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International Journal of Molecular... Oct 2023The effect of high-temperature (HT) stress on nicotine biosynthesis in was examined. Nicotine content was measured in mature leaves, young sink leaves, and in roots...
The effect of high-temperature (HT) stress on nicotine biosynthesis in was examined. Nicotine content was measured in mature leaves, young sink leaves, and in roots from well-watered plants grown at 25 °C as controls and from plants exposed to 38 °C and 43 °C temperatures applied for 24, 48, 72, and 96 h duration. At 38 °C, all leaf nicotine levels were significantly less than control plants for up to 72 h exposure but rose sharply thereafter to levels significantly greater than controls with 96 h exposure. In contrast, plants exposed to 43 °C never exhibited a reduction in leaf nicotine content and showed an increase in content with just 48 h exposure. Using radioactive CO and NO, we found that HT stress reduced both CO fixation and nitrate uptake. Furthermore, radiocarbon flux analysis revealed that 'new' carbon partitioning (as C) into the C-radiolabeled amino acid (AA) pool was significantly reduced with HT stress as were yields of [C]-aspartic acid, an important AA in nicotine biosynthesis, and its beta-amido counterpart [C]-asparagine. In contrast, [C]-aspartic acid levels appeared unaffected at 38 °C but were elevated at 43 °C relative to controls. [C]-Asparagine levels were noted to be elevated at both stress temperatures. Since HT reductions in carbon input and nitrogen uptake were noted to impede de novo AA biosynthesis, protein degradation at HT was examined as a source of AAs. Here, leaf total soluble protein (TSP) content was reduced 39% with long exposures to both stress temperatures. However, Ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco) which was 41% TSP appeared unaffected. Altogether, these results support the theory that plant proteins other than Rubisco degrade at elevated temperatures freeing up essential AAs in support of nicotine biosynthesis.
Topics: Nicotiana; Nicotine; Hot Temperature; Ribulose-Bisphosphate Carboxylase; Carbon Dioxide; Asparagine; Aspartic Acid; Photosynthesis; Carbon; Plant Leaves
PubMed: 37958493
DOI: 10.3390/ijms242115509 -
International Journal of Radiation... Mar 2024The aim of this study was to investigate the treatment results and long-term quality of life in patients with early-stage extranodal natural killer/T-cell lymphoma who...
Phase 2 Clinical Trial of Simultaneous Boost Intensity Modulated Radiation Therapy With 3 Dose Gradients in Patients With Stage I-II Nasal Type Natural Killer/T-Cell Lymphoma: Long-Term Outcomes of Survival and Quality of Life.
PURPOSE
The aim of this study was to investigate the treatment results and long-term quality of life in patients with early-stage extranodal natural killer/T-cell lymphoma who were prospectively treated with simultaneous boost intensity modulated radiation therapy (SIB-IMRT) with 3 dose gradients.
METHODS AND MATERIALS
Sixty patients with stage I-II nasal cavity natural killer/T-cell lymphoma (NKTCL) and Waldeyer's ring NKTCL were enrolled in a single-arm, prospective, phase 2 clinical trial from August 2011 to April 2015. All patients were treated with definitive radiation therapy combined with short-course induction chemotherapy. A newly designed SIB-IMRT scheme was uniformly adopted, with 54.6 Gy for the gross tumor volume (GTV) of the primary tumor and GTV of the positive lymph nodes, 50.7 Gy for the high-risk clinical target volume (CTV), and 45.5 Gy for the low-risk CTV, all delivered in 26 daily fractions. Before SIB-IMRT, L-asparaginase-based induction chemotherapy was used in 95.0% (57/60) of patients.
RESULTS
With a median follow-up time of 95.8 months, the 5-year locoregional recurrence-free survival, progression-free survival, and overall survival rates were 83.3%, 81.7%, and 88.3%, respectively. Dosimetric analysis in the first 21 patients showed satisfying conformality for planning target volume of GTV, high-risk CTV, and low-risk CTV, while the organs at risk were well protected. The results of long-term quality-of-life investigations in patients without progression were favorable, and nasal discomfort was the most common symptom. No grade 3 or 4 acute or late toxicities were observed.
CONCLUSIONS
The scheme of target volume delineation and dose setting that we designed has favorable clinical effects with mild side effects in treating patients with stage I-II nasal cavity NKTCL and Waldeyer's ring NKTCL.
Topics: Humans; Radiotherapy, Intensity-Modulated; Quality of Life; Prospective Studies; Radiotherapy Dosage; Lymphoma, Extranodal NK-T-Cell; Killer Cells, Natural
PubMed: 37939733
DOI: 10.1016/j.ijrobp.2023.09.031 -
Journal of Hematology Oct 2023Treatment with non-anthracycline (ANT)-based chemotherapy has increased survival in patients with extranodal natural killer/T-cell lymphoma (ENKTCL). However, the...
BACKGROUND
Treatment with non-anthracycline (ANT)-based chemotherapy has increased survival in patients with extranodal natural killer/T-cell lymphoma (ENKTCL). However, the relative efficacy of various drug combinations has been contentious. We aimed to identify the most effective chemotherapy regimens for newly diagnosed ENKTCL.
METHODS
A network meta-analysis was performed to evaluate the differences in survival and treatment responses across various regimens. The primary objective was overall survival (OS), while secondary outcomes included progression-free survival (PFS), objective response rate (ORR), and complete response (CR). We utilized a Bayesian framework to perform the network meta-analysis. Rank probabilities were assessed by the surface under the cumulative ranking curve (SUCRA). Node-splitting method was used to assess the inconsistency.
RESULTS
A total of 1,113 patients were enrolled across 10 studies. Chemotherapy regimens were grouped into five modalities, for which six types of direct comparisons were available. We identified the asparaginase (ASP)/gemcitabine (GEM)-based regimens superiority over ANT-based, non-ASP/ANT-based and ASP/methotrexate (MTX)-based regimens on OS. Although no significant differences were observed compared with ASP/not otherwise specified-based, ASP/GEM-based regimens were still the best option chemotherapy for OS. Moreover, the ASP/GEM-based regimens demonstrated advantages in PFS, ORR and CR.
CONCLUSIONS
According to our network meta-analysis, it appears that ASP/GEM-based regimens could potentially serve as the most effective frontline chemotherapy option for ENKTCL.
PubMed: 37936976
DOI: 10.14740/jh1169 -
The Malaysian Journal of Medical... Oct 2023L-asparaginase is effective as part of the first line childhood acute lymphoblastic leukaemia (ALL) treatment regimen but suffers the risk of antibody production causing... (Review)
Review
A Review of L-Asparaginase Hypersensitivity in Paediatric Acute Lymphoblastic Leukaemia Patients with Regard to the Measurement of Anti-Asparaginase Antibodies and Their Genetic Predisposition.
L-asparaginase is effective as part of the first line childhood acute lymphoblastic leukaemia (ALL) treatment regimen but suffers the risk of antibody production causing immune-mediated sequelae. This article aimed to describe the clinical implication of L-asparaginase hypersensitivity and review the types of antibodies and genetic polymorphisms contributing to it. Clinical or subclinical L-asparaginase hypersensitivity may lead to suboptimum therapeutic effect and jeopardise the clinical outcome in ALL children. Anti-asparaginase antibodies immunoglobulin (Ig)G, IgM and IgE were identified in the L-asparaginase hypersensitivities. Enzyme-linked immunosorbent assay (ELISA) is commonly used to quantify the IgG and IgM levels. The role of IgE in mediating L-asparaginase hypersensitivity is contradictory. Moreover, the presence of antibodies may not necessarily correlate inversely with the L-asparaginase efficacies in some studies. Patients with specific genetic variants have been shown to be more susceptible to clinical hypersensitivity of L-asparaginase. With the advance of technology, gene polymorphisms have been identified among Caucasians using whole-genome or exon sequencing, but the evidence is scanty among Asians. There is lack of pre-clinical study models that could help in understanding the pathophysiological pathway co-relating the gene expression and anti-asparaginase antibody formation. In conclusion, future research studies are required to fill the current gap in understanding the immune mediated reactions towards L-asparaginase upon its administration and its potential impact to the disease outcome.
PubMed: 37928798
DOI: 10.21315/mjms2023.30.5.4 -
Frontiers in Oncology 2023The systemic immune-inflammation index (SII) is based on the neutrophil, platelet, and lymphocyte counts, and has been identified as a prognostic marker in multiple...
BACKGROUND
The systemic immune-inflammation index (SII) is based on the neutrophil, platelet, and lymphocyte counts, and has been identified as a prognostic marker in multiple types of cancer. However, the potential value of the SII for predicting survival outcomes in patients with extranodal natural killer/T-cell lymphoma (ENKTCL) has not been investigated thus far.
METHOD
This study included 382 patients with ENKTCL treated with asparaginase-base regimens from 2021 to 2017 in West China Hospital (Chengdu, China). Clinical and demographic variables, as well as the prognostic value of the SII, were analyzed using Cox proportional hazards regression analysis.
RESULTS
The complete and objective response rates were 55.8% and 74.9%, respectively. Patients with high SII were associated with a lower rate of complete response, higher rate of B symptoms, and serum lactate dehydrogenase levels above or equal to the upper limits of normal ( < 0.01). Patients with low SII were linked to better overall survival and progression-free survival than those with high SII ( < 0.01). Patients with early-stage disease or prognostic model for natural killer lymphoma with Epstein-Barr virus, defined as the low-risk group, could be further stratified according to the SII ( < 0.01). Negative prognostic factors were determined using the Cox proportional hazards regression analysis, which identified four variables: Eastern Cooperative Oncology Group performance status score ≥2, Stage III/IV disease, positivity for Epstein-Barr virus DNA in plasma, and high SII. Predictive nomograms for the prediction of 3- and 5-year overall survival, as well as progression-free survival, were constructed based on those four variables. The nomograms demonstrated favorable discriminating power.
CONCLUSION
The SII is a novel prognostic marker for ENKTCL, which may be used for the prediction of poorer survival in low-risk patients.
PubMed: 37909016
DOI: 10.3389/fonc.2023.1273504 -
Cancer Medicine Dec 2023The clinicopathologic characteristics and prognosis of nasal and nonnasal extranodal natural killer T-cell lymphoma (ENKTL) are considered to be different. However, the...
BACKGROUND
The clinicopathologic characteristics and prognosis of nasal and nonnasal extranodal natural killer T-cell lymphoma (ENKTL) are considered to be different. However, the underlying features responsible for these differences are not well clarified especially in the era of asparaginase therapy.
METHODS
In total, 1007 newly diagnosed ENKTL patients from 11 medical centers were included in this study. Clinicopathologic characteristics and survival data were collected. The chi-squared test and Kruskal-Wallis test were utilized for the comparison of different groups. Univariable and multivariable Cox proportional hazards models were used to screen prognostic factors.
RESULTS
Overall, 869 (86.3%) patients were nasal forms. Compared to patients with nasal ENKTL, nonnasal patients were at more advanced stages and had poor performance status, bone marrow involvement, elevated serum lactate dehydrogenase (LDH), and CD56-negative status (p < 0.05). The 5-year overall survival (OS) for nasal and nonnasal patients were 65.6% and 45.0%, respectively. The OS of nasal forms patients were superior to nonnasal patients, especially in Eastern Cooperative Oncology Group performance status (ECOG PS) (≥2), advanced stage, KPI (HIR/HR), IPI (HIR/HR), PINK (HR), and high EBV DNA load groups. In patients treated with pegaspargase/L-asparaginase-based regimens, the OS of nasal patients was better than that of nonnasal patients. After adjusting the covariates of age, stage, ECOG PS score, LDH, B symptoms, and BM involvement, results showed that the nonnasal site was associated with poor survival of ENKTL.
CONCLUSIONS
The clinicopathologic characteristics and prognosis of nasal and nonnasal ENKTL patients are different. Nasal forms patients had superior OS than nonnasal patients, especially in the era of asparaginase.
Topics: Humans; Asparaginase; Lymphoma, Extranodal NK-T-Cell; Neoplasm Staging; Prognosis; Retrospective Studies
PubMed: 37902266
DOI: 10.1002/cam4.6674 -
World Journal of Gastrointestinal... Oct 2023Asparaginase (ASP) is an important drug in combined chemotherapy regimens for pediatric acute lymphoblastic leukemia (ALL); ASP-associated pancreatitis (AAP) is the main...
BACKGROUND
Asparaginase (ASP) is an important drug in combined chemotherapy regimens for pediatric acute lymphoblastic leukemia (ALL); ASP-associated pancreatitis (AAP) is the main adverse reaction of ASP. Recurrent pancreatitis is a complication of AAP, for which medication is ineffective.
AIM
To evaluate the efficacy and safety of endoscopic retrograde cholangiopancreatography (ERCP) in treating recurrent pancreatitis due to AAP.
METHODS
From May 2018 to August 2021, ten children (five males and five females; age range: 4-13 years) with AAP were treated using ERCP due to recurrent pancreatitis. Clinical data of the ten children were collected, including their sex, age, weight, ALL risk grading, clinical symptoms at the onset of pancreatitis, time from the first pancreatitis onset to ERCP, ERCP operation status, and postoperative complications. The symptomatic relief, weight change, and number of pancreatitis onsets before and after ERCP were compared.
RESULTS
The preoperative symptoms were abdominal pain, vomiting, inability to eat, weight loss of 2-7 kg, and 2-9 pancreatitis onsets. After the operation, nine of ten patients did not develop pancreatitis, had no abdominal pain, could eat normally; the remaining patient developed three pancreatitis onsets due to the continuous administration of ASP, but eating was not affected. The postoperative weight gain was 1.5-8 kg. There was one case of post ERCP pancreatitis and two cases of postoperative infections; all recovered after medication.
CONCLUSION
ERCP improved clinical symptoms and reduced the incidence of pancreatitis, and was shown to be a safe and effective method for improving the management of recurrent pancreatitis due to AAP.
PubMed: 37900113
DOI: 10.4253/wjge.v15.i10.614 -
Engineering and Expression Strategies for Optimization of L-Asparaginase Development and Production.International Journal of Molecular... Oct 2023Genetic engineering for heterologous expression has advanced in recent years. Model systems such as , and are often used as host microorganisms for the enzymatic... (Review)
Review
Genetic engineering for heterologous expression has advanced in recent years. Model systems such as , and are often used as host microorganisms for the enzymatic production of L-asparaginase, an enzyme widely used in the clinic for the treatment of leukemia and in bakeries for the reduction of acrylamide. Newly developed recombinant L-asparaginase (L-ASNase) may have a low affinity for asparagine, reduced catalytic activity, low stability, and increased glutaminase activity or immunogenicity. Some successful commercial preparations of L-ASNase are now available. Therefore, obtaining novel L-ASNases with improved properties suitable for food or clinical applications remains a challenge. The combination of rational design and/or directed evolution and heterologous expression has been used to create enzymes with desired characteristics. Computer design, combined with other methods, could make it possible to generate mutant libraries of novel L-ASNases without costly and time-consuming efforts. In this review, we summarize the strategies and approaches for obtaining and developing L-ASNase with improved properties.
Topics: Humans; Asparaginase; Asparagine; Leukemia; Escherichia coli; Models, Biological; Antineoplastic Agents
PubMed: 37894901
DOI: 10.3390/ijms242015220 -
Epigenetics Dec 2023Asparaginase is an important agent for the treatment of acute lymphoblastic leukaemia (ALL), but it is occasionally associated with severe adverse events. Thus, for...
Asparaginase is an important agent for the treatment of acute lymphoblastic leukaemia (ALL), but it is occasionally associated with severe adverse events. Thus, for safer and more efficacious therapy, a clinical biomarker predicting asparaginase sensitivity is highly anticipated. Asparaginase depletes serum asparagine by deaminating asparagine into aspartic acid, and ALL cells are thought to be sensitive to asparaginase due to reduced asparagine synthetase (ASNS) activity. We have recently shown that allele-specific methylation of the gene is highly involved in asparaginase sensitivity in B-precursor ALL (BCP-ALL) by using next-generation sequence (NGS) analysis of bisulphite PCR products of the genomic DNA. Here, we sought to confirm the utility of methylation status of the gene evaluated with high-performance liquid chromatography (HPLC) analysis of bisulphite PCR products for future clinical applications. In the global methylation status of 23 CpG sites at the boundary region of promoter and exon 1 of the gene, a strong positive correlation was confirmed between the mean percent methylation evaluated with the HPLC method and that with the NGS method in 79 BCP-ALL cell lines (R = 0.85, = 1.3 × 10) and in 63 BCP-ALL clinical samples (R = 0.84, = 5.0 × 10). Moreover, methylation status of the gene evaluated with the HPLC method was significantly associated with asparaginase sensitivities as well as gene and protein expression levels of ASNS. These observations indicated that the gene methylation status evaluated with the HPLC method is a reliable biomarker for predicting the asparaginase sensitivity of BCP-ALL.
Topics: Humans; Asparaginase; Asparagine; Aspartate-Ammonia Ligase; Chromatography, High Pressure Liquid; Pharmacogenetics; DNA Methylation; Cell Line, Tumor; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 37839090
DOI: 10.1080/15592294.2023.2268814 -
Blood Advances Oct 2023
Alquezar-Artieda N, Kuzilkova D, Roberts J, et al. Restored biosynthetic pathways induced by MSCs serve as rescue mechanism in leukemia cells after L-asparaginase therapy. Blood Adv. 2023;7(10):2228-2236.
Topics: Humans; Asparaginase; Biosynthetic Pathways; Antineoplastic Agents; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 37819641
DOI: 10.1182/bloodadvances.2023011150