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  • 1
    Language: English
    Description: The immune system plays a critical role in cancer prevention and development. The stimulation of natural immune reaction in a cancer patient by adoptive T-cell therapy has shown success in treating metastatic melanomas and renal cell carcinomas. However, the use of adoptive T-cell therapy remains limited due to unpredictable outcomes and low response rates. In particular, adoptive T-cell therapy for breast cancer has not been realized, despite of the presence of immunogenic antigens such as over-expressed HER2, present in 20-40% of breast tumours. Using a unique transgenic mouse model, the global profiles of gene expression, miRNA abundance and single nucleotide variants (SNVs) were investigated to identify the molecular difference of murine mammary tumours with isogenic background, which exhibited complete regression (CR), partial regression (PR) or progressive disease (PD) outcome of adoptive T-cell therapy. The bioinformatics analyses were further carried out to identify uniquely activated pathways, prognostic gene expression signatures, the effect of post-transcriptional gene regulation and mutated genes unique to tumours with specific outcome. The largest differences in gene expression, miRNA and SNV profiles were repeatedly observed between the regressing (CR, PR) and non-regressing (PD) tumours, supporting the attribution of molecular differences to the immunotherapy outcome. In particular, the gene expression signatures derived from genes in immune-related pathways were experimentally validated to be strong prognostic markers for predicting the CR outcome. Comparison with the human breast cancer subtypes further revealed similarities of the non-regressing tumours with the basal subtype, and the regressing tumours with the HER2 subtype. The difference in miRNA profiles between CR and PR tumours suggested potential translational activities unique to PR, which was nearly identical to CR at the transcriptome level. The findings from this study show that tumour-derivied factors that either promote or suppress the immune system are responsible for the varying outcome of immunotherapy, and that the molecular characteristics can be further applied for the development of clinical prognostic tools, cancer vaccines and drug targets to enhance the efficacy of adoptive T-cell therapy.
    Source: Networked Digital Library of Theses and Dissertations
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  • 2
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 15 January 2013, Vol.110(3), pp.1041-1046
    Description: The molecular etiology of human progenitor reprogramming into self-renewing leukemia stem cells (LSC) has remained elusive. Although DNA sequencing has uncovered spliceosome gene mutations that promote alternative splicing and portend leukemic transformation, isoform diversity also may be generated by RNA editing mediated by adenosine deaminase acting on RNA (ADAR) enzymes that regulate stem cell maintenance. In this study, wholetranscriptome sequencing of normal, chronic phase, and serially transplantable blast crisis chronic myeloid leukemia (CML) progenitors revealed increased IFN-γ pathway gene expression in concert with BCR-ABL amplification, enhanced expression of the IFN-responsive ADAR1 p150 isoform, and a propensity for increased adenosine-to-inosine RNA editing during CML progression. Lentiviral overexpression experiments demonstrate that ADAR1 p150 promotes expression of the myeloid transcription factor PU. 1 and induces malignant reprogramming of myeloid progenitors. Moreover, enforced ADAR1 p150 expression was associated with production of a misspliced form of GSK3β implicated in LSC self-renewal. Finally, functional serial transplantation and shRNA studies demonstrate that ADAR1 knockdown impaired in vivo self-renewal capacity of blast crisis CML progenitors. Together these data provide a compelling rationale for developing ADAR1-based LSC detection and eradication strategies.
    Keywords: Biological sciences -- Biology -- Genetics ; Biological sciences -- Biology -- Cytology ; Health sciences -- Medical conditions -- Diseases ; Biological sciences -- Biology -- Cytology ; Biological sciences -- Biology -- Physiology ; Physical sciences -- Chemistry -- Chemical compounds ; Biological sciences -- Biology -- Genetics ; Biological sciences -- Biology -- Genetics ; Health sciences -- Medical conditions -- Diseases ; Biological sciences -- Biology -- Cytology
    ISSN: 00278424
    E-ISSN: 10916490
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  • 3
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 15 December 2015, Vol.112(50), pp.15444-9
    Description: Formative research suggests that a human embryonic stem cell-specific alternative splicing gene regulatory network, which is repressed by Muscleblind-like (MBNL) RNA binding proteins, is involved in cell reprogramming. In this study, RNA sequencing, splice isoform-specific quantitative RT-PCR, lentiviral transduction, and in vivo humanized mouse model studies demonstrated that malignant reprogramming of progenitors into self-renewing blast crisis chronic myeloid leukemia stem cells (BC LSCs) was partially driven by decreased MBNL3. Lentiviral knockdown of MBNL3 resulted in reversion to an embryonic alternative splice isoform program typified by overexpression of CD44 transcript variant 3, containing variant exons 8-10, and BC LSC proliferation. Although isoform-specific lentiviral CD44v3 overexpression enhanced chronic phase chronic myeloid leukemia (CML) progenitor replating capacity, lentiviral shRNA knockdown abrogated these effects. Combined treatment with a humanized pan-CD44 monoclonal antibody and a breakpoint cluster region - ABL proto-oncogene 1, nonreceptor tyrosine kinase (BCR-ABL1) antagonist inhibited LSC maintenance in a niche-dependent manner. In summary, MBNL3 down-regulation-related reversion to an embryonic alternative splicing program, typified by CD44v3 overexpression, represents a previously unidentified mechanism governing malignant progenitor reprogramming in malignant microenvironments and provides a pivotal opportunity for selective BC LSC detection and therapeutic elimination.
    Keywords: Cd44v3 ; Mbnl3 ; RNA Splicing ; Adhesion Molecules ; Self-Renewal ; Alternative Splicing -- Genetics ; Cell Self Renewal -- Genetics ; Human Embryonic Stem Cells -- Metabolism ; Leukemia, Myelogenous, Chronic, BCR-Abl Positive -- Genetics
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 4
  • 5
    Language: English
    In: Cancer Research, 10/01/2014, Vol.74(19 Supplement), pp.3087-3087
    ISSN: 0008-5472
    E-ISSN: 1538-7445
    Source: CrossRef
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  • 6
    Language: English
    In: The Journal of Cell Biology, 12/22/2014, Vol.207(6), p.2076OIA225
    ISSN: 0021-9525
    E-ISSN: 1540-8140
    Source: CrossRef
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  • 7
    Language: English
    In: The Korean journal of pain, July 2012, Vol.25(3), pp.161-7
    Description: Neck and shoulder pain (NSP) is fairly common in adolescents, which is associated with a high prevalence of NSP found during adulthood as well; therefore, its significance during adolescence should not be underestimated. We surveyed the prevalence of recurrent NSP, lifestyle, and risk factors in Korean high school students, and examined the influence of recurrent NSP on the quality of life. Nine hundred thirty one male students (16-19 years old) from two academic high schools in Seoul were included in this study. The survey consisted of a questionnaire to assess the prevalence of recurrent NSP, with questions regarding having an occurrence more than once a week, characteristics of NSP, activity and lifestyle of the students, and the risk factors for recurrent NSP. A 36-item Short Form questionnaire was also examined. We found that 44.3% of the high school students surveyed had recurrent NSP (more than once a week) and the overall prevalence of NSP was 79.1%. The average sitting time was 10.2 ± 2.7 h/day. 59.0% did not sit straight, 14.7% used assisting devices during reading, and 11.9% answered that they stretched regularly. Found from their self assessed health, frequent fatigue and frequent depressed mood presented significant associations with the higher prevalence of recurrent NSP. Korean high school students had a high prevalence of recurrent NSP. Clinical attention is needed for the prevention and resolution of recurrent NSP found in high school students.
    Keywords: Associated Factors ; Neck Pain ; Prevalence ; Shoulder Pain ; Students
    ISSN: 20059159
    E-ISSN: 2093-0569
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  • 8
    Language: English
    Description: The immune system plays a critical role in cancer prevention and development. The stimulation of natural immune reaction in a cancer patient by adoptive T-cell therapy has shown success in treating metastatic melanomas and renal cell carcinomas. However, the use of adoptive T-cell therapy remains limited due to unpredictable outcomes and low response rates. In particular, adoptive T-cell therapy for breast cancer has not been realized, despite of the presence of immunogenic antigens such as over-expressed HER2, present in 20-40% of breast tumours. Using a unique transgenic mouse model, the global profiles of gene expression, miRNA abundance and single nucleotide variants (SNVs) were investigated to identify the molecular difference of murine mammary tumours with isogenic background, which exhibited complete regression (CR), partial regression (PR) or progressive disease (PD) outcome of adoptive T-cell therapy. The bioinformatics analyses were further carried out to identify uniquely activated pathways, prognostic gene expression signatures, the effect of post-transcriptional gene regulation and mutated genes unique to tumours with specific outcome. The largest differences in gene expression, miRNA and SNV profiles were repeatedly observed between the regressing (CR, PR) and non-regressing (PD) tumours, supporting the attribution of molecular differences to the immunotherapy outcome. In particular, the gene expression signatures derived from genes in immune-related pathways were experimentally validated to be strong prognostic markers for predicting the CR outcome. Comparison with the human breast cancer subtypes further revealed similarities of the non-regressing tumours with the basal subtype, and the regressing tumours with the HER2 subtype. The difference in miRNA profiles between CR and PR tumours suggested potential translational activities unique to PR, which was nearly identical to CR at the transcriptome level. The findings from this study show that tumour-derivied factors that either promote or suppress the immune system are responsible for the varying outcome of immunotherapy, and that the molecular characteristics can be further applied for the development of clinical prognostic tools, cancer vaccines and drug targets to enhance the efficacy of adoptive T-cell therapy.
    Source: Networked Digital Library of Theses and Dissertations
    Library Location Call Number Volume/Issue/Year Availability
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  • 9
    Language: English
    In: PLoS ONE, 01 January 2016, Vol.11(7), p.e0159689
    Description: Type 2 diabetes is caused by both insulin resistance and relative insulin deficiency. To investigate age-related changes in glucose metabolism and development of type 2 diabetes, we compared glucose homeostasis in different groups of C57BL/6J mice ranging in age from 4 months to 20 months (4, 8, 12, 16 and 20 months). Interestingly, we observed that non-fasting glucose levels were not significantly changed, but glucose tolerance gradually increased by 20 months of age, whereas insulin sensitivity declined with age. We found that the size of islets and glucose-stimulated insulin secretion increased with aging. However, mRNA expression of pancreatic and duodenal homeobox 1 and granuphilin was decreased in islets of older mice compared with that of 4-month-old mice. Serum calcium (Ca2+) levels were significantly decreased at 12, 20 and 28 months of age compared with 4 months and calcium sensing receptor (CaSR) mRNA expression in the islets significantly increased with age. An extracellular calcium depletion agent upregulated CaSR mRNA expression and consequently enhanced insulin secretion in INS-1 cells and mouse islets. In conclusion, we suggest that decreased Ca2+ levels and increased CaSR expression might be involved in increased insulin secretion to compensate for insulin resistance in aged mice.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 10
    Language: English
    In: Bass, A. J., V. Thorsson, I. Shmulevich, S. M. Reynolds, M. Miller, B. Bernard, T. Hinoue, et al. 2014. “Comprehensive molecular characterization of gastric adenocarcinoma.” Nature 513 (7517): 202-209. doi:10.1038/nature13480. http://dx.doi.org/10.1038/nature13480.
    Description: Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein–Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also knownasPD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies.
    Keywords: Article;
    ISSN: 0028-0836
    E-ISSN: 14764687
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