bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B68: Calorie restriction normalizes global microRNA expression by preventing the loss of Dicer expression during mammary tumorigenesis
Authors: Devlin Kaylyn L. , Sanford Tiffany , Mambo Elizabeth , Hursting Stephen D. 
Published: May 2016

Abstract
MicroRNA (miRNAs) are small, post-transcriptional regulators that play an integral role in maintenance of cellular functions and whose dysregulation has been shown to promote many types of cancer, including breast cancer. Global downregulation of miRNAs has emerged as a common theme in human breast tumors and has been shown to contribute to oncogenesis. One of the primary mechanisms through which miRNAs are globally dysregulated is downregulation of enzymes involved in miRNA biogenesis. We aim to establish how calorie restriction (CR), which potently inhibits breast cancer progression, regulates global miRNA expression and the expression of miRNA biogenesis enzymes in mammary tumors. To address these questions, 100 female Sprague Dawley rats were administered either dimethylbenz(a)anthracene (DMBA) or vehicle control at 50 days of age, then randomized to receive either control (AIN-76A) diet ad-libitum (n=40) or a 30% CR diet regiment (n=60). Resultant mammary tumors were allowed to develop for 12 weeks. Calorie restriction significantly increased survival to study endpoint relative to control diet (75% vs 35%, respectively) (p=0.0047). Furthermore, of the animals that developed tumors, CR significantly decreased median tumor area by 56% compared to control diet (109.4 mm2 vs 250.9 mm2, respectively) (p=0.0286). Global miRNA expression was analyzed by miRNA-specific sequencing. Calorie restriction had a broad effect on miRNA expression, illustrated by the fact that of all the miRNAs with a greater than two-fold expression difference between CR and control, 80% are overexpressed in CR tumors compared to control tumors. These results can be explained by the additional finding that CR was able to prevent the loss of Dicer expression, a key miRNA biogenesis enzyme, observed in control-fed mammary tumor tissue compared to normal tissue. This important finding suggests that global miRNA normalization through the retention of Dicer expression during cancer progression could be a contributing mechanism to CR's anticancer effects. We are further investigating these findings by exogenously overexpressing Dicer in Rama25 cells (derived from a DMBA-induced mammary tumor in a Sprague Dawley rat) and MCF7 cells, and analyzing the resultant tumorigenic potential in vitro and in vivo. The results obtained will provide insights into the mechanisms of breast cancer progression and how CR inhibits progression through microRNA modulation.
Citation Format: Kaylyn L. Devlin, Tiffany Sanford, Elizabeth Mambo, Stephen D. Hursting. Calorie restriction normalizes global microRNA expression by preventing the loss of Dicer expression during mammary tumorigenesis. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr B68.
Abstract IA03: Metabolic heterogeneity in cancer cells and tumors
Authors: DeBerardinis Ralph J. 
Published: May 2016

Abstract
Most diseases are accompanied by altered metabolism at the cellular level. In cancer, metabolic reprogramming that is, the regulated alteration of metabolism as a consequence of tumorigenic mutations and other factors is viewed as an essential component of malignant transformation. Research in cancer metabolism is motivated in part by the hope that understanding the basis of metabolic reprogramming will stimulate the development of new approaches in cancer imaging and therapy, both of which have historically capitalized on the altered metabolic states of tumors. Over the past decade, a large number of mechanisms by which oncogene-directed perturbations of signal transduction regulate intermediary metabolism have been defined. Conversely, it has also become apparent that metabolites themselves influence gene expression and signaling in ways that appear to promote malignancy. However, there is still little agreement as to the breadth of metabolic programs that can support cancer cell survival and growth, and more importantly, about which of the myriad metabolic activities observed in culture are relevant to bona fide tumor metabolism in vivo. I will discuss approaches to address these two challenges. First, I will discuss efforts to link functional metabolic pathway choices with oncogenotypes, gene expression networks and therapeutic sensitivities using a systematic analysis of a large panel of lung cancer cell lines. In these studies, cell-autonomous metabolic phenotypes were scored using a set of quantitative features (nutrient consumption, nutrient addiction, 13C labeling patterns), then cross-referenced against a rich set of orthogonal databases to identify genotype-phenotype connections and novel relationships between metabolism and therapeutic sensitivities. Second, I will describe efforts to probe metabolism in human tumors using methods that report on both cell-autonomous and non-cell autonomous influences. We have developed clinical studies involving a combination of pre-surgical imaging and intra-operative 13C infusions to assess metabolic heterogeneity between individual non-small cell lung cancers in human patients, and to characterize the extent of metabolic heterogeneity within individual tumors. Together, these efforts identify a complex but finite set of metabolic phenotypes that support cell growth and may predict therapeutic vulnerabilities. They also underscore the potential for both existing and novel imaging approaches to inform about metabolic phenotypes in vivo.
Citation Format: Ralph J. DeBerardinis. Metabolic heterogeneity in cancer cells and tumors. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr IA03.
Abstract IA20: Hypoxia, metabolism, and tumor progression
Authors: Simon Marie Celeste 
Published: May 2016

Abstract
Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney malignancy. It is both chemotherapy and radiation resistant and current treatment options for this disease are limited, particularly because 1 out of 4 patients are diagnosed at a disseminated, metastatic disease state. Underlying these clinical characteristics are a number of changes at the molecular level, the most pronounced of which are metabolic alterations that promote malignancy. One of these modifications is to the urea cycle, which is the second most underexpressed metabolic pathway in ccRCC. The urea cycle occurs in the kidney and is involved in detoxification of free ammonia species. Two key enzymes in this cycle are arginase II (ARG2) and argininosuccinate synthase 1 (ASS1); ARG2 is included on chromosome 14q and loss of this region correlates with high malignancy grade and a poorer prognosis in ccRCC. Data from nearly 500 primary ccRCC tumors in The Cancer Genome Atlas (TCGA) dataset demonstrates that ARG2 exhibits copy number loss in 40% of ccRCC and is underexpressed at the mRNA level, whereas ASS1 is significantly underexpressed, but not deleted, in ccRCC compared to normal kidney tissue. In preliminary experiments, we have demonstrated that re-expressing these enzymes in ccRCC cell lines suppresses proliferation in vitro and in vivo during xenograft tumor growth. Furthermore, re-expression of ARG2 and ASS1 reduces glycolytic flux and decreases mTOR activity. The central hypothesis of our work is that ARG2 and ASS1 act as tumor suppressors by modulating urea cycle and glycolytic metabolism and by repressing mTORC1 dependent growth pathways. The objective is to define the molecular mechanisms by which ARG2 and ASS1 loss alters cellular metabolism to promote ccRCC tumor growth. Delineating these mechanisms will provide new therapeutic avenues to target in this disease.
Citation Format: Marie Celeste Simon. Hypoxia, metabolism, and tumor progression. [abstract]. In: Proceedings of the AACR Special Conference: Metabolism and Cancer; Jun 7-10, 2015; Bellevue, WA. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(1_Suppl):Abstract nr IA20.
Abstract A33: Dual loss of the SWI/SNF complex ATPases SMARCA4/BRG1 and SMARCA2/BRM is highly sensitive and specific for small cell carcinoma of the ovary, hypercalcemic type.
Authors: Karnezis Anthony N. , Wang Yemin , Ramos Pilar , Hendricks William , Yin Holly , Oliva Esther , D'Angelo Emanuela , Prat Jaime , Nucci Marisa R. , Nielsen Torsten O. , Weissman Bernard E. , Trent Jeffrey M. , Gilks C Blake , Huntsman David G. 
Published: May 2016

Abstract
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a lethal and sometimes familial ovarian tumor of young women and children. We and others recently discovered that over 90% of SCCOHT harbor inactivating mutations in the chromatin remodeling gene SMARCA4 with concomitant loss of its encoded protein SMARCA4 (BRG1), one of two mutually-exclusive ATPases of the SWI/SNF chromatin remodeling complex. To determine the specificity of SMARCA4 loss for SCCOHT, we examined the expression of SMARCA4 by immunohistochemistry (IHC) in more than 3000 primary gynecologic tumors. Among ovarian tumors, it was only absent in clear cell carcinoma (15 of 360, 4%). In the uterus, it was absent in endometrial stromal sarcomas (4 of 52, 8%) and high-grade endometrioid carcinomas (2 of 338, 1%). Recent studies have shown that SMARCA2 (BRM), the other mutually exclusive ATPase of the SWI/SNF complex, is necessary for survival of tumor cells lacking SMARCA4. Therefore, we examined SMARCA2 expression and discovered that all SMARCA4-negative SCCOHTs also lacked SMARCA2 protein by IHC, including the SCCOHT cell lines BIN67 and SCCOHT1. Among ovarian tumors, the SMARCA4/SMARCA2 dual loss phenotype appears completely specific for SCCOHT. SMARCA2 loss was not due to mutation but rather from an absence of mRNA expression, which was restored by treatment with the histone deacetylase (HDAC) inhibitor trichostatin A. Treatment with HDAC inhibitors or re-expression of either SMARCA4 or SMARCA2 potently inhibited the growth of BIN67 and SCCOHT1 cell lines. Our results indicate that SMARCA4 loss, either alone or with SMARCA2 loss, is the first highly sensitive and specific diagnostic immunohistochemical marker of SCCOHT, and that HDAC inhibitors are promising agents to explore for the treatment of SCCOHT.
Citation Format: Anthony N. Karnezis, Yemin Wang, Pilar Ramos, William Hendricks, Holly Yin, Esther Oliva, Emanuela D'Angelo, Jaime Prat, Marisa R. Nucci, Torsten O. Nielsen, Bernard E. Weissman, Jeffrey M. Trent, C Blake Gilks, David G. Huntsman. Dual loss of the SWI/SNF complex ATPases SMARCA4/BRG1 and SMARCA2/BRM is highly sensitive and specific for small cell carcinoma of the ovary, hypercalcemic type. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A33.
Abstract A73: CDK4/6 inhibition as maintenance therapy in ovarian cancer.
Authors: Iyengar Mangala , Coffman Lan , Buckanovich Ronald 
Published: May 2016

Abstract
Over 70% of patients with ovarian cancer who achieve a clinical remission with initial surgery and chemotherapy will relapse and die of their disease. Effective maintenance therapies that can improve the survival of ovarian cancer patients are clearly needed. CDK4/6 inhibitors have been studied as maintenance therapy in hematologic and breast malignancies. CDK4/6 inhibition prevents the G1-S cell cycle phase transition in retinoblastoma (RB1) wild-type cells, causing G0/G1 arrest. Thus, CDK4/6 inhibitor therapy could significantly slow the growth of residual cancer cells after chemotherapy and improve outcomes. Indeed, the CDK4/6 inhibitor palbociclib doubled progression-free survival from 10 to 20 months in late-stage breast cancer.
CDK4/6 inhibitors remain untested in ovarian cancer. TCGA analysis shows that almost 40% of ovarian cancer patients bear mutations or dysregulation of genes in the CDK4/6 pathway that could sensitize them to CDK4/6 inhibition. We therefore investigated the CDK4/6 inhibitor LEE-011 (Novartis) in serous ovarian cancer. As expected, LEE-011 treatment led to a dose-dependent delay in the growth of multiple RbWT cell lines. Growth arrest was associated with an increase in the number of cells in the G1/G0 phase of the cell cycle and a decrease in the number of cells in S/M phases of the cell cycle. By contrast, LEE-011 did not produce these effects in the Rbnull COV362 cell line. LEE-011 treatment produced a significant, dose-dependent increase in senescence associated β-galactosidase. Despite significant expression of senescence-associated markers, cells could regrow after termination of LEE-011 therapy, suggesting a potential pseudo-senescent state. Finally, LEE-011 treatment concurrent with cisplatin therapy significantly inhibited the re-growth of RbWT ovarian cancer cells. LEE-011 maintenance therapy after cisplatin treatment led to growth arrest in vitro. Interestingly, although LEE-011 alone failed to show an effect on the Rbnull COV362 cells, LEE-011 maintenance therapy following cisplatin decreased COV362 cell regrowth. This was associated with a dose-dependent decrease in the percentage of ALDH+ cancer stem-like cells.
Taken together, these data suggest that LEE-011 may be an effective maintenance therapy for ovarian cancer in not only RbWT cells but potentially even in Rbnull cells. In vivo studies confirming these results are ongoing.
Citation Format: Mangala Iyengar, Lan Coffman, Ronald Buckanovich. CDK4/6 inhibition as maintenance therapy in ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities; Oct 17-20, 2015; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(2 Suppl):Abstract nr A73.
Understanding Intratumoral Heterogeneity: Lessons from the Analysis of At-Risk Tissue and Premalignant Lesions in the Colon
Authors: Sievers Chelsie K. , Leystra Alyssa A. , Clipson Linda , Dove William F. , Halberg Richard B. 
Published: May 2016

Abstract
Advances in DNA sequencing have created new opportunities to better understand the biology of cancers. Attention is currently focused on precision medicine: does a cancer carry a mutation that is targetable with already available drugs? But, the timing at which multiple, targetable mutations arise during the adenoma to carcinoma sequence remains unresolved. Borras and colleagues identified mutations and allelic imbalance in at-risk mucosa and early polyps in the human colon. Their analyses indicate that mutations in key genes can arise quite early during tumorigenesis and that polyps are often multiclonal with at least two clones. These results are consistent with the “Big Bang” model of tumorigenesis, which postulates that intratumoral heterogeneity is a consequence of a mutational burst in the first few cell divisions following initiation that drives divergence from a single founder with unique but related clones coevolving. Emerging questions center around the ancestry of the tumor and impact of early intratumoral heterogeneity on tumor establishment, growth, progression, and most importantly, response to therapeutic intervention. Additional sequencing studies in which samples, especially at-risk tissue and premalignant neoplasms, are analyzed from animal models and humans will further our understanding of tumorigenesis and lead to more effective strategies for prevention and treatment. Cancer Prev Res; 9(8); 638–41. ©2016 AACR.
See related article by Borras, et al., Cancer Prev Res 2016;9(6):417–427
Abstract A152: The macrophage migration inhibitory factor promotes breast cancer metastasis through interaction with the host immune response
Authors: Balogh Kristen N. , Cross Janet V. 
Published: May 2016

Abstract
The Macrophage Migration Inhibitory Factor (MIF) is an inflammatory cytokine that has been well-characterized as a mediator of numerous inflammatory disease processes, including in the setting of breast cancer. Ongoing research has shown that increased levels of MIF in breast cancer patient serum and biopsy samples are a marker of poor prognosis. We have previously demonstrated that expression of MIF in the primary tumor is required for spontaneous pulmonary metastasis in the 4T1 murine model of breast cancer. We hypothesized that MIF, as a cytokine, would promote metastasis by controlling some aspect of the interaction between the tumor and the host immune system. This was supported by our observation that MIF expression was no longer required for metastasis in an immunodeficient host lacking T, B, and NK cells. Using flow cytometry, we discovered that MIF expression in the primary tumor increased the abundance of a subset of myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. Furthermore, systemic depletion of MDSCs from tumor-bearing mice prevented spontaneous metastasis, suggesting that the MIF-induced increase in MDSCs is likely mediating the enhanced metastasis. These observations support a model in which MIF and MDSCs may be cooperating to protect the tumor cells from immune attack not only in the primary tumor, but also at sites of metastasis. Therefore, we hypothesize that MIF and MDSCs are functioning together to promote formation of a “metastatic niche” in the lung. Our ongoing studies aim to determine if MIF expression in the primary tumor drives matrix remodeling and/or establishment of an immunosuppressive microenvironment in the lungs of tumor-bearing mice, as well as whether inhibiting MIF pharmacologically can interrupt the process of niche formation. A more complete understanding of the role MIF plays in breast cancer development and metastasis will support deployment of MIF-targeted therapeutic interventions, as well as providing critical support for studies of how MIF inhibition might be combined with other immune-targeted therapies to enhance patient survival.
Citation Format: Kristen N. Balogh, Janet V. Cross. The macrophage migration inhibitory factor promotes breast cancer metastasis through interaction with the host immune response. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A152.
Calmodulin Mediates Ca
2+
-Dependent Inhibition of Tie2 Signaling and Acts as a Developmental Brake During Embryonic Angiogenesis
Authors: Yang Chansik , Ohk Jiyeon , Lee Ji Yeun , Kim Eun Jin , Kim Jiyoon , Han Sangyeul , Park Dongeun , Jung Hosung , Kim Chungho 
Published: May 2016

Objective—
Angiogenesis, the process of building complex vascular structures, begins with sprout formation on preexisting blood vessels, followed by extension of the vessels through proliferation and migration of endothelial cells. Based on the potential therapeutic benefits of preventing angiogenesis in pathological conditions, many studies have focused on the mechanisms of its initiation as well as control. However, how the extension of vessels is terminated remains obscure. Thus, we investigated the negative regulation mechanism.

Approach and Results—

We report that increased intracellular calcium can induce dephosphorylation of the endothelial receptor tyrosine kinase Tie2. The calcium-mediated dephosphorylation was found to be dependent on Tie2–calmodulin interaction. The Tyr1113 residue in the C-terminal end loop of the Tie2 kinase domain was mapped and found to be required for this interaction. Moreover, mutation of this residue into Phe impaired both the Tie2-calmodulin interaction and calcium-mediated Tie2 dephosphorylation. Furthermore, expressing a mutant Tie2 incapable of binding to calmodulin or inhibiting calmodulin function in vivo causes unchecked growth of the vasculature in
Xenopus
. Specifically, knockdown of Tie2 in
Xenopus
embryo retarded the sprouting and extension of intersomitic veins. Although human Tie2 expression in the Tie2-deficient animals almost completely rescued the retardation, the Tie2(Y1113F) mutant caused overgrowth of intersomitic veins with strikingly complex and excessive branching patterns.

Conclusions—
We propose that the calcium/calmodulin-dependent negative regulation of Tie2 can be used as an inhibitory signal for vessel growth and branching to build proper vessel architecture during embryonic development.
Survival Analysis After Extracorporeal Membrane Oxygenation in Critically Ill Adults
Authors: Chang Chia-Hsuin , Chen Hsi-Chieh , Caffrey James L. , Hsu Jiun , Lin Jou-Wei , Lai Mei-Shu , Chen Yih-Sharng 
Published: May 2016

Background—
Extracorporeal membrane oxygenation (ECMO) provides circulatory and respiratory support for patients with severe acute cardiopulmonary failure. The objective of this study was to examine the survival outcomes for patients who received ECMO.

Methods and Results—
Adult patients who received ECMO from September 1, 2002, to December 31, 2012, were identified from the Taiwan National Health Insurance Database associated with coronary artery bypass graft surgery, myocardial infarction/cardiogenic shock, injury, and infection/septic shock. A Cox regression model was used to determine hazard ratios and to compare 30-day and 1-year survival rates with the myocardial infarction/cardiogenic shock group used as the reference. The mean±SD age of the 4227-patient cohort was 57±17 years, and 72% were male. The overall mortalities were 59.8% and 76.5% at 1 month and 1 year. Survival statistics deteriorated sharply when ECMO was required for >3 days. Acute (30-day) survival was more favorable in the infection/septic shock (n=1076; hazard ratio, 0.61; 95% confidence interval, 0.55–0.67), coronary artery bypass graft surgery (n=1077; hazard ratio, 0.68; 95% confidence interval, 0.61–0.75), and injury (n=369, hazard ratio, 0.82; 95% confidence interval, 0.70–0.95) groups. The extended survival rapidly approached an asymptote near 20% for the infection/septic shock, myocardial infarction/cardiogenic shock (n=1705), and coronary artery bypass graft surgery groups. The pattern of survival for the injury group was somewhat better, exceeding 30% at year-end.

Conclusions—
Regardless of initial pathology, patients requiring ECMO were critically ill with similar guarded prognoses. Those in the trauma group had somewhat better outcomes. Determining the efficacy and cost-effectiveness of ECMO should be a critical future goal.