19/efeitos adversos , Criança , Hipersensibilidade a Drogas/etiologia , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Adulto Jovem
12.
Am J Hematol ; 96(11): 1481-1490, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34449095

RESUMO

Extranodal natural killer/T-cell lymphoma, nasal-type (ENKTL) is a distinct subtype of non-Hodgkin lymphoma and most of the patients presented localized disease. Combined modality therapy (CMT), namely chemotherapy combined with radiotherapy, has been recommended for patients with early-stage ENKTL. However, the optimal CMT has not been fully clarified. This study reports the efficacy and toxicity of sequential P-GEMOX (pegaspargase, gemcitabine and oxaliplatin) and radiotherapy in a large Chinese cohort comprising of 202 patients diagnosed with early-stage ENKTL from six medical centers. The observed best overall response rate was 96.0% and 168 (83.2%) patients achieved complete remission. With a median follow-up of 44.1 months, the 3-year progression-free survival (PFS) and overall survival (OS) were 74.6% and 85.2%, respectively. Multivariate analysis suggested that extensive primary tumor (PFS, hazard ratio [HR] 3.660, 95% CI 1.820-7.359, p < 0.001; OS, HR 3.825, 95% CI 1.442-10.148, p = 0.007) and Eastern Cooperative Oncology Group performance status ≥ 2 (PFS, 3.042, 95% CI 1.468-6.306, p = 0.003; OS, HR 3.983, 95% CI 1.678-9.457, p = 0.02) were independent prognostic factors for survival outcomes. Among the established prognostic models for ENKTL, the nomogram-revised risk index model had optimal prognostic risk stratification ability (PFS, p < 0.001; OS, p < 0.001) and relatively balanced population distribution. The adverse events of this CMT were well-tolerated and manageable. In conclusion, sequential P-GEMOX and radiotherapy showed favorable efficacy with acceptable toxicity, and could be an effective treatment option for early-stage ENKTL patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Asparaginase/uso terapêutico , Desoxicitidina/análogos & derivados , Linfoma Extranodal de Células T-NK/tratamento farmacológico , Linfoma Extranodal de Células T-NK/radioterapia , Polietilenoglicóis/uso terapêutico , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Asparaginase/efeitos adversos , Desoxicitidina/efeitos adversos , Desoxicitidina/uso terapêutico , Feminino , Humanos , Linfoma Extranodal de Células T-NK/diagnóstico , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/efeitos adversos , Compostos Organoplatínicos/uso terapêutico , Polietilenoglicóis/efeitos adversos , Prognóstico , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
13.
J Mol Graph Model ; 109: 108007, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34461521

RESUMO

The l-asparaginase enzyme is used in cancer therapy, mainly acute lymphoid leukemia (ALL). Commercial enzymes (EcASNase2) cause adverse reactions during treatment, such as immunogenicity. A human enzyme could be a non-immunogenic substitute. However, no candidate was found showing efficient kinetic properties. HASNase1 is an l-asparaginase that comes from the N-terminal domain of a protein called 60 kDa-lysophospholipase and its 3D structure has not been resolved. HASNase1 is homologous to EcASNase1 and gpASNase1, and this last one has shown efficient kinetic properties. Homology modeling was used to find the 3D structure of hASNase1, so one could submit it to Molecular Dynamics (MD), in order to understand structural differences that lead to different catalytic efficiency compared to EcASNase2 and gpASNase1. The interaction potential between L-Asn and active site residues showed that the substrate can rotate in the site when Region1 is open. Region1 residues sequence favors deformations and movements as shown in MD. Region2-A is linear in gpASNase1, and it features a helix portion in hASNase1, which leaves the Tyr308 position projected to the active site ratifying its role in catalytic efficiency. Analysis of Lys188 orientation and movement showed the effect of positive cooperativity in hASNase1. It was found that the presence of Asn at the allosteric site helps, not only in Region1 stabilization, but also in Lys188 stabilization for the maintenance of the triad. Despite structural similarities in hASNase1, gpASNase1, and EcASNase2, there are differences in structural determinants that, in addition to allosterism, may explain the different kinetic properties.


Assuntos
Simulação de Dinâmica Molecular , Leucemia-Linfoma Linfoblástico de Células Precursoras , Asparaginase/metabolismo , Domínio Catalítico , Humanos , Cinética
14.
Talanta ; 234: 122676, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34364476

RESUMO

Stimuli-responsive polymer enzyme reactors have become a major area of research interest, from their fundamental aspects to applications in bio-living science. However, the polymer materials, that enable the controllable enzymolysis based on ultraviolet-visible (UV)-responsive properties, have remained unexplored. Herein, an enzyme reactor was fabricated by immobilization of l-asparaginase on an UV-responsive porous polymer membrane (UV-PPMER), which consisted of poly(styrene-maleicanhydride-4-[(4-methacryloyloxy)phenylazo]benzoic acid) [P(St-MAn-MPABA)], and explored its controllable enzymolysis. By controlling the "on/off" switch of 365 nm UV irradiation, the configuration of polymer membrane surface changed to improve and tune the enzymolysis. Using l-asparagine (L-Asn) as the substrate, the enzymatic efficiency of the UV-PPMER was evaluated by a chiral capillary electrophoresis technique. Upon UV irradiation, the PMPABA moiety in the membrane changed from a trans- to a cisconfiguration and encapsulated the enzyme and substrate into a narrow cavity, further improving the enzymatic efficiency due to the confinement effect. It was found that the enzymatic reaction rate with the UV-PPMER under UV irradiation (13.3 mM min-1) was 4.5 times higher than that of UV irradiation was off (2.94 mM min-1). Additionally, the low cytotoxicity and excellent UV-responsivity of UV-PPMER were verified in the living cells and serum samples.


Assuntos
Asparaginase , Polímeros , Reatores Biológicos , Eletroforese Capilar , Humanos , Membranas
15.
ESMO Open ; 6(4): 100206, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34242966

RESUMO

BACKGROUND: This study evaluated the survival benefit of asparaginase (ASP)-based versus non-ASP-based chemotherapy combined with radiotherapy in a real-world cohort of patients with early-stage extranodal nasal-type natural killer/T-cell lymphoma (ENKTCL). PATIENTS AND METHODS: We identified 376 patients who received combined radiotherapy with either ASP-based (ASP, platinum, and gemcitabine; n = 286) or non-ASP-based (platinum and gemcitabine; n = 90) regimens. The patients were stratified into low-, intermediate-, and high-risk groups using the early stage-adjusted nomogram-revised risk index. Overall survival (OS) and distant metastasis (DM)-free survival (DMFS) between the chemotherapy regimens were compared using inverse probability of treatment weighting (IPTW) and multivariable analyses. RESULTS: ASP-based (versus non-ASP-based) regimens significantly improved 5-year OS (84.5% versus 73.2%, P = 0.021) and DMFS (84.4% versus 74.5%, P = 0.014) for intermediate- and high-risk patients, but not for low-risk patients in the setting of radiotherapy. Moreover, ASP-based regimens decreased DM, with a 5-year cumulative DM rate of 14.9% for ASP-based regimens compared with 25.1% (P = 0.014) for non-ASP-based regimens. The survival benefit of ASP-based chemotherapy and radiotherapy remained consistent after adjusting the confounding variables using IPTW and multivariate analyses; additional sensitivity analyses confirmed these results. CONCLUSIONS: The findings provided support for ASP-based chemotherapy and radiotherapy as a first-line treatment strategy for intermediate- and high-risk early-stage ENKTCL.


Assuntos
Asparaginase , Linfoma Extranodal de Células T-NK , Asparaginase/uso terapêutico , Humanos , Linfoma Extranodal de Células T-NK/tratamento farmacológico , Linfoma Extranodal de Células T-NK/radioterapia , Estadiamento de Neoplasias , Risco
16.
Cell Death Dis ; 12(7): 709, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34267184

RESUMO

Asparaginase depletes extracellular asparagine in the blood and is an important treatment for acute lymphoblastic leukemia (ALL) due to asparagine auxotrophy of ALL blasts. Unfortunately, resistance occurs and has been linked to expression of the enzyme asparagine synthetase (ASNS), which generates asparagine from intracellular sources. Although TP53 is the most frequently mutated gene in cancer overall, TP53 mutations are rare in ALL. However, TP53 mutation is associated with poor therapy response and occurs at higher frequency in relapsed ALL. The mutant p53-reactivating compound APR-246 (Eprenetapopt/PRIMA-1Met) is currently being tested in phase II and III clinical trials in several hematological malignancies with mutant TP53. Here we present CEllular Thermal Shift Assay (CETSA) data indicating that ASNS is a direct or indirect target of APR-246 via the active product methylene quinuclidinone (MQ). Furthermore, combination treatment with asparaginase and APR-246 resulted in synergistic growth suppression in ALL cell lines. Our results thus suggest a potential novel treatment strategy for ALL.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Asparaginase/farmacologia , Proliferação de Células/efeitos dos fármacos , Mutação , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Quinuclidinas/farmacologia , Proteína Supressora de Tumor p53/agonistas , Carbono-Nitrogênio Ligases com Glutamina como Doadora de N-Amida/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Sinergismo Farmacológico , Humanos , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
17.
Bioresour Technol ; 339: 125599, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34303095

RESUMO

L-asparaginase shows great potential as a food enzyme to reduce acrylamide formation in fried and baked products. But for food applications, enzymes must be stable at high temperatures and have higher catalytic efficiency. These desirable characteristics are conferred by the immobilization of enzymes on a suitable matrix. The present study aimed to immobilize the L-asparaginase enzyme on magnetic nanoparticles to reduce acrylamide content in the food system. Immobilized preparations were characterized using SEM, TEM, FTIR, UV-spectrometry, and XRD diffraction analyses. These nanoparticles enhanced the thermal stability of the enzyme up to four-fold at 70 °C compared to the free enzyme. Kinetic parameters exhibited an increase in Vmax, Km, and catalytic efficiency by ~ 38% than the free counterpart. The immobilized preparations were reusable for up to five cycles. Moreover, their application in the pre-treatment coupled with blanching of potato chips led to a significant reduction (greater than 95%) of acrylamide formation.


Assuntos
Asparaginase , Nanopartículas de Magnetita , Acrilamida , Asparaginase/metabolismo , Catálise , Estabilidade Enzimática , Enzimas Imobilizadas/metabolismo , Cinética
18.
Int J Biol Macromol ; 185: 966-982, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34237367

RESUMO

Herein, our suggestion is to immobilize enzymes in-situ on absorbable shape-memory stents instead of injecting therapeutic enzymes into the blood. Chitosan (CHI)-based stents were tailored as novel support and the enzyme-immobilizing ability was elucidated using L-asparaginase (L-ASNase). For developing shape-memory stents, CHI-glycerol (GLY) solution was prepared and further blended with different ratios of polyethylene glycol (PEG), and polyvinyl alcohol (PVA). Afterward, the blends were modified by ionic crosslinking with sodium tripolyphosphate to obtain a shape-memory character. L-ASNase was included in the blends by using in-situ method before ionic crosslinking. The prepared stents, with or without L-ASNase, were comprehensively characterized by using several techniques. Collectively, immobilized L-ASNase exhibited much better performance in immobilization parameters than free one, thanks to its improved stability and reusability. For instance, CHI/GLY/PEG-3@L-ASNase retained about 70% of the initial activity after storage at 30 °C for 2 weeks, whereas the free form lost half of its initial activity. Besides, it retained 73.4% residual activity after 15 consecutive cycles. Most importantly, stent formulations exhibited ~60% activity in the bioreactor system after 4 weeks of incubation. Given the above results, shape-memory stents can be a promising candidate as a new platform for immobilization, especially in the blood circulation system.


Assuntos
Asparaginase/farmacologia , Quitosana/química , Polietilenoglicóis/química , Álcool de Polivinil/química , Asparaginase/química , Estabilidade de Medicamentos , Estabilidade Enzimática , Enzimas Imobilizadas/química , Enzimas Imobilizadas/farmacologia , Concentração de Íons de Hidrogênio , Cinética , Polietilenoglicóis/farmacologia , Stents , Temperatura , Molhabilidade
19.
World J Microbiol Biotechnol ; 37(7): 120, 2021 Jun 16.
Artigo em Inglês | MEDLINE | ID: mdl-34132920

RESUMO

The diversity of actinobacteria associated with marine ascidian Phallusia nigra from Andaman Islands was investigated. A total of 10 actinobacteria were isolated and based on the biochemical and molecular characterization, the isolates were assigned to 7 different actinobacterial genera. Eight putatively novel species belonging to genera Rhodococcus, Kineococcus, Kocuria, Janibacter, Salinispora and Arthrobacter were identified based on 16S rDNA sequence similarity with the NCBI database. The organic extracts of ten isolates displayed considerable bioactivity against test pathogens, which were Gram-positive and Gram-negative in nature. PCR-based screening for type I and type II polyketide synthases (PKS-I, PKS-II) and nonribosomal peptide synthetases (NRPS) revealed that, 10 actinobacterial isolates encoded at least one type of polyketide synthases biosynthesis gene. Majority of the isolates found to produce industrially important enzymes; amylase, protease, gelatinase, lipase, DNase, cellulase, urease, phosphatase and L-asparaginase. The present study emphasized that, ascidians are a prolific resource for novel bioactive actinobacteria with potential for novel drug discovery. This result expands the scope to functionally characterize the novel ascidian associated marine actinobacteria and their metabolites could be a source for the novel molecules of commercial interest.


Assuntos
Actinobacteria/classificação , Actinobacteria/enzimologia , Actinobacteria/genética , Organismos Aquáticos/microbiologia , Simbiose , Urocordados/microbiologia , Actinobacteria/metabolismo , Amilases/metabolismo , Animais , Antibacterianos/metabolismo , Asparaginase/metabolismo , Proteínas de Bactérias/metabolismo , Técnicas de Tipagem Bacteriana , Biodiversidade , Celulase/metabolismo , Celulose/metabolismo , DNA Bacteriano , Microbiologia Industrial , Ilhas , Lipase/metabolismo , Peptídeo Hidrolases/metabolismo , Peptídeo Sintases/genética , Policetídeo Sintases/genética , RNA Ribossômico 16S , Análise de Sequência de DNA
20.
Cancer Chemother Pharmacol ; 88(4): 655-664, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34170389

RESUMO

PURPOSE: We evaluated effects of asparaginase dosage, schedule, and formulation on CSF asparagine in children with acute lymphoblastic leukemia (ALL). METHODS: We evaluated CSF asparagine (2114 samples) and serum asparaginase (5007 samples) in 482 children with ALL treated on the Total XVI study (NCT00549848). Patients received one or two 3000 IU/m2 IV pegaspargase doses during induction and were then randomized in continuation to receive 2500 IU/m2 or 3500 IU/m2 IV intermittently (four doses) on the low-risk (LR) or continuously (15 doses) on the standard/high risk (SHR) arms. A pharmacokinetic-pharmacodynamic model was used to estimate the duration of CSF asparagine depletion below 1 uM. RESULTS: During induction, CSF asparagine depletion after two doses of pegaspargase was twice as long as one dose (median 30.7 vs 15.3 days, p < 0.001). During continuation, the higher dose increased the CSF asparagine depletion duration by only 9% on the LR and 1% in the SHR arm, consistent with the nonlinear pharmacokinetics of serum asparaginase. Pegaspargase caused a longer CSF asparagine depletion duration (1.3-5.3-fold) compared to those who were switched to erwinase (p < 0.001). The median (quartile range) serum asparaginase activity needed to maintain CSF asparagine below 1 µM was 0.44 (0.20, 0.99) IU/mL. Although rare, CNS relapse was higher with decreased CSF asparagine depletion (p = 0.0486); there was no association with relapse at any site (p = 0.3). CONCLUSIONS: The number of pegaspargase doses has a stronger influence on CSF asparagine depletion than did dosage, pegaspargase depleted CSF asparagine longer than erwinase, and CSF asparagine depletion may prevent CNS relapses.


Assuntos
Antineoplásicos/administração & dosagem , Asparaginase/administração & dosagem , Asparagina/líquido cefalorraquidiano , Polietilenoglicóis/administração & dosagem , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Antineoplásicos/farmacocinética , Asparaginase/farmacocinética , Criança , Relação Dose-Resposta a Droga , Esquema de Medicação , Humanos , Modelos Biológicos , Polietilenoglicóis/farmacocinética , Estudos Prospectivos
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