bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B41: The angiotensin receptor blocker telmisartan inhibits the growth of pancreatic ductal adenocarcinoma and improves survival
Authors: Grahovac Jelena , Han Shiwei , Liu Hao , Jain Rakesh , Boucher Yves 
Published: December 2016

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer with a 5-year survival rate of less than 5%. PDAC is highly resistant to chemotherapy, which impels search for novel approaches for treatment. Our group has previously shown in PDAC models that the angiotensin II type 1 receptor (AT1R) blocker losartan decreases desmoplasia and solid stress, which enhances blood flow, and improves the delivery and effectiveness of cytotoxic agents (Chauhan et al, Nature Comm 2013). In contrast to losartan, which had no effects on the growth of primary PDAC, we recently found that the AT1R blocker telmisartan significantly reduces the growth of PDAC. In addition to inhibiting AT1R activity telmisartan is also a partial agonist of Peroxisome Proliferator Activated Receptor γ (PPARγ). We determined in a panel of PDAC cell lines the effects of telmisartan on cellular viability. Our findings suggest that the sensitivity to telmisartan treatment correlates with low steady-state expression of PPARγ and a mesenchymal morphology. Furthermore, telmisartan induced a transcriptional profile distinct from the response to the direct PPARγ agonist pioglitazone. In support of our correlative results, the genetic knockdown of PPARγ increased the sensitivity to telmisartan and stimulated epithelial to mesenchymal transition (e.g. decreased expression of E-cadherin, increased expression of the mesenchymal markers Snail and N-cadherin). We also tested the effects of telmisartan in orthotopically implanted and genetically engineered mouse models of PDAC. Telmisartan inhibited the growth of primary tumors, decreased the incidence of metastasis and improved mice survival. In summary, our findings show that telmisartan reduces the viability of PDAC cells with a mesenchymal morphology and low expression of PPARγ, inhibits PDAC growth and improves the survival of mice.
Citation Format: Jelena Grahovac, Shiwei Han, Hao Liu, Rakesh Jain, Yves Boucher.{Authors}. The angiotensin receptor blocker telmisartan inhibits the growth of pancreatic ductal adenocarcinoma and improves survival. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B41.
Abstract B65: The combination of beta-cyclodextrin & 2-deoxyglucose worked synergistically with TRAIL to induce apoptosis in 90% of Panc-1 cells at 10ng/ml of TRAIL
Authors: Yamaguchi Ryuji 
Published: December 2016

Abstract
Since over 95% of pancreatic cancer cells express P-glycoprotein which could exclude chemotherapeutics from entering the cell, making it difficult to treat pancreatic cancer. To address this problem we used 2-deoxyglucose (2DG), beta-cyclodextrin (bCD) and TNFa-Related Apoptosis Inducing Ligand (TRAIL) combination to induce apoptosis in pancreatic cancer cells. 2DG can enter highly glycolytic cells through glucose transporters, while bCD could deplete cholesterol from the plasma membranes without entering the cell, inhibiting the signal transduction between PI3K and AKT, and TRAIL could activate TRAIL-receptors, activating caspases from outside. These three agents worked synergistically to induce apoptosis in Panc-1 pancreatic cancer cells; Panc-1 cells were incubated in medium containing 10 mM 2DG and 25 mM glucose for 90 minutes. Then 10 mM methyl-beta-cyclodextrin (MBCD) was added, and 30 minutes later, 10 ng/ml of TRAIL was added. 2 hours later, cells were washed and incubation continued. When cells were harvested 16 hours later, over 90% of cells were propidium iodide (PI) positive, while 0% of cells treated with TRAIL alone, and less than 30% of cells treated with 2DG-MBCD were PI positive.
Citation Format: Ryuji Yamaguchi.{Authors}. The combination of beta-cyclodextrin & 2-deoxyglucose worked synergistically with TRAIL to induce apoptosis in 90% of Panc-1 cells at 10ng/ml of TRAIL. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B65.
Abstract B84: Physiologic pancreatic cancer imaging using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)
Authors: Fischer Laura E. , Schabel Matthias , Foster Bryan , Thomas Charles R. , Rooney William , Sheppard Brett C. , Gilbert Erin W. 
Published: December 2016

Abstract
Background: Accurately identifying and monitoring pancreatic ductal adenocarcinoma (PDA) remains a significant challenge. Whereas conventional imaging (CT and MRI) report only anatomic information, dynamic contrast-enhanced MRI (DCE-MRI) has the ability to show physiologic differences in tissue perfusion based on the kinetics of IV-contrast. We coupled DCE-MRI with data-modeling methods to obtain reproducible, high-resolution physiologic images in a series of patients with and without PDA in order to more accurately identify PDA.
Methods: Patients with borderline-resectable PDA (BR-PDA) or at high-risk for PDA (HR), but without cancer were imaged with DCE-MRI. T1-weighted images were collected during IV contrast injections [Figure 1]. Both tumor and the pancreatic body or non-tumor pancreas were identified and using dual-compartment pharmacokinetic modelling, DCE-MRI parameters were quantified and compared between groups.
Results: Between 6/2014 and 2/2015, 12 DCE-MRIs were completed: 9 HR and 3 BR-PDA. Significant differences in the DCE-MRI parameters blood flow (F), first-pass extraction (E), mean capillary transit-time (tc), transfer constant (Ktrans), volume of extravascular-extracellular space (Ve) and blood volume (Vb) were found in normal HR pancreases vs. the tumors in BR-PDA patients [Table 1A]. When comparing non-tumoral pancreases in both cohorts, only F, Ktrans, and Vb differed [Table 1B].
Conclusions: DCE-MRI of the pancreas is feasible and provides imaging biomarkers of vascular structure and function in both tumoral and non-tumoral pancreases which may allow for earlier and more accurate identification of PDA in these high risk populations.
Citation Format: Laura E. Fischer, Matthias Schabel, Bryan Foster, Charles R. Thomas, Jr., William Rooney, Brett C. Sheppard, Erin W. Gilbert.{Authors}. Physiologic pancreatic cancer imaging using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B84.
Abstract IA16: Reconstructing compartment−specific regulatory programs in pancreatic cancer
Authors: Maurer H. Carlo , He Jing , Alvarez Mariano J. , Giorgi Federico , Holmstrom Sam , Califano Andrea , Olive Kenneth P. 
Published: December 2016

Abstract
Pancreatic cancer is characterized by an expansive, desmoplastic stroma that responds to neoplastic signals from the malignant epithelium while also instigating a cacophony of signals from diverse stromal cell types that in turn modulate the malignant process. Several published efforts have reported the global signaling profiles of bulk pancreatic tumors, which have proven useful for defining different molecular subtypes of the disease. However, in order to facilitate the precise assessment of both neoplastic and stromal signaling profiles, we developed a robust pipeline to perform RNA-sequencing from laser-capture microdissected tissues. We applied this technique to a collection of 200+ frozen primary pancreatic ductal adenocarcinomas, deriving both malignant epithelial and stromal gene expression profiles from each. These compartment-specific profiles may serve to define novel molecular subtypes grounded in the biology of the distinct compartments. This technique also enabled profiling of the epithelium and stromal from microscopic PanIN-1 proliferations, facilitating the precise delineation of changes arising during malignant progression. Using computational modelling of paired epithelial and stromal samples, we developed a novel digital deconvolution model that generates virtual compartment-specific gene expression signatures from bulk pancreatic tumor profiles. Thus, findings from our experimentally dissected sample set can be leveraged to analyze multiple publically-available gene expression datasets.
In order to learn more about the regulatory processes that drive malignancy in both the epithelial and stromal compartments, we used a systems biology approach to reconstruct their global regulatory networks in pancreatic cancer. Briefly, regulatory models comprising ~700,000 interactions were computationally reconstructed for each compartment from the LCM-RNA-seq datasets using the ARACNe algorithm. These networks then served as a scaffold for the application of the MARINa and VIPER algorithms, which define master regulatory proteins whose activity drives (or restrains) the PanIN-1 to PDA progression. We will discuss early results of master regulator analyses that illuminate both oncogenic signaling in the epithelium, and large-scale changes in stromal microenvironment that occur during progression from PanIN-1 to PDA.
Citation Format: H. Carlo Maurer, Jing He, Mariano J. Alvarez, Federico Giorgi, Sam Holmstrom, Andrea Califano, Kenneth P. Olive.{Authors}. Reconstructing compartment−specific regulatory programs in pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr IA16.
Abstract IA17: The global phospho-proteome of K-Ras mutant cells and tissues
Authors: Haigis Kevin 
Published: December 2016

Abstract
K-Ras is the most commonly mutated oncogene in cancer and it plays a predominant role in the pathogenesis of cancers of the pancreas, colon, and lung. Mutationally activated K-Ras influences cellular behaviors through broad and complex effects on downstream signal transduction pathways. In an effort to understand the molecular mechanisms underlying the oncogenic properties of mutant forms of K-Ras, we are using mass spectroscopy (MS) to quantify proteome-wide changes in protein phosphorylation in primary mouse tissues that are engineered to express mutant forms of K-Ras. In total, we have obtained relative quantification of 5,936 and 11,455 phospho-peptides from mouse pancreas and colon of varying K-Ras genotype. The dataset paints a complex picture of signaling downstream of K-Ras, as phosphorylation of many proteins in known Ras effector pathways (i.e. MAPK and PI3K) are unaffected or down-regulated by mutationally activated K-Ras. Moreover, we have found that different activating K-Ras alleles often have polar effects on the phosphorylation state of a given downstream protein. The biological significance of any given phosphorylation change in a large dataset such as this is often difficult to interpret, since the vast majority of quantified sites have no functional annotation. To combat this issue, we developed phospho-site set enrichment analysis (PSSEA), a computational tool that identifies kinases that are activated in a given sample based on the representation of known substrates in the phospho-MS dataset. PSSEA revealed, for example, that casein kinase 2 (Csnk2a1) is selectively activated by K-RasG12D in the pancreas, but not in the colon. Overall, this study provides an unprecedented view of K-Ras signaling on a global scale and reveals a variety of novel insights into the signal transduction properties of different K-Ras alleles. Ultimately, systems-level and bioinformatic analyses of these data will reveal new therapeutic targets for cancers expressing mutant forms of K-Ras.
Citation Format: Kevin Haigis.{Authors}. The global phospho-proteome of K-Ras mutant cells and tissues. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr IA17.
Abstract IA22: Reprograming the tumor microenvironment to facilitate responses to immunotherapy
Authors: DeNardo David Glenn 
Published: December 2016

Abstract
Immunotherapeutics represent highly promising agents with the potential to improve patient outcomes in a variety of cancer types. Unfortunately, single-agent immunotherapy has achieved limited clinical benefit to date in patients suffering from pancreatic ductal adenocarcinoma (PDAC). This may be due to the presence of a uniquely immunosuppressive tumor microenvironment (TME) present in PDACs, which creates a barrier to effective immune surveillance. Critical obstacles to immunotherapy in PDAC tumors include the dense desmoplastic stroma that acts as a barrier to T-cell infiltration and the high numbers of tumor-associated immunosuppressive cells.
We have identified hyperactivated focal adhesion kinase (FAK) activity in neoplastic PDAC cells as a significant regulator of the fibrotic and immunosuppressive TME. We found that FAK activity was elevated in human PDAC tissues and correlates with high levels of fibrosis and poor CD8+ cytotoxic T-cell infiltration. Single-agent FAK inhibition (VS-4718) significantly limited tumor progression, resulting in a doubling of survival in the p48-Cre/LSL-KrasG12D/p53Flox/+ (KPC) mouse model of human PDAC. This alteration in tumor progression was associated with dramatically reduced tumor fibrosis, decreased numbers of tumor-infiltrating immature myeloid cells and immunosuppressive macrophages. We postulated that these desirable effects of FAK inhibition on the TME might render PDAC tumors more sensitive to immunotherapy. Accordingly, we found that FAK inhibition rendered the previously unresponsive KPC mouse model responsive to anti-PD1 and anti-CTLA4 antagonists leading to a nearly tripling of survival times. These data suggest that FAK inhibition increases immune surveillance by overcoming the fibrotic and immunosuppressive PDAC TME and thus renders tumors responsive to immunotherapy. The results of these pre-clinical studies have led to the development of a new clinical trial (NCT02546531) testing the combination of FAK inhibition (Defactinib) with Pembrolizumab and Gemcitabine in advanced PDAC Patients.
Citation Format: David Glenn DeNardo.{Authors}. Reprograming the tumor microenvironment to facilitate responses to immunotherapy. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr IA22.
Abstract IA23: Immune landscape of human pancreatic cancer
Authors: Balli David , Rech Andrew J. , Stanger Ben Z. , Vonderheide Robert H. 
Published: December 2016

Abstract
Survival rates for pancreatic ductal adenocarcinoma (PDA) remain dismal. Immunotherapy has the potential to improve outcomes, but clinical trial results – particularly those employing single-agent CTLA4 or PD1/PD-L1 inhibition – have thus far been disappointing. We stratified human PDA based on a signature of cytolytic T-cell activity. Differences in cytolytic index correlated with defined PDA subtypes and distinct mutational events. Specifically, PDA tumors with low cytolytic activity exhibited increased genomic structural variation, including reproducible copy number alterations in MYC, FGFR1, NOTCH2, and CDKN2. In contrast to other tumors such as kidney cancer or melanoma, PDA tumors with a high cytolytic index lacked an increased mutation or neo-epitope load. Tumors with high cytolytic activity exhibited increased expression of several immune checkpoint genes, but PD-L1 expression was uniformly low. These data establish a link between genomic alterations and immune activation in PDA and suggest that immune checkpoints other than PD-L1/PD-1 may be attractive therapeutic targets in this lethal disease.
Citation Format: David Balli, Andrew J. Rech, Ben Z. Stanger, Robert H. Vonderheide.{Authors}. Immune landscape of human pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr IA23.
Loss of RasGAP Tumor Suppressors Underlies the Aggressive Nature of Luminal B Breast Cancers
Authors: Olsen Sarah Naomi , Wronski Ania , Castaño Zafira , Dake Benjamin , Malone Clare , De Raedt Thomas , Enos Miriam , DeRose Yoko S. , Zhou Wenhui , Guerra Stephanie , Loda Massimo , Welm Alana , Partridge Ann H. , McAllister Sandra S. , Kuperwasser Charlotte , Cichowski Karen 
Published: December 2016

AbstractLuminal breast cancers are typically estrogen receptor–positive and generally have the best prognosis. However, a subset of luminal tumors, namely luminal B cancers, frequently metastasize and recur. Unfortunately, the causal events that drive their progression are unknown, and therefore it is difficult to identify individuals who are likely to relapse and should receive escalated treatment. Here, we identify a bifunctional RasGAP tumor suppressor whose expression is lost in almost 50% of luminal B tumors. Moreover, we show that two RasGAP genes are concomitantly suppressed in the most aggressive luminal malignancies. Importantly, these genes cooperatively regulate two major oncogenic pathways, RAS and NF-κB, through distinct domains, and when inactivated drive the metastasis of luminal tumors in vivo. Finally, although the cooperative effects on RAS drive invasion, NF-κB activation triggers epithelial-to-mesenchymal transition and is required for metastasis. Collectively, these studies reveal important mechanistic insight into the pathogenesis of luminal B tumors and provide functionally relevant prognostic biomarkers that may guide treatment decisions.Significance: The lack of insight into mechanisms that underlie the aggressive behavior of luminal B breast cancers impairs treatment decisions and therapeutic advances. Here, we show that two RasGAP tumor suppressors are concomitantly suppressed in aggressive luminal B tumors and demonstrate that they drive metastasis by activating RAS and NF-κB. Cancer Discov; 7(2); 202–17. ©2016 AACR.See related commentary by Sears and Gray, p. 131.This article is highlighted in the In This Issue feature, p. 115
The Rodent Liver Undergoes Weaning-Induced Involution and Supports Breast Cancer Metastasis
Authors: Goddard Erica T. , Hill Ryan C. , Nemkov Travis , D'Alessandro Angelo , Hansen Kirk C. , Maller Ori , Mongoue-Tchokote Solange , Mori Motomi , Partridge Ann H. , Borges Virginia F. , Schedin Pepper 
Published: December 2016

Abstract
Patients with postpartum breast cancer are at increased risk for metastasis compared with age-matched nulliparous or pregnant patients. Here, we address whether circulating tumor cells have a metastatic advantage in the postpartum host and find the postlactation rodent liver preferentially supports metastasis. Upon weaning, we observed liver weight loss, hepatocyte apoptosis, extracellular matrix remodeling including deposition of collagen and tenascin-C, and myeloid cell influx, data consistent with weaning-induced liver involution and establishment of a prometastatic microenvironment. Using intracardiac and intraportal metastasis models, we observed increased liver metastasis in post-weaning BALB/c mice compared with nulliparous controls. Human relevance is suggested by a ∼3-fold increase in liver metastasis in patients with postpartum breast cancer (n = 564) and by liver-specific tropism (n = 117). In sum, our data reveal a previously unknown biology of the rodent liver, weaning-induced liver involution, which may provide insight into the increased liver metastasis and poor prognosis of women diagnosed with postpartum breast cancer.
Significance: We find that patients with postpartum breast cancer are at elevated risk for liver metastasis. We identify a previously unrecognized biology, namely weaning-induced liver involution, that establishes a prometastatic microenvironment, and which may account in part for the poor prognosis of patients with postpartum breast cancer. Cancer Discov; 7(2); 177–87. ©2016 AACR.
This article is highlighted in the In This Issue feature, p. 115
Reasons for the persistent incidence of venous thromboembolism
Authors: Heit John A. , Ashrani Aneel A. , Crusan Daniel J. , McBane Robert D. , Petterson Tanya M. , Bailey Kent R. 
Published: December 2016

SummaryReasons for trends in venous thromboembolism (VTE) incidence are uncertain. It was our objective to determine VTE incidence trends and risk factor prevalence, and estimate population-attributable risk (PAR) trends for each risk factor. In a population-based cohort study of all residents of Olmsted County, Minnesota from 1981–2010, annual incidence rates were calculated using incident VTE cases as the numerator and age- and sex-specific Olmsted County population estimates as the denominator. Poisson regression models were used to assess the relationship of crude incidence rates to year of diagnosis, age at diagnosis, and sex. Trends in annual prevalence of major VTE risk factors were estimated using linear regression. Poisson regression with time-dependent risk factors (person-years approach) was used to model the entire population of Olmsted County and derive the PAR. The age- and sex-adjusted annual VTE incidence, 1981–2010, did not change significantly. Over the time period, 1988–2010, the prevalence of obesity, surgery, active cancer and leg paresis increased. Patient age, hospitalisation, surgery, cancer, trauma, leg paresis and nursing home confinement jointly accounted for 79 % of incident VTE; obesity accounted for 33 % of incident idiopathic VTE. The increasing prevalence of obesity, cancer and surgery accounted in part for the persistent VTE incidence. The PAR of active cancer and surgery, 1981–2010, significantly increased. In conclusion, almost 80 % of incident VTE events are attributable to known major VTE risk factors and one-third of incident idiopathic VTE events are attributable to obesity. Increasing surgery PAR suggests that concurrent efforts to prevent VTE may have been insufficient.Supplementary Material to this article is available online at www.thrombosis-online.com.