bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B17: Tumor-associated stellate cells promote an invasive phenotype of pancreatic cancer cells
Authors: Karnevi Emelie , Rosendahl Ann H. , Saleem Moin A. , Andersson Roland 
Published: October 2015

Abstract
At the time of diagnosis, almost 80% of pancreatic cancer patients present with either new-onset type 2 diabetes or impaired glucose tolerance. Pancreatic cancer is associated with a highly abundant stroma, which is believed to influence the pathogenesis of the disease. In the local tumor microenvironment, both elevated glucose levels and the presence of tumor-associated stellate cells are hypothesized to promote the tumor progression and invasion by tumor cells. In this study, the influence by the microenvironment on pancreatic cancer cell invasion was investigated in vitro. Epithelial-to-mesenchymal transition (EMT) of human pancreatic cancer cells co-cultured in normal (5mM) or high (25 mM) glucose conditions with tumor-associated pancreatic stellate cells (TPSCs) was monitored by Western immunoblotting. In addition, a three-dimensional organotypic model was established to study and visualize the pancreatic cancer cell invasion. After co-culture, the expression of several EMT-markers was altered. The levels of E-cadherin were reduced by more than 95% (P&lt;0.001) while vimentin was increased by 45% (P&lt;0.05). In addition, high glucose conditions reduced the levels of ZO-1 and β-catenin compared to normal glucose. TGF-β stimulation, a known inducer of EMT, resulted in a similar modulation of EMT markers. The organotypic model showed differences in the extent of invasion between the cell lines investigated, of which PANC-1 human pancreatic cells were shown to be the most invasive and also formed a highly proliferative epithelium. In high glucose conditions, the invasion of PANC-1 cells appeared to increase both in number and distance covered by the cells. Immunofluorescent staining of EMT-markers in organotypic sections displayed a lack of E-cadherin and extensive expression of vimentin in the tumor epithelium. In conclusion, this study show TPSCs to induce changes in pancreatic cancer cells associated with enhanced invasiveness. In addition, a three-dimensional model visualized the invasive potential of the pancreatic cancer cells, which was further enhanced by high glucose conditions. This study contributes to further elucidate the interplay between, and influence of, the cell types present in the local tumor microenvironment, which promotes the tumor cell invasion as an important step in the pancreatic tumor progression.
Citation Format: Emelie Karnevi, Ann H. Rosendahl, Moin A. Saleem, Roland Andersson. Tumor-associated stellate cells promote an invasive phenotype of pancreatic cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B17.
Abstract B44: The histone deacetylase SIRT6 regulates metabolism in pancreatic ductal adenocarcinoma
Authors: Kugel Sita , Sebastián Carlos , Perera Rushika M. , Bardeesy Nabeel , Mostoslavsky Raul 
Published: October 2015

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death and one of the most aggressive and deadly malignancies, with limited therapeutic options. Sirtuin 6 (SIRT6) is a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase that functions as a novel tumor suppressor, which regulates aerobic glycolysis in cancer cells. Whether glycolysis plays a role in pancreatic cancer development remains a topic of intense study. Importantly, we found SIRT6 to be downregulated in human PDAC and most pancreatic cancer cell lines, resulting in increased expression of glycolytic genes. To determine the role of SIRT6 in pancreatic cancer we utilized human PDAC cell lines that demonstrated low expression of SIRT6 compared to a human pancreatic ductal epithelial (HPDE) control cell line. Restoration of SIRT6 expression decreased the levels of glycolytic gene expression, reduced glucose uptake, and inhibited cell growth. Conversely, knockdown of SIRT6 in HPDE cells increased glycolytic gene expression, glucose uptake and enhanced cell growth. To further explore the role of SIRT6 in a genetically defined PDAC model, we used an autochthonous mouse model with conditional alleles for KRASG12D, p53, and SIRT6, together with a p48-Cre allele to delete SIRT6 and p53 while expressing oncogenic Ras exclusively in the pancreas. SIRT6null, KRASG12D, p53+/- p48 tumor cells also exhibited increased expression of glycolytic genes and had enhanced glucose uptake compared to SIRT6+/+, KRASG12D, p53+/- p48 tumor cells, a phenotype which is reversed by restoration of wild-type but not catalytically inactive SIRT6 expression. Understanding how SIRT6 regulates PDAC metabolism through the modulation of chromatin dynamics will hopefully lead to new therapies to tackle aberrant metabolism in this devastating disease.
Citation Format: Sita Kugel, Carlos Sebastián, Rushika M. Perera, Nabeel Bardeesy, Raul Mostoslavsky. The histone deacetylase SIRT6 regulates metabolism in pancreatic ductal adenocarcinoma. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B44.
Abstract B48: Pancreatic cancer cells exhibit heterogeneous glucose and glutamine metabolic dependencies
Authors: Bryant Kirsten L. , Maitra Anirban , Der Channing J. 
Published: October 2015

Abstract
Pancreatic cancer cells demonstrate altered metabolism that is consistent with amplified aerobic glycolysis, fueled by increased glucose uptake. Concurrently, additional studies have established an enhanced dependence on glutamine to power anabolic processes. Recently, there has been a renewed interest in understanding the altered metabolic requirements of cancer cells with the goal of targeting differential nutrient dependencies for therapeutic gain. We screened a panel of twelve well established and widely studied KRAS mutant pancreatic tumor-derived cell lines, as well as seven low passage KRAS mutant pancreatic patient-derived xenograft (PDX)-established tumor cell lines for the ability to proliferate in growth media deficient in glucose and/or glutamine. While 11 of 12 established cell lines were unable to proliferate in these nutrient-depleted conditions, we identified one (Capan-2) that was capable of proliferation in the complete absence of glucose. By comparison, of the seven PDX-derived cell lines screened, four demonstrated complete glucose or glutamine dependency, whereas one was capable of proliferation in the absence of glutamine and two proliferated in the absence of glucose. Our ongoing studies are focused on elucidating the mechanistic basis for glucose or glutamine independent growth. Defining these mechanisms may identify pharmacologic approaches that target metabolic pathways for the treatment of KRAS mutant pancreatic cancer.
Citation Format: Kirsten L. Bryant, Anirban Maitra, Channing J. Der. Pancreatic cancer cells exhibit heterogeneous glucose and glutamine metabolic dependencies. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B48.
Abstract B64: A Lys-Ala-Leu-Ala (KALA) repeated peptide modification in DNA nanoparticles of DOPE/CHEMS, follows GPCR mediated transgene expression in dendritic cell
Authors: Shaheen Sharif Mohammad , Akita Hidetaka , Harashima Hideyoshi 
Published: October 2015

Abstract
Cellular uptake process of cationic peptide modified liposome is still obscured in perspective of cell biology. The mechanisms responsible for the internalization of oligo arginine, oligo-lysine, TAT and other arginine or lysine enriched peptide have focused on macropinocytosis. No information was reported about the uptake process of repeated cationic arginine or lysine (hydrophilic moiety) followed by leucine or alanine (hydrophobic moiety) with lipid bilayer based DNA nanocargoes. Here we orchestrated the concept of repeated lys-ala-leu-ala (KALA) peptide modified DNA-protamine-lipid nanoparticle, proclaimed a promising transfection activity in dendritic cell, following GPCR mediated endocytosis. Chemical inhibitors studies of chlorpromazine, Fillipin, and Amiloride did not support the concept of macropinocytosis, clathrin mediated endocytosis and cavaeola mediated endocytosis. Cetirizine hydrochloride, a GPCR blocker shut down the KALA mediated transgene expression. Confocal studies showed no liposomal uptake in KALA modification rather than R8 modification, which implies to receptor mediated endocytosis and thereby transgene expression. Low concentration of KALA pretreatment allowed a R8 MEND (usually non-expressed) to that of the same expression of KALA MEND and vice versa of high concentration KALA pretreatment. In a nut-shell performance of KALA ensured an engulfment of GPCR based endocytosis as well as GPCR activation thereby, that outcomes a boom transgene expression in dendritic cell.
Citation Format: Sharif Mohammad Shaheen, Hidetaka Akita, Hideyoshi Harashima. A Lys-Ala-Leu-Ala (KALA) repeated peptide modification in DNA nanoparticles of DOPE/CHEMS, follows GPCR mediated transgene expression in dendritic cell. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B64.
Abstract B74: Minimally invasive ablative therapy for mucinous cystic neoplasms (MCN) in a genetically engineered mouse model
Authors: Cuevas Carlos , Dotson Ashley M. , Hingorani Sunil R. 
Published: October 2015

Abstract
Pancreatic cystic neoplasms are an increasing health problem in the adult population due to their inherent potential to progress to invasive adenocarcinomas. The only available treatment is resection with the consequential significant morbidity and mortality associated with pancreatic surgery. Direct percutaneous injection of an ablative substance represents a potential new approach to this problem. Limited studies performed in human subjects speak to the potential feasibility of this approach, but no systematic or rigorous assessment of agents and outcomes has been possible. We have undertaken an effort to evaluate the effectiveness of intracystic injections of different chemical ablative substances (including ethanol and sodium tetradecyl sulfate) or chemotherapeutic drugs (including gemcitabine and paclitaxel) for the treatment of mucinous cystic neoplasms (MCN) in a murine model of the disease. We have developed a genetically engineered mouse model of MCN (KrasLSL-G12D;Dpc4fl/fl;Cre) that recapitulates the prototypical features of the human correlate, including development of an ovarian-type stroma with estrogen receptor (ER) and progesterone receptor (PR)-positive cells. An MCN is first identified in the mouse with high-resolution ultrasound imaging (HRUS) and the cyst fluid aspirated; the cyst is then injected with one of the treatment regimens. Study feasibility was first established with image-guided India ink injections followed by necropsy to evaluate successful aspiration and injection. Following treatment, disease response is evaluated by serial HRUS and detailed histopathologic and molecular analyses on recovered tissues at study termination. Through these studies we hope to define the optimal therapeutic regimen for non-surgical management of MCN in anticipation of a future clinical trial. We have successfully identified, aspirated and injected MCN with either saline (control) or ablative substances under real time ultrasound guidance in a longitudinal cohort. Challenges to this approach are also discussed including the posterior localization of the treated lesions within the diffusely abnormal pancreas typically found in this animal model.
Citation Format: Carlos Cuevas, Ashley M. Dotson, Sunil R. Hingorani. Minimally invasive ablative therapy for mucinous cystic neoplasms (MCN) in a genetically engineered mouse model. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B74.
Abstract B93: A data base of N of 1 case reports from pancreatic cancer patients enrolled in First-in-man studies 2002 through 2012
Authors: Garrido-Laguna Ignacio , Tometich Danielle , Boucher Kenneth , Sharma Sunil 
Published: October 2015

Abstract
Background: First-in-man (FIM) studies test different doses of novel therapeutics for the first time in humans. The purpose of this work was to develop a data base with FIM studies published in the last decade and to identify extraordinary responses to therapy in patients with advanced pancreatic cancer.
Methods: We conducted a search in Scopus of all FIM studies published between 2002 and 2012. We collected the following information: author, date and journal of publication, class of drug, route of administration, dose escalation design, patient demographic information, grade 3-4 toxicities, dose limiting toxicities, deaths during trial (including treatment related deaths), radiologic response, trial location and tumor types included in each trial.
Results: We identified 3065 references through the Scopus search. Among these we found 118 FIM studies enrolling 5369 patients with advanced cancers from 2002 through 2012. The most common tumor types were colorectal cancer 1055 (19.6%), lung cancer 456 (8.4%), melanoma 475 (8.8%), breast cancer 319 (5.9%) and pancreatic ductal adenocarcinoma 296 (5.5%). There were 194 deaths including 17 (0.3%) treatment related deaths. 12 patients (0.2%) had complete response as best response to therapy including a patient with pancreatic cancer treated with bosutinib (a novel Src/abl tyrosin kinase inhibitor). 1 patient with pancreatic cancer had partial response to CHR-3996 (a novel histone deacetylase inhibitor) with a progression free survival (PFS) of 12 months. A second patient had a partial response to trametinib (MEK inhibitor) with a PFS of 11.75 months. Interestingly histone deacetylases are components of core signaling pathways in pancreatic cancer such Cell cycle and Notch pathway. Moreover, Src is commonly activated in pancreatic cancer.
Conclusions: Novel approaches are urgently needed to treat pancreatic cancer. This includes identifying novel treatment opportunities through N of 1 case reports. We have retrospectively identified extraordinary responses to therapy in patients with advanced pancreatic enrolled in FIM studies with Src, HDAC and MEK inhibitors. Efforts should be now focused on understanding the underpinning biology of the disease in these patients.
Citation Format: Ignacio Garrido-Laguna, Danielle Tometich, Kenneth Boucher, Sunil Sharma. A data base of N of 1 case reports from pancreatic cancer patients enrolled in First-in-man studies 2002 through 2012. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B93.
Abstract IA13: Acinar cell transdifferentiation sets the stage for early tumor heterogeneity
Authors: Takeuchi Kenneth K. , Delgiorno Kathleen E. , Halbrook Christopher J. , Crawford Howard C. 
Published: October 2015

Abstract
Prior to PanIN formation, acinar cells harboring oncogenic Kras gradually lose their acinar character and take on a ductal phenotype in a process known as acinar-to-ductal metaplasia. Rather than mimicking a normal pancreatic duct, metaplastic ducts take on a proliferative biliary progenitor phenotype, marked by the expression of SOX17 and PDX1 and the presence of numerous tuft cells, recently identified as a PanIN initiating cells. Manipulation of SOX17 and PDX1 in vivo reveal them to be a transdifferentiation promoter and suppressor, respectively, both greatly affecting tuft cell genesis and tumor formation. These opposing roles of developmental transcription factors during tumorigenesis implicate the usurpation of a differentiation program that significantly contributes to cellular heterogeneity within early pre-cancerous lesions of the pancreas.
Citation Format: Kenneth K. Takeuchi, Kathleen E. Delgiorno, Christopher J. Halbrook, Howard C. Crawford. Acinar cell transdifferentiation sets the stage for early tumor heterogeneity. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr IA13.
Abstract IA15: Circulating tumor DNA
Authors: Diaz Luis A. 
Published: October 2015

Abstract
The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction–based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We found that ctDNA was detectable in &gt;75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway. Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer.
Citation Format: Luis A. Diaz. Circulating tumor DNA. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr IA15.
Abstract IA26: Pancreatic adenocarcinoma and altered whole-body metabolism
Authors: Wolpin Brian M. 
Published: October 2015

Abstract
Pancreatic cancer is the fourth leading cause of cancer mortality in the United States, and the vast majority of patients live less than 12 months. A defining feature of pancreatic ductal adenocarcinoma (PDAC) is its relationship with altered systemic metabolism. The risk of developing PDAC is increased among individuals with chronic obesity, hyperglycemia, and hyperinsulinemia. Furthermore, weight loss and new-onset diabetes frequently develop within the 2 years before diagnosis, and PDAC is strongly associated with development of cachexia and muscle loss (sarcopenia), which impair patient quality of life and survival.
We hypothesized that alterations in whole-body metabolism could be detected in patients with pancreatic cancer prior to diagnosis, with potential utility for disease screening and identifying novel treatment approaches. To investigate this hypothesis, circulating metabolites were profiled in prediagnostic plasma from pancreatic cancer cases and matched controls using a liquid chromatography-tandem mass spectrometry (LC-MS) metabolomics platform. In nearly 1,500 participants from four prospective cohort studies, we identified metabolites associated with future pancreatic cancer diagnosis independent of known measures of obesity, energy balance and insulin resistance. Experimental studies indicate that multiple years elapse between formation of the initial PDAC clone and development of cells with the capacity for metastatic spread. Thus, we considered whether the circulating metabolites identified in humans were also seen in mice with early pancreatic cancers and used labeled metabolites to trace the source of metabolic alterations in model systems. This work indicates that systemic metabolic alterations can be seen in humans and model systems prior to pancreatic cancer diagnosis, with implications for understanding the biology of early pancreatic tumors and host-tumor interactions.
Citation Format: Brian M. Wolpin. Pancreatic adenocarcinoma and altered whole-body metabolism. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr IA26.
Abstract IA5: Translating genetic discoveries to patient care
Authors: Hruban Ralph H. 
Published: October 2015

Abstract
Next-generation sequencing technologies have changed the speed at which cancer genetics research can be performed and this research has fundamentally changed our understanding of pancreatic cancer.
1. Families: It has been estimated that 10% of pancreatic cancer has an inherited basis. Whole-exome and whole-genome sequencing studies have led to the discovery of several new familial pancreatic cancer genes including PALB2 and ATM. It is hoped that new multi-institutional collaborative efforts will dramatically increase the pace of discovery. Patients found to harbor a genetic alteration that predisposes them to pancreatic cancer will be the first to benefit from early detection efforts.
2. Cystic neoplasms: Some cystic lesions in the pancreas are harmless benign tumors, while others are precancerous. Lives can be saved if significant precursor lesions can be identified and removed, but there is a risk of over-treatment if the benign harmless cysts are removed. Whole-exome sequencing all of the four major types of cystic neoplasms of the pancreas has revealed a pattern of mutations specific for each cyst type. In the future, cyst fluid can be sampled and cyst type determined by sequencing.
3. Early detection: The genetic alterations in a cancer and in its precursor lesions offer extremely sensitive and highly specific markers for the early detection of pancreatic neoplasia. These genetic alterations can be detected in pancreatic juice collected at endoscopy and even in the plasma.
4. Invasive cancer: Genetic alterations in a cancer can be the basis for individualized therapies.
5. Metastatic cancer: The sequencing of metastatic cancer has helped define the timeline of tumor progression in the pancreas.
In sum, and in short, these are exciting times in the war against pancreatic cancer. The translation of discoveries made by sequencing pancreatic tumors to patient care holds the promise for reducing mortality from this terrible disease.
Citation Format: Ralph H. Hruban. Translating genetic discoveries to patient care. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr IA5.