- Identification and validation of l-asparaginase as a potential metabolic target against Mycobacterium tuberculosis. [Journal Article]
- JCJ Cell Biochem 2018 Sep 19
- Multidrug-resistant Mycobacterium tuberculosis (Mtb) has emerged as a major health challenge, necessitating the search for new molecular targets. A secretory amidohydrolase, l-asparaginase of Mtb (Mt...
Multidrug-resistant Mycobacterium tuberculosis (Mtb) has emerged as a major health challenge, necessitating the search for new molecular targets. A secretory amidohydrolase, l-asparaginase of Mtb (MtA), originally implicated in nitrogen assimilation and neutralization of acidic microenvironment inside human alveolar macrophages, has been proposed as a crucial metabolic enzyme. To investigate whether this enzyme could serve as a potential drug target, it was studied for structural details and active site-specific inhibitors were tested on cultured Mycobacterial strain. The structural details of MtA obtained through comparative modeling and molecular dynamics simulations provided insights about the orchestration of an alternate reaction mechanism at the active site. This was contrary to the critical Tyr flipping mechanism reported in other asparaginases. We report the novel finding of Tyr to Val replacement in catalytic triad I along with the structural reorganization of a β-hairpin loop upon substrate binding in MtA active site. Further, 5 MtA-specific, active-site-based inhibitors were obtained by following a rigorous differential screening protocol. When tested on Mycobacterium culture, 3 of these, M3 (ZINC 4740895), M26 (ZINC 33535), and doxorubicin showed promising results with inhibitory concentrations (IC 50 ) of 431, 100, and 56 µM, respectively. Based on our findings and considering stark differences with human asparaginase, we project MtA as a promising molecular target against which the selected inhibitors may be used to counteract Mtb infection effectively.
- Insulin-dependent diabetes: A chronic complication to acute pancreatitis in childhood acute lymphoblastic leukemia. [Journal Article]
- PBPediatr Blood Cancer 2018 Sep 14; :e27437
- Pancreatitis is a frequent toxicity to acute lymphoblastic leukemia (ALL) treatment, significantly associated with asparaginase use, and may be followed by severe complications such as acute hypergly...
Pancreatitis is a frequent toxicity to acute lymphoblastic leukemia (ALL) treatment, significantly associated with asparaginase use, and may be followed by severe complications such as acute hyperglycaemia, need for mechanical ventilation, pseudocysts, and death. Here, we provide novel data on seven patients diagnosed with diabetes after pancreatitis and still requiring insulin treatment after a median follow-up of 4.2 years (range: 1.7-9.2). We describe the clinical course of pancreatitis and illustrate the association between pancreatic pseudocysts, older age, and development of insulin-dependent diabetes. Together, this study documents the persisting burden of pancreatitis in childhood ALL and underlines the need for plasma glucose level monitoring.
- Long-Term Risk of Venous Thromboembolism in Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study. [Journal Article]
- JCJ Clin Oncol 2018 Sep 14; :JCO2018784595
- Purpose To estimate the incidence of late-occurring venous thromboembolism (VTE) among survivors of childhood cancer and to identify risk factors for VTE to facilitate diagnosis and prevention. Metho...
Purpose To estimate the incidence of late-occurring venous thromboembolism (VTE) among survivors of childhood cancer and to identify risk factors for VTE to facilitate diagnosis and prevention. Methods The Childhood Cancer Survivor Study is a multi-institutional cohort of 24,355 5-year childhood cancer survivors (diagnosed between 1970 and 1999; median age at last follow-up, 28.7 years [range, 5.6 to 58.9 years]; median follow-up since diagnosis, 21.3 years [range, 5.0 to 39.2 years]) and 5,051 sibling participants. The primary end point was self-reported late (≥ 5 years after cancer diagnosis) VTE. Rate ratios (RRs) were estimated with multivariable piecewise exponential models. Results Late VTE incidence among survivors and siblings was 1.1 and 0.5 events per 1,000 person-years, respectively (RR, 2.2; 95% CI, 1.7 to 2.8), with 2.5 excess events per 100 survivors over 35 years. Among survivors, risk factors for VTE were female sex (RR, 1.3; 95% CI, 1.1 to 1.6), cisplatin (reference none; 1 to 199 mg/m2: RR, 3.0 [95% CI, 1.4 to 6.5]; 200 to 399 mg/m2: RR, 1.9 [95% CI, 1.0 to 3.6]; ≥ 400 mg/m2: RR, 2.0 [95% CI, 1.2 to 3.3]), l-asparaginase (RR, 1.3; 95% CI, 1.0 to 1.7), obesity or underweight (reference body mass index [BMI] 18.5 to 24.9 kg/m2; BMI ≥ 30.0 kg/m2: RR, 1.6 [95% CI, 1.2 to 2.0]; BMI < 18.5 kg/m2: RR, 2.4 [95% CI, 1.7 to 3.4]), and late cancer recurrence or subsequent malignant neoplasm (RR, 4.6; 95% CI, 3.6 to 5.8). Among lower-extremity osteosarcoma survivors, limb salvage (reference amputation; RR, 3.1; 95% CI, 1.2 to 7.5) and cisplatin 200 to 399 or ≥ 400 mg/m2 (reference none; RR, 4.0 [95% CI, 1.1 to 14.6] and 2.9 [95% CI, 1.1 to 8.0], respectively) were independently associated with late VTE. VTE was associated with increased risk for nonexternal cause late mortality (RR, 1.9; 95% CI, 1.6 to 2.3). Conclusion Childhood cancer survivors are at increased risk for VTE across their lifespan and a diagnosis of VTE increases mortality risk. Interventions that target potentially modifiable comorbidities, such as obesity, warrant consideration, with prophylaxis for high-risk survivors, including those treated with cisplatin and limb-sparing approaches.
- Feasibility of the Combination of Venetoclax and Asparaginase-based Chemotherapy for Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia. [Journal Article]
- CLClin Lymphoma Myeloma Leuk 2018 Aug 27
- Asparaginase conjugated magnetic nanoparticles used for reducing acrylamide formation in food model system. [Journal Article]
- BTBioresour Technol 2018 Aug 22; 269:121-126
- Acrylamide is a potent carcinogen and neurotoxin formed by the Maillard reaction when l-asparagine reacts with starch at high temperature. It is formed in food materials mainly deep fried and bakery ...
Acrylamide is a potent carcinogen and neurotoxin formed by the Maillard reaction when l-asparagine reacts with starch at high temperature. It is formed in food materials mainly deep fried and bakery products. Enzymatic pretreatment of these food products with asparaginase enzyme leads to reduction in acrylamide. However, enzymatic process is quite expensive due to high cost, low catalytic efficiency as well as problem with enzyme reusability. Present work deals with these problems by exploring l-asparaginase from Bacillus aryabhattai. Asparaginase enzyme was immobilized on APTES modified magnetic nanoparticles. It was found to be more than three-fold increase their thermal stability from free enzyme and retained 90% activity after fifth cycle. The immobilized enzyme also showed better affinity towards its substrate. During pretreatment of asparagine in a starch-asparagine food model system and it was clearly demonstrated that asparaginase nanoconjugates had reduced the formation of acrylamide by more than 90% within 30 min.
- A critical analysis of L-asparaginase activity quantification methods-colorimetric methods versus high-performance liquid chromatography. [Journal Article]
- ABAnal Bioanal Chem 2018 Aug 29
- L-asparaginase or ASNase (L-asparagine aminohydrolase, E.C.188.8.131.52) is an enzyme clinically accepted as an antitumor agent to treat acute lymphoblastic leukemia (ALL) and lymphosarcoma through the de...
L-asparaginase or ASNase (L-asparagine aminohydrolase, E.C.184.108.40.206) is an enzyme clinically accepted as an antitumor agent to treat acute lymphoblastic leukemia (ALL) and lymphosarcoma through the depletion of L-asparagine (L-Asn) resulting in cytotoxicity to leukemic cells. ASNase is also important in the food industry, preventing acrylamide formation in processed foods. Several quantification techniques have been developed and used for the measurement of the ASNase activity, but standard pharmaceutical quality control methods were hardly reported, and in general, no official quality control guidelines were defined. To overcome this lack of information and to demonstrate the advantages and limitations, this work properly compares the traditional colorimetric methods (Nessler; L-aspartic acid β-hydroxamate (AHA); and indooxine) and the high-performance liquid chromatography (HPLC) method. A comparison of the methods using pure ASNase shows that the colorimetric methods both overestimate (Nessler) and underestimate (AHA and indooxine) the ASNase activity when compared to the values obtained with HPLC, considered the most precise method as this method monitors both substrate consumption and product formation, allowing for overall mass-balance. Correlation and critical analysis of each method relative to the HPLC method were carried out, resulting in a demonstration that it is crucial to select a proper method for the quantification of ASNase activity, allowing bioequivalence studies and individualized monitoring of different ASNase preparations. Graphical abstract ᅟ.
- Extranodal natural killer/T cell lymphoma, nasal type in the middle cranial fossa: A case report. [Case Reports]
- MMedicine (Baltimore) 2018; 97(34):e12028
- CONCLUSIONS: NK/T cell lymphomas should be considered to be a potential cause of facial numbness and diplopia. A L-asparaginase-based regimen resulted in reasonable tumor suppression, but adverse effects, including fatal neutropenia, should be carefully considered.
- Purification, characterization and immunogenicity assessment of glutaminase free L-asparaginase from Streptomyces brollosae NEAE-115. [Journal Article]
- BPBMC Pharmacol Toxicol 2018 Aug 23; 19(1):51
- CONCLUSIONS: The study reveals the excellent property of this enzyme which makes it highly valuable for development of chemotherapeutic drug.
- [Clinical analysis of autologous hematopoietic stem cell transplantation in the treatment of advanced/recurrent nasal type extranodal NK/T-cell lymphoma]. [Journal Article]
- ZXZhonghua Xue Ye Xue Za Zhi 2018 Jul 14; 39(7):569-572
- CONCLUSIONS: L-asparaginase based regimens bridging auto-HSCT is a safe and highly effective for advanced-stage and relapsed ENKTL treatment.
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- Successful Use of Nilotinib in the Therapy of a Patient with a Chemoresistant Relapse of BCR-ABL1-Like Phenotype Acute Lymphoblastic Leukemia. [Journal Article]
- OROncol Res Treat 2018 Aug 20; 41(9)