bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-277: Induction chemotherapy induces enrichment of leukemic stem cells in PDX models of acute myeloid leukemia
Authors: Zhang Cathy C. , Yan Zhengming , Pascual Bernadette , Huang Stephen , Zong Qing , Elliot Mark , Lappin Patrick 
Published: July 2016

Abstract
Human leukemic stem cells may be one of the leading causes for resistance or treatment failure in acute myeloid leukemia patients. To gain insights into the mechanisms underlying chemo-resistance of AML disease, we evaluated the biomarkers and the pharmacological properties of minimal residual disease post induction therapy. The PDX models were established by iv injecting acute myeloid leukemia patient cells in NOD/SCID/Il2rg(-/-) mice (NSG). The disease progression was tracked by the AML counts in peripheral blood and bone marrow via FACS analysis. In the PDX models, daunorubicin/cytarabine (DA) chemotherapy showed early antileukemic efficacy through apoptosis induction and antiproliferation. However, treatment showed minimal survival benefits and all treated leukemic mice relapsed due to the minimal residual disease (MRD). FACS analysis showed that DA therapy induced enrichment of CD34+ and CLL1+/CD117- cells in the MRD of the BM0407 and BM2407 AML PDX models, respectively. Subsequently, we performed self-renewal functional test by in vivo reimplantation of sorted CD34+ and CLL1+/CD117- cells. The limiting delusion analysis showed that the chemo- resistant CD34+ and CLL1+/CD117- cells are much more tumorigenic than their counterpart CD34- and CLL1+/CD117+ cells, respectively. This work provides insights into the mechanism of chemo-resistance and helps identifying new strategies to improve AML therapy.
Citation Format: Cathy C. Zhang, Zhengming Yan, Bernadette Pascual, Stephen Huang, Qing Zong, Mark Elliot, Patrick Lappin. Induction chemotherapy induces enrichment of leukemic stem cells in PDX models of acute myeloid leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-277.
Abstract LB-290: UCSC TumorMap: Exploring cancer signatures on an interactive dynamic landscape
Authors: Newton Yulia , Novak Adam , Swatlowski Teresa , Chopra Sahil , Salama Sofie , Morozova Olena , Haussler David , Stuart Joshua 
Published: July 2016

Abstract
Cancer is caused by accumulated changes in a cell's DNA sequence that disrupt the regulation of genetic networks. Mutation type, cell of origin, and tissue microenvironment all influence the initiation and progression of disease. The Cancer Genome Atlas (TCGA) catalogues the molecular changes of thousands of tumor samples of various tumor types using different data modalities including genomic, transcriptomic, proteomic, and epigenomic views. The goal is to find similarities amongst cancers of different tissues and to reveal clinically-relevant subtypes sharing common molecular abnormalities. While various analyses for interpreting these rich datasets exist, few methods are available to enable intuitive global overviews of these rich compendia. There is a need for methods that can tap the statistical power of large cohorts, to aid in analysis of smaller cohorts and of individual patient samples. Patterns present in many tumors may reveal driving genomic aberrations and pathway signatures that inform therapy. Here, we present a TumorMap, a tool that generates a map of cancer samples for interactive exploration, data overlay visualization, and statistical analysis. TumorMap arranges samples on a hexagonal 2-dimensional grid based on sample similarity. Different maps can be made for each distinct platform of data. Herein we demonstrate the utility of TumorMap for revealing commonalities between cancers of different tissue types, and its ability to aid in pan-cancer hypothesis generation. TumorMap maps for various cancer cohorts are available for free online at http://tumormap.ucsc.edu.
Citation Format: Yulia Newton, Adam Novak, Teresa Swatlowski, Sahil Chopra, Sofie Salama, Olena Morozova, David Haussler, Joshua Stuart. UCSC TumorMap: Exploring cancer signatures on an interactive dynamic landscape. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-290.
Abstract LB-306: Molecular mechanisms of trastuzumab-mediated cardiomyopathy: Implications of autophagy in trastuzumab-induced cardiotoxicity
Authors: Mohan Nishant , Shen Yi , Wu Wen J. 
Published: July 2016

Abstract
Trastuzumab is a humanized monoclonal antibody directed against the extracellular domain IV of human epidermal growth factor receptor 2 (HER2) and approved for the treatment of HER-2 positive breast cancer and gastric cancer. Trastuzumab therapy is associated with considerable cardiotoxicity, the mechanism of which remains unclear. Dysregulation of autophagy has been implicated in various cardiovascular diseases. In this investigation, we explored a novel mechanism by which trastuzumab dysregulates HER2 signaling and impairs basal autophagic process in human primary cardiomyocytes. Specifically, trastuzumab treatment leads to the phosphorylation of HER1-Y845 and HER2-Y1248 and the activation of Erk. This in turn results in up-regulation of mTOR/Ulk1 pathway and subsequently inhibition of autophagy in primary cardiomyocytes, by downregulating LC3I/II and increase in p62. We further demonstrate that trastuzumab-mediated inhibition of autophagy resulted in the increased production of reactive oxygen species (ROS) in cardiomyocytes. Pertuzumab, another anti-HER2 therapeutic mAb binding to HER2 domain II, fails to modulate HER2 signaling and is unable to influence autophagy in cardiomyocytes. This study provides novel mechanistic insights into trastuzumab-induced cardiotoxicity, which may assist in formulating novel approaches for clinical management of trastuzumab-induced cardiomyopathy.
Citation Format: Nishant Mohan, Yi Shen, Wen J. Wu. Molecular mechanisms of trastuzumab-mediated cardiomyopathy: Implications of autophagy in trastuzumab-induced cardiotoxicity. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-306.
Abstract LB-311: Elevated kynureninase protein expression is associated with KEAP1 mutant non-small cell lung cancer and is predictive of poor overall survival
Authors: Fahrmann Johannes F. , Dennison Jennifer , Murage Eunice , Wang Hong , Ostrin Edwin J. , Taguchi Ayumu , Hanash Samir 
Published: July 2016

Abstract
Purpose: To identify signatures related to tryptophan metabolism independent of indoleamine 2,3-dioxygenase (IDO) that are predictive of tumor behavior.
Introduction: Recent evidence has pointed to the importance of tryptophan catabolites on immune suppression and promotion of tumor growth. IDO1 is a rate-limiting enzyme in tryptophan catabolism currently targeted in clinical trials. Tryptophan catabolism can occur in IDO-negative tumors and resulting metabolites may have immunosuppressive and potential autocrine functions. Our late breaking finding is that we have uncovered signatures related to tryptophan metabolism independent of IDO that impact clinical outcome in NSCLC.
Experimental Procedures: We initially carried out integrated genomic and proteomic profiling of 114 cancer cell lines. Small interfering RNA transfection experiments were used to evaluate the effect of KYNU knockdown on cell viability. TCGA data was analyzed to determine clinical relevance.
Results: We identified kynureninase (KYNU), an enzyme involved in tryptophan metabolism that mediates formation of anthranilate and 3-hydroxyanthranilate, as uniquely overexpressed at the RNA and protein levels in NSCLC compared to other cancer types. These findings were not conserved for IDO or tryptophan 2,3-dioxygenase (TDO2), rate-limiting enzymes in tryptophan metabolism. Knockdown of KYNU reduced cell viability of NSCLC cell lines tested. Upregulation of KYNU was highly associated with KEAP1 mutational status and positively correlated with numerous Nrf-2 regulated-genes at both the protein and mRNA level. These findings were confirmed using TCGA data. KYNU mRNA levels predicted worse outcomes in stage II and III NSCLC adenocarcinoma and squamous cell carcinoma in TCGA cohorts independently of other covariates (P = : 0.008).
Conclusion: We have uncovered a unique signature in NSCLC reflective of aberrant tryptophan metabolism mediated by elevated KYNU but not IDO/TDO2. KYNU expression is highly associated with KEAP1 mutational status. High KYNU mRNA levels was predictive of worse clinical outcomes in NSCLC.
Citation Format: Johannes F. Fahrmann, Jennifer Dennison, Eunice Murage, Hong Wang, Edwin J. Ostrin, Ayumu Taguchi, Samir Hanash. Elevated kynureninase protein expression is associated with KEAP1 mutant non-small cell lung cancer and is predictive of poor overall survival. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-311.
Abstract LB-315: Bone marrow adipocytes alter the metabolic phenotype of metastatic prostate cancer cells through the activation of HIF-1a
Authors: Diedrich Jonathan , Rajagurubandara Erandi , Herroon Mackenzie , Podgorski Izabela 
Published: July 2016

Abstract
Bone is a preferential site of metastasis from prostate cancer (PCa). Age and obesity, conditions that increase adipocyte numbers in bone marrow, are risk factors for skeletal metastases from PCa. Research in our laboratory focuses on understanding the interactions between adipocytes and tumor cells that have infiltrated the bone marrow. Specifically, we are examining how the secretion, transport, and uptake of adipocyte-supplied factors promote metastatic progression in bone. We have previously shown that bone marrow adipocytes enhance a glycolytic phenotype in PCa cells through paracrine activation of glycolytic enzymes GLUT1, HK2, PDK1, ENO2, and LDHa at both the mRNA and protein levels. This correlated with an increase in glycolytic activity as measured by higher levels of lactate secretion and decreases in oxidative phosphorylation, indicative of an enhanced Warburg-like metabolic signature. We then assessed HIF-1a activity through mRNA analysis of HIF-1a target genes carbonic anhydrase 9 (CA9) and vascular endothelial growth factor (VEGF). We found that CA9 and VEGF had elevated expression levels in tumor cells exposed to adipocytes, indicative of enhanced HIF-1a activity. Notably, PCa cells exposed to bone marrow adipocytes had significantly enhanced presence of HIF-1a in the nucleus, result further confirming HIF-1α, activation in tumor cells exposed to marrow adipocytes. Hypoxia chamber experiments revealed that these effects were observable regardless of the presence or absence of oxygen, indicating the presence of oxygen-independent HIF-1a signaling or a state of pseudohypoxia in tumor cells. These results were further validated in multiple in vitro cell culture and in vivo mouse models, where an increased production of both glycolytic genes and HIF-1α target genes was shown to correlate with marrow adiposity. Our overall hypothesis is that bone marrow adipocyte-supplied lipids within the bone microenvironment cause HIF-1a activation and metabolic switch to glycolysis in metastatic PCa cells in bone, leading to their increased aggressiveness and resistance to therapy.
Citation Format: Jonathan Diedrich, Erandi Rajagurubandara, Mackenzie Herroon, Izabela Podgorski. Bone marrow adipocytes alter the metabolic phenotype of metastatic prostate cancer cells through the activation of HIF-1a. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-315.
Abstract LB-375: Childhood body size at age 13 years and associations with ovarian cancer in adult life
Authors: Aarestrup Julie , Gamborg Michael , Wentzensen Nicolas , Ulrich Lian G. , Sørensen Thorkild IA , Baker Jennifer L. 
Published: July 2016

Abstract
Background: Among women, body mass index (BMI; kg/m2) and attained height are positively associated with ovarian cancer. Few studies have, however, investigated associations with childhood body size. As such, it remains largely unknown if it is body size development in early life or adult life that contributes to these associations. Therefore, we examined if childhood BMI and height at age 13 years were associated with ovarian cancer in adult life.
Methods: Individuals were girls in the Copenhagen School Health Records Register who were born between 1930 and1989 and had available measures of height and weight at age 13 years. BMI and height z-scores were calculated from an internal age-specific reference. Via a personal identification number, individuals were followed up for ovarian cancer diagnosis by linkage to the Danish Cancer Registry. Cox proportional hazard regressions were performed and stratified by birth cohort.
Results: Among the included 137,416 girls, 1048 cases of ovarian cancer occurred during 5.2 million person-years of follow-up with a median age of diagnosis of 57 years (range: 19-83 years). BMI tended to be non-linearly associated with ovarian cancer such that only the heaviest girls had positive associations with ovarian cancer. Compared with a 13-year-old girl of average-size (BMI z-score = 0, corresponding to a weight of 45 kg and a height of 157 cm), an equally tall girl who was at least 9 kg heavier (corresponding to a BMI z-score &gt;1.28) had a hazard ratio (HR) for ovarian cancer of 1.33 (95% confidence interval [CI]: 1.08-1.63). In analyses adjusted for childhood height, the association was only marginally attenuated (HR = 1.30, 95% CI: 1.06-1.60). Childhood height was positively and statistically significantly associated with ovarian cancer. At age 13 years, per height z-score (corresponding to approximately 7 cm), the HR for ovarian cancer was 1.07 (95% CI: 1.01-1.14).
Conclusion: Body size in early life was associated with ovarian malignancies later in life suggesting that childhood height and BMI might impact if women are later diagnosed with ovarian cancer. As ovarian cancers vary widely in their etiologies, associations with childhood body size may differ depending on the tumor type, which will be investigated.
Citation Format: Julie Aarestrup, Michael Gamborg, Nicolas Wentzensen, Lian G. Ulrich, Thorkild IA Sørensen, Jennifer L. Baker. Childhood body size at age 13 years and associations with ovarian cancer in adult life. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-375.
Abstract LB-376: Hormone therapy use and DNA methylation in breast tissue
Authors: Harlid Sophia , Xu Zongli , Kirk Erin L. , Wilson Lauren E. , Troester Melissa A. , Taylor Jack A. 
Published: July 2016

Abstract
The association between use of hormone therapy (HT) and breast cancer risk has been consistently replicated in epidemiologic studies, but the biological effects of HT on breast tissue are poorly understood. We hypothesized that postmenopausal exposure to HT leads to changes in DNA methylation in breast tissue. We used fresh frozen samples from the Normal Breast Study (NBS), a hospital based study conducted between 2009 and 2013 at the University of North Carolina in Chapel Hill. Women undergoing breast surgery for reduction mammoplasty, prophylactic resection, or tumor resection donated samples of histologically normal-appearing breast tissue. Out of 474 enrolled participants 106 reported ever using hormone therapy, 37 of which had used it within one year of surgery (classified as current users) and 17 of which had used HT within 1-5 years prior to surgery (classified as recent users). Current and recent users were compared with 36 age frequency-matched controls that had never used HT. Frozen tissue DNA samples from these 90 women were evaluated using the Illumina HumanMethylation450 BeadChip. Genome wide DNA methylation data was analyzed using the reference-free cell mixture method to test for associations between HT-use and the methylation level at each CpG site. In the model we adjusted for SVA derived surrogate variables, to control for unobserved confounders, and multiple comparisons using the false discovery rate (FDR). Although methylation differences between current and never users were small in magnitude (β&lt;0.05), 290 CpGs were significantly differentially methylated (FDR, q&lt;0.05). The top CpG was located in an intronic region of the DDX10 gene (p = 7.9E-10, q = 0.0003), previously known to be translocated in estrogen receptor-negative (ER-) breast cancer. Our results extend the evidence base for hormonally derived epigenetic changes in breast tissue.
Citation Format: Sophia Harlid, Zongli Xu, Erin L. Kirk, Lauren E. Wilson, Melissa A. Troester, Jack A. Taylor. Hormone therapy use and DNA methylation in breast tissue. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-376.
Abstract PL02-02: Transcriptional regulation by the MAX-like protein MLX is required for adaptive metabolic responses in development and tumorigenesis
Authors: Carroll Patrick A. , Cheng Pei-Feng , Muller Charles H. , Hunt Liam , Demontis Fabio , Ayer Don E. , Eisenman Robert N. 
Published: July 2016

Abstract
The MYC transcription factor, together with its obligate dimerization partner, MAX, regulates widespread gene expression and is implicated in the etiology of a broad spectrum of cancers. MYC and MAX are members of the MAX-MLX superfamily of bHLHZ transcription factors (which includes MYC, MAX, MXD, MLX, and MONDO/ChREBP). Members of this highly conserved family respond to environmental cues to modulate gene expression programs and control cellular fate. We recently showed that metabolic reprogramming and survival in MYC-driven cancer cells is coordinately regulated by MYC-MAX and MONDOA-MLX. While knockdown of MONDOA or MLX affected multiple metabolic pathways in MYC-induced tumors, we found that decreased fatty acid synthesis primarily accounted for the loss of viability (Carroll et al. Cancer Cell 27:271, 2015)
To explore the physiological role of the MLX branch of the MAX-MLX network we generated mice with targeted deletion of Mlx. Mlx null mice appeared to develop normally; however, we found that Mlx null males are infertile, with strikingly diminished sperm production, viability, and motility. MondoA knockout mice exhibited a similar phenotype. By employing tissue-specific Cre-mediated deletion of Mlx, we uncovered metabolic defects in both Sertoli cells as well as germ cells, including loss of lipogenic enzymes and altered lipid content. Moreover, we found that human male germ cell tumors (MGCTs) overexpress MAX-MLX network proteins and undergo apoptosis upon loss of MONDOA/MLX. Importantly, the same metabolic pathways shown to be crucial for survival of neuroblastoma are also required for survival of MGCTs.
Furthermore. we have uncovered a critical role for MLX in myokine production required for myoblast fusion in vitro. Moreover, mice bearing homozygous deletion of Mlx fail to regenerate muscle following cardiotoxin treatment (Hunt et al. Genes Dev. 29:2475, 2015). Taken together, our studies suggest a critical role for the MLX arm of the MAX-MLX network in adaptive metabolic responses in tumorigenesis and development.
Funding: NIH grants CA57138 (to RNE) and GM055668 (to DEA); ALSAC of St. Jude Children's Research Hospital, the Ellison Medical Foundation, the Glenn Foundation for Medical Research, and the American Federation for Aging Research (AFAR) (to FD).
Citation Format: Patrick A. Carroll, Pei-Feng Cheng, Charles H. Muller, Liam Hunt, Fabio Demontis, Don E. Ayer, Robert N. Eisenman. Transcriptional regulation by the MAX-like protein MLX is required for adaptive metabolic responses in development and tumorigenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr PL02-02.
Abstract SY03-01: Macrophage PI3Kgamma drives cancer immune suppression
Authors: Varner Judith A. 
Published: July 2016

Abstract
Innate immune cells can switch from a proinflammatory state that defends against pathogens and to an anti-inflammatory state that repairs damaged tissue. Proinflammatory myeloid cells activate cytotoxic T cells to eliminate pathogens, but anti-inflammatory myeloid cells inhibit T-cell-mediated immunity, stimulate angiogenesis, and stimulate fibrosis, all of which promote tumor progression. The predominant isoform of PI(3)Kinase in myeloid cells, PI3Kgamma, controls this switch between immune stimulation and immune suppression during inflammation and cancer. Myeloid cell PI3Kgamma and its effectors Akt1, mTor, and S6Kinase stimulate C/EBPbeta-dependent expression of immunosuppressive factors, including Arginase and TGFbeta, while also suppressing NFkappaB-dependent expression of proinflammatory cytokines such as IL12 and IFNgamma, thereby inducing tumor immune suppression and consequent tumor growth and metastasis.
In contrast, inhibition of PI3Kgamma activity by genetic or pharmacological means suppresses C/EPBbeta-mediated transcription of anti-inflammatory factors and stimulates NFkappaB-mediated transcription of the proinflammatory cytokines IL12 and IFNgamma, thereby restoring CD8+ T-cell-dependent cytotoxicity that inhibits tumor growth and metastasis. Therefore, inhibitory targeting of PI3Kgamma indirectly restores cytotoxic T-cell immune responses that elicit tumor suppression without unwanted side effects. Our studies highlight the strong therapeutic potential of targeting this kinase to control inflammation and cancer.
This work was supported by grants to JAV from the NIH (5R01CA126820), the Landon Foundation-AACR (12-60-27-VARN), the Lustgarten Foundation for Pancreatic Research and the Whitworth Foundation for Cancer Research.
Citation Format: Judith A. Varner. Macrophage PI3Kgamma drives cancer immune suppression. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr SY03-01.