- The prevalence and etiology of extreme hypertriglyceridemia in children: Data from a tertiary children's hospital. [Journal Article]
- JCJ Clin Lipidol 2018 Jan 12
- CONCLUSIONS: Extreme HTG is rare in children and majority of the children had secondary causes. Patients with diabetes mellitus or receiving drugs, such as, L-asparaginase, corticosteroids, and sirolimus, should be closely monitored for eHTG. Prevalence of T1HLP is approximately 1 in 6000 at a tertiary care center with an estimated population prevalence of 1 in 3,00,000. Early neonatal screening and intervention for T1HLP can prevent life-threatening morbidities such as acute pancreatitis.
- Pediatric-Inspired Treatment Regimens for Adolescents and Young Adults With Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia: A Review. [Journal Article]
- JOJAMA Oncol 2018 Feb 15
- CONCLUSIONS: The accumulating data increasingly support treating AYAs with ALL and LBL with a pediatric-inspired regimen or an approved institutional or national clinical trial tailored for this patient group. A need to develop clinical trials specifically for AYAs and to encourage their participation is paramount, with a goal to improve both the quantity and quality of survival.
- -----------Time-resolved analysis of amino acid stress identifies eIF2 phosphorylation as necessary to inhibit mTORC1 activity in liver. [Journal Article]
- JBJ Biol Chem 2018 Feb 15
- Amino acid availability is sensed by general control nonderepressible 2 (GCN2) and mechanistic target of rapamycin complex 1 (mTORC1), but how these two sensors coordinate their respective signal tra...
Amino acid availability is sensed by general control nonderepressible 2 (GCN2) and mechanistic target of rapamycin complex 1 (mTORC1), but how these two sensors coordinate their respective signal transduction events remains mysterious. In this study we utilized mouse genetic models to investigate the role of GCN2 in hepatic mTORC1 regulation upon amino acid stress induced by a single injection of asparaginase. We found that deletion ofGcn2prevented hepatic phosphorylation of eukaryotic initiation factor 2 alpha (eIF2) to asparaginase and instead unleashed mTORC1 activity. This change in intracellular signaling occurred within minutes and resulted in increased 5' terminal oligopyrimidine (TOP) mRNA translation instead of activating transcription factor 4 (ATF4) synthesis. Asparaginase also promoted hepatic mRNA levels of several mTORC1 inhibitors between 3 and 18 h and these were blunted or blocked in the absence ofGcn2, but their timing could not explain the early discordant effects in mTORC1 signaling. Pre-conditioning mice with a chemical endoplasmic reticulum (ER) stress agent before amino acid stress rescued normal mTORC1 repression in the liver ofGcn2-/-mice but not in livers with bothGcn2and the ER stress kinase,Perk, deleted. Furthermore, treating wild type andGcn2-/-mice with ISRIB, an inhibitor of PERK signaling, also failed to alter hepatic mTORC1 responses to asparaginase, although administration of ISRIB alone had an inhibitory GCN2-independent effect on mTORC1 activity. Taken together, the data show that ATF4 is not required but eIF2 phosphorylation is necessary to prevent mTORC1 activation during amino acid stress.
- Novel mutant of Escherichia coli asparaginase II to reduction of the glutaminase activity in treatment of acute lymphocytic leukemia by molecular dynamics simulations and QM-MM studies. [Journal Article]
- MHMed Hypotheses 2018; 112:7-17
- L-Asparaginases (ASNase) belong to a family of amidohydrolases, have both asparaginase and glutaminase activity. Acute lymphocytic leukemia (ALL) is an outrageous disease worldwide. Bacterial ASNase ...
L-Asparaginases (ASNase) belong to a family of amidohydrolases, have both asparaginase and glutaminase activity. Acute lymphocytic leukemia (ALL) is an outrageous disease worldwide. Bacterial ASNase has been used for the treatment of ALL. Glutaminase activity of enzyme causes some side effect and it is not essential for anticancer activity. The aim of this study was engineering of Escherichia coli asparaginase II to find a mutant with reduced glutaminase activity by molecular docking, molecular dynamics (MD) and QM-MM (Quantum mechanics molecular dynamics) simulations. Residues with low free energy of binding to Asn and high free binding energy to Gln were chosen for mutagenesis. Then, a mutant with higher glutaminase free binding energy was selected for further studies. Additionally, the MD simulation and QM-MM computation of wild type (WT) were employed and the selected mutated ASNase were analyzed and discussed. Our data showed that V27T is a good candidate to reduction the glutaminase activity, while has no remarkable effect on asparaginase activity of the enzyme. The simulation analysis revealed that V27T mutant is more stable than WT and mutant simulation was successful completely. QM-MM results confirmed the successfulness of our mutagenesis.
- Glutamine metabolism regulates FLIP expression and sensitivity to TRAIL in triple-negative breast cancer cells. [Journal Article]
- CDCell Death Dis 2018 Feb 12; 9(2):205
- Glutamine plays an important role in the metabolism of tumor cells through its contribution to redox homeostasis, bioenergetics, synthesis of macromolecules, and signaling. Triple-negative breast can...
Glutamine plays an important role in the metabolism of tumor cells through its contribution to redox homeostasis, bioenergetics, synthesis of macromolecules, and signaling. Triple-negative breast cancers (TNBC) are highly metastatic and associated with poor prognosis. TNBC cells show a marked dependence on extracellular glutamine for growth. Herein we demonstrate that TNBC cells are markedly sensitized to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis upon glutamine deprivation. Upregulation of pro-apoptotic TRAIL receptor 2 (TRAIL-R2/DR5) and downregulation of FLICE-inhibitory protein (FLIP) are observed in glutamine-deprived TNBC cells. Activation of the amino-acid-sensing kinase general control nonderepressible 2 (GCN2) upon glutamine deprivation is responsible for TRAIL-R2 upregulation through a signaling pathway involving ATF4 and CHOP transcription factors. In contrast, FLIP downregulation in glutamine-deprived TNBC occurs by a GCN2-independent mechanism. Importantly, silencing FLIP expression by RNA interference results in a marked sensitization of TNBC cells to TRAIL-induced apoptosis. In addition, pharmacological or genetic inhibition of transaminases increases TRAIL-R2 expression and downregulates FLIP levels, sensitizing TNBC cells to TRAIL. Interestingly, treatment with L-asparaginase markedly sensitizes TNBC cells to TRAIL through its glutaminase activity. Overall, our findings suggest that targeting the glutamine addiction phenotype of TNBC can be regarded as a potential antitumoral target in combination with agonists of proapoptotic TRAIL receptors.
- Levocarnitine for asparaginase-induced hepatic injury: a multi-institutional case series and review of the literature. [Journal Article]
- LLLeuk Lymphoma 2018 Feb 12; :1-9
- Asparaginase, an important treatment component for acute lymphoblastic leukemia (ALL), causes severe hepatotoxicity in some patients. Levocarnitine is a mitochondrial co-factor that can potentially a...
Asparaginase, an important treatment component for acute lymphoblastic leukemia (ALL), causes severe hepatotoxicity in some patients. Levocarnitine is a mitochondrial co-factor that can potentially ameliorate the mitochondrial toxicity of asparaginase. In this retrospective case series, we describe the clinical presentation and management of six pediatric and young adult patients (mean age 12.7, range 9-24 years) with ALL who developed Grade 3-4 hyperbilirubinemia following administration of asparaginase as part of induction/re-induction therapy. Five of these patients were treated with levocarnitine with subsequent improvement of hyperbilirubinemia, while one patient was given levocarnitine prophylactically during induction and developed Grade 3 hyperbilirubinemia, but did not require therapy adjustments or delays. Increased awareness in the pediatric oncology community regarding asparaginase-associated hepatic toxicity and the potential role of levocarnitine in management is warranted.
- Asparagine bioavailability governs metastasis in a model of breast cancer. [Journal Article]
- NatNature 2018 Feb 15; 554(7692):378-381
- Using a functional model of breast cancer heterogeneity, we previously showed that clonal sub-populations proficient at generating circulating tumour cells were not all equally capable of forming met...
Using a functional model of breast cancer heterogeneity, we previously showed that clonal sub-populations proficient at generating circulating tumour cells were not all equally capable of forming metastases at secondary sites. A combination of differential expression and focused in vitro and in vivo RNA interference screens revealed candidate drivers of metastasis that discriminated metastatic clones. Among these, asparagine synthetase expression in a patient's primary tumour was most strongly correlated with later metastatic relapse. Here we show that asparagine bioavailability strongly influences metastatic potential. Limiting asparagine by knockdown of asparagine synthetase, treatment with l-asparaginase, or dietary asparagine restriction reduces metastasis without affecting growth of the primary tumour, whereas increased dietary asparagine or enforced asparagine synthetase expression promotes metastatic progression. Altering asparagine availability in vitro strongly influences invasive potential, which is correlated with an effect on proteins that promote the epithelial-to-mesenchymal transition. This provides at least one potential mechanism for how the bioavailability of a single amino acid could regulate metastatic progression.
- Pegaspargase-related high-grade hepatotoxicity in a pediatric-inspired adult acute lymphoblastic leukemia regimen does not predict recurrent hepatotoxicity with subsequent doses. [Journal Article]
- LRLeuk Res 2018; 66:49-56
- Pediatric acute lymphoblastic leukemia (ALL) regimens, including higher cumulative asparaginase doses, have been investigated in adult ALL to improve outcomes. Preliminary results are promising, but ...
Pediatric acute lymphoblastic leukemia (ALL) regimens, including higher cumulative asparaginase doses, have been investigated in adult ALL to improve outcomes. Preliminary results are promising, but hepatotoxicity rates with long-acting pegaspargase are greater in adults than children. However, adult pegaspargase-related hepatotoxicity is not as clearly defined despite being the commonest adult toxicity. We studied the frequency and characteristics of high-grade pegaspargase-related hepatotoxicity in newly diagnosed adults on a pediatric-inspired regimen that included six planned pegaspargase doses, 2000 IU/m2/dose intravenously, with doses given at least four weeks apart and not discontinued or dose-reduced for previous hepatotoxicity. Pegaspargase-related toxicity was monitored weekly after 185 delivered doses and reported by NCI CTCAE v3.0. Fifty-one patients, aged 18-57, received 192 pegaspargase doses (3.8 doses/patient). High-grade hyperbilirubinemia occurred in 16 (31.4%) patients and 23 (12.4%) doses; high-grade transaminitis occurred in 33 (64.7%) patients and 62 (33.5%) doses. Of 11 patients with high-grade hyperbilirubinemia who received at least one subsequent pegaspargase dose, six (54.5%) experienced recurrent toxicity; of 24 patients with high-grade transaminitis who received at least one subsequent pegaspargase dose, 15 (62.5%) developed recurrent toxicity. Pegaspargase at this dose and interval is associated with high hepatotoxicity rates, but patients can be rechallenged despite earlier pegaspargase-related hepatotoxicity.
- Successful Treatment of Adolescents and Young Adults with Philadelphia-Negative Acute Lymphoblastic Leukemia by Novel L-Asparaginase-Intensified Induction Therapy and Cord Blood Transplantation: A Single-Center Decade Report. [Journal Article]
- JAJ Adolesc Young Adult Oncol 2018 Feb 06
- A novel induction therapy, including intensive L-asparaginase, was designed in 2007 for patients aged <45 years with Philadelphia-negative acute lymphoblastic leukemia (ALL). We analyzed seven de nov...
A novel induction therapy, including intensive L-asparaginase, was designed in 2007 for patients aged <45 years with Philadelphia-negative acute lymphoblastic leukemia (ALL). We analyzed seven de novo cases and one case of recurrence who received this treatment. The median age was 21 years (range: 16-35 years). Four patients had T-ALL and the others had B-ALL. All the patients achieved complete remission and proceeded to cord blood transplantation. In the median 72-month follow-up, there were no cases of observed mortality or recurrence. Our results indicate scope for further development of both induction therapy and postremission therapy.
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- Coagulopathic side effect of L-asparaginase on fibrinogen level in childhood acute lymphoblastic leukemia during induction phase. [Journal Article]
- HOHematol Oncol Stem Cell Ther 2018 Feb 01
- CONCLUSIONS: Significant reduction in fibrinogen level occurred in childhood ALL patients after treatment with L-asparaginase.