Thesis (Ph.D) --Murdoch University, 2004. / Thesis submitted to the Division of Health Sciences. Includes bibliographical references (leaves 328-352).

Thesis (Ph.D.)--University of Western Australia, 2007.

Thesis (M.S.)--University of British Columbia, 2005. / Includes bibliographical references (leaves 33-41). Also available online (PDF file) by a subscription to the set or by purchasing the individual file.

Thesis (M. Sc.)--University of British Columbia, 2005. / Includes bibliographical references (leaves 33-41).

京都大学 / 新制・課程博士 / 博士(医学) / 甲第23101号 / 医博第4728号 / 新制||医||1050(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 髙折 晃史, 教授 松田 文彦, 教授 藤田 恭之 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Introduction The problem at hand is understanding if pediatric acute lymphoblastic leukemia (ALL) treatment affects neurocognitive function or development. As the children battle ALL and are given treatments such as cranial radiation therapy and chemotherapy, they are having issues later on in life because the treatment regimens are very strong and are given during a crucial period of development. Purpose Statement and Question Does one pediatric treatment option affect neurocognitive development more than another later in life? Literature Review Research was conducted online via Google Scholar and East Tennessee State University Library database. Key terms used were pediatric ALL and neurocognitive effects of chemotherapy and radiation. Five studies were collected all pertaining to the question at hand. Findings The findings from the research collected was that certain demographics have a stronger effect on the development of a child post-ALL treatment. The treatment regimen and the strength of the treatment affect cognitive development. Cognitive impairment related to attention occurs with all children treated for ALL. Conclusion Nurses see first-hand the effects treatment have on children as the grow. We have to provide resources to help with attention deficits among other cognitive issues that result from treatment. The literature gave a great insight to what effects are to be expected post-treatment.

Indiana University-Purdue University Indianapolis (IUPUI) / Cancer cells display increased metabolic demands to support their proliferation and biosynthetic needs. It has been extensively shown in cancers, that amino acids have functions beyond the role of mRNA translation. The breadth of functions makes amino acid restriction an effective strategy for cancer therapy; hence an important line of research involves targeting amino acid acquisition and metabolism therapeutically. Currently, asparagine depletion via L-Asparaginase in acute lymphoblastic leukemia (ALL) remains the only clinically approved therapy to date. In the first project, we showed that ALL cells are auxotrophic for asparagine and rely on exogenous sources for this non-essential amino acid. However, sensitivity to L-Asparaginase therapy is mitigated by the expression of the enzyme asparagine synthetase (ASNS), involved in de novo asparagine biosynthesis. We showed that this adaptive response requires two essential steps; demethylation of the ASNS promoter and recruitment of activating transcription factor 4 (ATF4) to the promoter to drive ASNS transcription. Our follow-up study in ALL cells showed that asparagine bioavailability (through de novo biosynthesis or exogenous sources) is essential to maintain the expression of the critical oncogene c-MYC. c-MYC is a potent transcription factor and is dysregulated in over 60% of cancers, including hematopoietic malignancies. We showed that this regulation by asparagine is primarily at the translation level and c-MYC expression is rescued only when exogenous asparagine is available or when cells can undertake de novo biosynthesis. At the biochemical level, asparagine depletion also causes an induction of ATF4 mediated stress response and suppression of global translation mediated by decreased mammalian target of rapamycin complex 1 (mTORC1) activity. However, we found that neither inhibition of the stress response or rescuing global translation rescued c-MYC protein expression. We also extended this observation to c-MYC-driven lymphomas using cell lines and orthotopic in vivo models. We showed that genetic inhibition of ASNS or pharmacological inhibition of asparagine production can significantly limit c-MYC protein and tumor growth when environmental asparagine is limiting. Overall, our work shows an essential role for asparagine in lymphoid cancers and has expanded on the usage of L-Asparaginase to resistant leukemias and lymphomas.

Acute Lymphoblastic Leukemia (ALL) is an aggressive hematologic tumor and is the most common malignancy in children (Horton and Steuber 2014). This disease is characterized by the infiltration of bone marrow by malignant immature lymphoid progenitor cells and is invariably fatal without treatment. Although multi-agent combination chemotherapy is curative in a significant fraction of ALL patients, treatment currently fails in approximately 20% of children and up to 50% of adults with ALL, making relapse and drug resistance the most substantial challenge in the treatment of this disease(Fielding, Richards et al. 2007, Aster and DeAngelo 2013). Understanding what causes treatment failure is of great medical importance as second line therapies also fail in the majority of relapse T-cell ALL (TALL) patients (Fielding, Richards et al. 2007, Aster and DeAngelo 2013). Using next-generation sequencing to compare the genomes of tumors before and after therapy, mutations in gene cytosolic 5’-nucleotidase II (NT5C2) were discovered in 19% of pediatric samples with relapsed T-ALL(Tzoneva, Carpenter et al. 2013). Preliminary structure function analysis and subsequent in vitro experimental nucleotidase activity assays confirmed that these mutations lead to hyperactive NT5C2 protein. Furthermore, NT5C2 mutant proteins conferred resistance to 6-mercaptopurine and 6-thioguanine chemotherapy drugs when expressed in ALL lymphoblasts, suggesting NT5C2 is responsible for the inactivation of nucleoside-analog chemotherapy drugs. In order to assess the ability of these mutations to lead to novel inhibitor schemes, the functional impact of each mutation was analyzed through robust structure function methods. The result of this in silico analysis, is the identification of a potential allosteric regulatory mechanism of negative feedback inhibition never before described. Most notably, the majority of NT5C2 mutations identified have characteristics that suggest they abrogate the function of this proposed mechanism, yielding a novel viable target for the development of allosteric inhibitors specific for constitutively active NT5C2 mutant proteins. Overall these findings support a prominent role for activating mutations in NT5C2 and chemotherapy resistance in ALL, and highlight new avenues for relapsed ALL therapy development in the future.

Thesis (Ph. D.)--University of North Texas, Aug., 2007. / Title from title page display. Includes bibliographical references.

[Truncated abstract] Childhood acute lymphoblastic leukaemia (ALL) accounts for the largest number of cases of childhood cancer (25-35%) and is the primary cause of cancer related morbidity. Today more than 76% of children with ALL are alive and disease free at 5 years. Approximately one in 900 individuals between the ages of 16 and 44 years is a survivor of childhood cancer. In contrast, those patients who relapse with childhood ALL currently have a 6-year event free survival of 20-30%. The short arm of chromosome 9p is mutated or deleted in many cancers including leukaemia. Aberrations of the INK4A/ARF and INK4B loci at the 9p21 band are linked to the development and progression of cancer. In murine cancer models there is evidence to suggest that mutations of Ink4a/Arf and p53 gene loci promote resistance to chemotherapeutic drugs known to trigger apoptosis. The initial aim of this project was to develop an accurate, reproducible method to detect deletions at the INK4A/ARF locus in patient bone marrow specimens. This technique was then applied to detect the incidence of deletions of this locus in childhood ALL specimens. The hypothesis developed was that deletion at the INK4A/ARF locus at diagnosis in childhood ALL is an independent prognostic marker and is involved in disease progression. A secondary aim of this study was to determine which deletions at the INK4A/ARF and INK4B loci are the most relevant in leukaemogenesis in childhood ALL. ... This study has shown that deletion of the INK4A/ARF locus is an independent prognostic indicator in childhood ALL. In addition, the frequency of deletion at the INK4A/ARF and INK4B loci is increased at relapse compared to diagnosis in childhood ALL. In the relapse study group, deletion of the p16INK4A gene at diagnosis was associated with a decreased median time to relapse compared to other genes analysed. Murine studies suggest that such deletions may result in an increased resistance to chemotherapy. If the findings from this study are confirmed in a larger cohort, it is expected that therapeutic interventions based on assessment of the p16INK4A gene in diagnostic childhood ALL specimens will be implemented to prevent relapse in standard risk patients and help to improve the outcome in high risk patients.