bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B68: miR-218 opposes an important RTK–HIF signaling pathway in Glioblastoma
Authors: Mathew Lijoy K. , Skuli Nicolas , Mucaj Vera , Lee Samuel S. , Venneti Sriram , Lal Priti , Lathia Justin D. , Rich Jeremy N. , Keith Brian , Minn Andy J. , Simon M Celeste 
Published: May 2015

Abstract
Glioblastoma multiforme (GBM) are highly malignant primary brain tumors, and the Mesenchymal GBM subtype in particular, frequently exhibit regions of severe hypoxia and necrosis. As these features correlate with poor prognosis, we investigated miRNAs whose expression might regulate ischemic cell survival and growth. We found that miR-218 expression is significantly repressed in highly necrotic and chemoresistant Mesenchymal GBMs, compared to the Proneural subtype. Furthermore, restoring miR-218 expression in glioblastoma stem like cells (GSCs) significantly sensitizes orthotopic xenograft tumors to chemotherapeutic treatment, suggesting that low miR-218 confers GBM chemoresistance. Moreover, reduced miR-218 levels correlate with poor survival and rapid recurrence in human Mesenchymal GBM patients treated with radio- and chemotherapy (in contrast, no survival differences were observed in other GBM subtypes). Importantly, miR-218 targets multiple components of the receptor tyrosine kinase (RTK) signaling pathways, and reduced miR-218 expression increases their abundance and activity, thereby overcoming RTK inhibitory homeostatic mechanisms that normally modulate active signaling. We further demonstrate that HIFs, specifically HIF2α, function as downstream effectors of the low miR-218-RTK activation cascade in GSC cells. In strong support of our experimental findings, we observed a significant correlation between elevated HIF activity and low miR-218 expression in Mesenchymal GBM patient samples; in contrast, no correlation was observed in Proneural tumors. Altogether, our data reveal a novel functional association between miR-218 expression and HIF2α activity, and delineate RTK activation as the mechanistic link between the two in highly necrotic GBMs. Moreover, as tumor hypoxia is associated with chemoresistance and poor prognosis, our results uncover a new mechanism whereby miR-218 repression enhances HIF activity, and contributes to the chemoresistant phenotype predominantly seen in Mesenchymal GBM.
Citation Format: Lijoy K. Mathew, Nicolas Skuli, Vera Mucaj, Samuel S. Lee, Sriram Venneti, Priti Lal, Justin D. Lathia, Jeremy N. Rich, Brian Keith, Andy J. Minn, M Celeste Simon. miR-218 opposes an important RTK–HIF signaling pathway in Glioblastoma. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B68. doi:10.1158/1538-7445.CHTME14-B68
Abstract B77: The role of fibroblasts in invasive lobular breast carcinoma
Authors: Boelens Mirjam C. , Wientjens Ellen , Schut Eva , Klarenbeek Sjoerd , Visser Karin E. de , Jonkers Jos 
Published: May 2015

Abstract
Cancer-associated fibroblasts (CAFs) can promote breast cancer growth and metastasis, but the underlying mechanisms are still largely unknown. In order to study the role of CAFs in breast cancer development in an in vivo setting, we make use of a spontaneous mammary tumor mouse model for invasive lobular carcinoma (ILC). ILC is the second most common type of breast cancer, and is characterized by loss of E-cadherin, a rich stromal compartment, infiltrative growth, and treatment resistance. Often, the PI3K pathway is observed activated in the ILC subtype. Based on these characteristics, we have generated mouse models with mammary epithelial-specific conditional knockout of E-cadherin and PTEN that develop classical ILCs with a strong resemblance to human ILC. Using PDGFRβ as a fibroblast marker, we have observed an abundant presence of stromal fibroblasts in these ILCs, similar to human ILC. Based on a mammary gland transplantation setting using fluorescent labeled recipient mice, we have shown that fibroblasts get recruited from the host during tumor development. In vitro, we have also shown that tumor cells recruit fibroblasts. Inhibition of PDGFRβ in this in vitro model can at least in part inhibit this recruitment. We are currently investigating whether inhibition of PDGFRβ in vivo can prevent the recruitment of fibroblasts and subsequently tumor development or progression. In parallel, we have isolated fibroblasts from primary mouse ILCs and wild-type mammary glands to screen for other important players in the tumor-stroma crosstalk using RNA-seq and cytokine profiling. We will subsequently assess their functional significance during ILC development and progression.
This research is supported by a fellowship of the Dutch Cancer Society
Citation Format: Mirjam C. Boelens, Ellen Wientjens, Eva Schut, Sjoerd Klarenbeek, Karin E. de Visser, Jos Jonkers. The role of fibroblasts in invasive lobular breast carcinoma. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B77. doi:10.1158/1538-7445.CHTME14-B77
Abstract B87: Prolyl hydroxylase and the regulation of reactive oxygen species (ROS) levels in cancer cells
Authors: Philip Beatrice , Ito Koichi , Moreno-Sanchez Rafael , Ralph Stephen J. 
Published: May 2015

Abstract
Hypoxic microenvironments frequently exist within many solid tumors with oxygen levels fluctuating temporally and spatially from normoxia to hypoxia. The response to hypoxia in human cells is mainly regulated by hypoxia-inducible factors or HIFs, a family of transcription factors which orchestrate signalling events promoting cancer stem cells, leading to angiogenesis and increased tumorigenesis. Several events conspire together to stabilize HIF-αs to become constitutively expressed in many cancer cell types, regardless of oxygen levels. Prolyl hydroxylases (PHDs) play a crucial role in HIF regulation by hydroxylating HIF proline residues to target these proteins for proteasomal degradation. Hypoxic microenvironments existing within tumors and cytosolic accumulation of mitochondrial metabolites such as succinate or increased ROS production are known to suppress PHD function, resulting in HIF stabilisation and transcriptional activation in the nucleus thereby triggering various pro-oncogenic signalling pathways. Abnormal HIF-αα regulation has gained significant prominence in tumor biology over recent years and the hypoxic microenvironments have been shown to facilitate and trigger major molecular and immunological processes necessary as a driver promoting greater tumor malignancy. More recently, it has been realized that these hypoxic microenvironments also play significant roles in shielding tumour cells from immune attack by promoting immune suppression. We address many of these functions and their relationship to cancer stem cells and their metastastic properties. We also show that overexpressing prolyl hydroxylase reduces HIF expression and malignancy of cancer cells as well as affecting the levels of reactive oxygen species and respiratory chain function in these cells.
Citation Format: Beatrice Philip, Koichi Ito, Rafael Moreno-Sanchez, Stephen J. Ralph. Prolyl hydroxylase and the regulation of reactive oxygen species (ROS) levels in cancer cells. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr B87. doi:10.1158/1538-7445.CHTME14-B87
Abstract IA02: Macrophage entry in hypoxia: Implications for cancer and angiogenesis
Authors: Mazzone Massimiliano 
Published: May 2015

Abstract
Cancer typically has an inflammatory nature. Of all immune cells invading the tumor, the role of macrophages remains controversial because of their functionally distinct differentiation states. Classically activated (M1-like) macrophages and alternatively activated (M2-like) macrophages represent the two extremities of a continuum, in which the former are proinflammatory and tumoricidal, whereas the latter display pro-angiogenic and protumoral activities. This heterogeneity reflects the plasticity and versatility of these cells in response to microenvironmental signals. The tumor environment is constituted of cancer cells and stromal cells that coexist under different oxygen tensions and the influence of soluble factors. A plethora of (hypoxia-induced) cytokines and chemokines can define the macrophage phenotype and their positioning within the tumor. Understanding the signals that lead to macrophage positioning in different tumor niches and how this reflects macrophage phenotypes can open new opportunities for cancer treatment. We have elucidated an elegant mechanism by which macrophages are recruited and retained in avascular hypoxic niches of the tumor, where they exert their immunosuppressive and pro-angiogenic activity. Hypoxia by itself indeed strongly affects macrophage function, as the cells are forced to adapt and alter their metabolism, which is accompanied by a drastic change in their transcriptome and proteome. We have found that the resultant metabolic changes drive macrophages towards a pro-angiogenic phenotype in an attempt to restore oxygenation. Soluble factors derived from the tumor exacerbate this macrophage shift by further enforcing this metabolic adaptation. As a consequence, tumor blood vessels are abnormal and dysfunctional, thus perpetuating hypoxia, which in turn fosters metastasis. By using genetic tools in mice, we show that inhibiting macrophage recruitment in hypoxic niches, or altering their metabolic and energetic state can break this feed-forward loop, resulting in normalized blood vessels and thus, strongly reducing metastatic dissemination.
Citation Format: Massimiliano Mazzone. Macrophage entry in hypoxia: Implications for cancer and angiogenesis. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr IA02. doi:10.1158/1538-7445.CHTME14-IA02
Abstract PR16: Spatio-temporal heterogeneity in the tumor microenvironment influences the evolutionary dynamics of drug resistance
Authors: Mumenthaler Shannon , Foo Jasmine , Choi Nathan , Pao William , Agus David , Michor Franziska , Mallick Parag 
Published: May 2015

Abstract
Tumor growth is a complex evolutionary process driven by dynamic feedback between a heterogeneous cell population and selection pressures from the tumor microenvironment. Spatio-temporal heterogeneity in the microenvironment can create physical niches that facilitate cellular adaptation as seen in regions of hypoxia and acidosis where cells may up-regulate glycolysis and become resistant to acid-meditated toxicity in order to survive. In recent studies, using clinically prevalent subtypes of EGFR-related non-small cell lung cancer (NSCLC), we observe that nutrient and drug gradients resulting from a cells' proximity to vasculature, can produce selective pressures driving tumor evolution. We provide a detailed examination of the microenvironmental impact (i.e. oxygen, glucose, and drug) on growth rates of NSCLC cell lines that are either sensitive or resistant to the EGFR TKI, erlotinib. Often we consider drug resistance to be associated with a fitness cost to the cell in the absence of drug. However, here we demonstrate that the situation is more complex, with the local tumor microenvironment influencing the magnitude and the directionality of the selective effect. In fact, the resistant cells actually gain a selective advantage in nutrient-stressed environments compared to the sensitive cells. The resulting growth dynamics were used to inform a stochastic compartment-based tumor model of pre-existing drug resistance where each compartment represents a specific tumor environmental niche. This integrative modeling framework was then used to predict rebound growth kinetics and tumor composition (i.e. % resistance) and in particular, provide insight into the magnitude by which the microenvironment influences these results. These investigations strongly suggest that ignoring the microenvironment or using laboratory environmental conditions to inform tumor dynamics can lead to inaccurate conclusions. Therefore, knowledge of the selective advantage/disadvantage of different cell populations within different regions of the tumor will better guide model predictions, influence overall tumor dynamics, and impact treatment strategies.
This abstract is also presented as Poster A80.
Citation Format: Shannon Mumenthaler, Jasmine Foo, Nathan Choi, William Pao, David Agus, Franziska Michor, Parag Mallick. Spatio-temporal heterogeneity in the tumor microenvironment influences the evolutionary dynamics of drug resistance. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr PR16. doi:10.1158/1538-7445.CHTME14-PR16
Abstract A47: Self-renewing cellular compartments in embryonal rhabdomyosarcoma are modulated by hedgehog signaling
Authors: Satheesha Sampoorna , Bovay Amandine , Manzella Gabriele , Bode Peter , Feuchtgruber Simone , Koscielniak Ewa , Belle Reka , Casanova Elisa , Dogan Nurhak , Schäfer Beat W. 
Published: May 2015

Abstract
Rhabdomyosarcoma (RMS) is a heterogeneous group of malignancies with features of impaired skeletal muscle differentiation and represents the majority of soft tissue cancers in the pediatric age group. Current treatment regimens show clinical benefit but this has reached a plateau. Since there is significant risk of adverse side effects and secondary tumors later in life, identifying and targeting sub-populations with higher tumorigenic potential and self renewal capacity would not only decrease tumor burden but also lower the probability of relapse.
Using in vitro self renewal assays we could identify self-renewing cellular compartments within embryonal RMS (eRMS) cell lines. These compartments showed upregulation of several components of the sonic hedgehog pathway. Here, we now show using both genetic loss- and gain-of-function experiments and clinically relevant small molecule modulators that Hedgehog signalling is important for determining the self-renewal, tumor initiation capability both in vitro as well as in vivo. In addition, the hedgehog pathway can also influence chemoresistance of eRMS cells and altered the differentiation status of the cells by directly modulating the expression of various stem cell associated transcription factors. The pathway was found to be heterogeneously activated within eRMS patient samples in a comprehensive tissue microarray analysis. Importantly, the presence of Hedgehog-active cells identified using effector transcription factors could negatively predict patient survival in a retrospective analysis of this patient cohort. This work elucidates both a novel and central role played by the Hedgehog pathway in eRMS and underscores the importance of studying tumor heterogeneity in pediatric cancer.
Citation Format: Sampoorna Satheesha, Amandine Bovay, Gabriele Manzella, Peter Bode, Simone Feuchtgruber, Ewa Koscielniak, Reka Belle, Elisa Casanova, Nurhak Dogan, Beat W. Schäfer. Self-renewing cellular compartments in embryonal rhabdomyosarcoma are modulated by hedgehog signaling. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A47.
Abstract B15: Pediatric glioblastoma cell lines maintain response to developmental growth factors
Authors: Mooney Marie Renee 
Published: May 2015

Abstract
Glioblastoma (GBM) is a highly invasive brain tumor arising from an astrocytic cell lineage. In the United States, nearly 500 children each year develop GBMs. Pediatric GBM has a different mutational, methylation, and gene expression spectra than adult GBM, implicating a strong role for developmental processes in disease pathogenesis. The developmental growth factors that define the astrocytic lineage include epidermal growth factor (EGF) and platelet-derived growth factor (PDGF). Expression of these growth factors also distinguishes pediatric versus adult GBM. Here, we use EGF or PDGF as a stimulus for malignant behavior in GBM cell lines isolated from either adult or pediatric patients to understand whether the cell line models parallel growth factor receptor signaling preferences observed clinically. In response to these stimuli, pediatric cell lines demonstrate distinct protein signaling and invasion phenotypes from adult cell lines in vitro, and generate invasive, multifocal lesions in an orthotopic xenograft model. Thus, distinguishing features of adult and pediatric GBM are maintained in the cell line models that will be used to test therapeutic regiments preclinically. Both of the receptors activated by EGF and PDGF are known to interact with a promising therapeutic target in adult glioblastoma: signal transducer and activator 3 (STAT3). STAT3 acts as either an oncogene or tumor suppressor depending on cellular context such as the activating receptor complex and phosphatase and tensin homolog (PTEN) mutational status. Our studies will therefore address the differential implications of STAT3 therapy for pediatric versus adult GBM.
Citation Format: Marie Renee Mooney. Pediatric glioblastoma cell lines maintain response to developmental growth factors. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr B15.
Desempenho ocupacional, qualidade de vida e adesão ao tratamento de pacientes com epilepsia
Authors: Gritti Cristiane Carnaval , Paulino Vânia Uemura , Marques Lúcia Helena Neves , Castiglioni Lilian , Bianchin Maysa Alahmar 
Published: April 2015

<p>Os objetivos do estudo foram avaliar o desempenho ocupacional, qualidade de vida e adesão ao tratamento medicamentoso de pacientes com epilepsia de difícil controle. Trata-se de um estudo transversal e quantitativo com 30 pacientes em acompanhamento no ambulatório de neurologia em epilepsia de difícil controle da no ambulatório do Hospital de Base de São José do Rio Preto. Os instrumentos utilizados foram: ficha de Identificação, Teste de Morisky, Qualityof Life in Epilepsy Inventory – 31 e Medida Canadense de Desempenho Ocupacional. Os resultados apontaram que: 70% dos participantes obtiveram média adesão ao tratamento medicamentoso; em relação à qualidade de vida os piores resultados foram a preocupação com as crises e os efeitos adversos das drogas antiepilépticas. No Desempenho Ocupacional, as principais dificuldades levantadas constataram prevalência no funcionamento na comunidade, trabalho e socialização. O estudo possibilitou identificar o comportamento do paciente em relação ao uso da medicação, mensurar a qualidade de vida no contexto vivenciado pela doença e identificar as áreas variadas de desempenho ocupacionais prejudicadas.</p>
Atrial Fibrillation and Risk of ST-Segment–Elevation Versus Non–ST-Segment–Elevation Myocardial Infarction
Authors: Soliman Elsayed Z. , Lopez Faye , O’Neal Wesley T. , Chen Lin Y. , Bengtson Lindsay , Zhang Zhu-Ming , Loehr Laura , Cushman Mary , Alonso Alvaro 
Published: April 2015

Background—
It has recently been reported that atrial fibrillation (AF) is associated with an increased risk of myocardial infarction (MI). However, the mechanism underlying this association is currently unknown. Further study of the relationship of AF with the type of MI (ST-segment–elevation MI [STEMI] versus non–ST-segment–elevation MI [NSTEMI]) might shed light on the potential mechanisms.

Methods and Results—

We examined the association between AF and incident MI in 14 462 participants (mean age, 54 years; 56% women; 26% blacks) from the Atherosclerosis Risk in Communities (ARIC) study who were free of coronary heart disease at baseline (1987–1989) with follow-up through December 31, 2010. AF cases were identified from study visit ECGs and by review of hospital discharge records. Incident MI and its types were ascertained by an independent adjudication committee. Over a median follow-up of 21.6 years, 1374 MI events occurred (829 NSTEMIs, 249 STEMIs, 296 unclassifiable MIs). In a multivariable-adjusted model, AF (n=1545) as a time-varying variable was associated with a 63% increased risk of MI (hazard ratio,1.63; 95% confidence interval, 1.32–2.02). However, AF was associated with NSTEMI (hazard ratio, 1.80; 95% confidence interval, 1.39–2.31) but not STEMI (hazard ratio, 0.49; 95% confidence interval, 0.18–1.34;
P
for hazard ratio comparison=0.004). Combining the unclassifiable MI group with either STEMI or NSTEMI did not change this conclusion. The association between AF and MI, total and NSTEMI, was stronger in women than in men (
P
for interaction <0.01 for both).

Conclusions—
AF is associated with an increased risk of incident MI, especially in women. However, this association is limited to NSTEMI.
Circulating Tissue Factor Levels and Risk of Stroke
Authors: Iacoviello Licia , Di Castelnuovo Augusto , de Curtis Amalia , Agnoli Claudia , Frasca Graziella , Mattiello Amalia , Matullo Giuseppe , Ricceri Fulvio , Sacerdote Carlotta , Grioni Sara , Tumino Rosario , Napoleone Emanuela , Lorenzet Roberto , de Gaetano Giovanni , Panico Salvatore , Donati Maria Benedetta 
Published: May 2015

Background and Purpose—
Tissue factor (TF) expression is increased in inflammatory atherosclerotic plaques and has been related to their thrombogenicity. Blood-borne TF has been also demonstrated to contribute to thrombogenesis. However, few studies have evaluated the association of circulating levels of TF with stroke. We investigated the association of baseline circulating levels of TF with stroke events occurred in the European Prospective Investigation into Cancer and Nutrition-Italy cohort.

Methods—
Using a nested case–cohort design, a center-stratified random sample of 839 subjects (66% women; age range, 35–71 years) was selected as subcohort and compared with 292 strokes in a mean follow-up of 9 years. Blood samples were collected at baseline in citrate, plasma was stored in liquid nitrogen and TF was measured by ELISA (IMUBIND, TF ELISA, Instrumentation Laboratory, Milan, Italy). The odd ratios and 95% confidence intervals, adjusted by relevant confounders (covariates of TF) and stratified by center, were estimated by a Cox regression model using Prentice method.

Results—

Individuals in the highest compared with the lowest quartile of TF plasma levels had significantly increased risk of stroke (odds ratio
IVvsI quartile
, 2.01; 95% confidence interval, 1.25–3.23). The association was independent from several potential confounders (odds ratio
IVvsI quartile
, 1.91; 95% confidence interval, 1.15–3.19). No differences were observed between men and women. The increase in risk was restricted to ischemic strokes (odds ratio
IVvsI quartile
, 2.13; 95% confidence interval, 1.10–4.12; fully adjusted model), whereas high levels of TF were not associated with the risk of hemorrhagic stroke (odds ratio
IVvsI quartile
, 1.12; 95% confidence interval, 0.49–2.55; fully adjusted model).

Conclusions—
Our data provide evidence that elevated levels of circulating TF are potential risk factors for ischemic strokes.