bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A27: Exploring the role of glycosylation in pancreatic disease
Authors: Engle Dannielle , Tiriac Hervé , Pommier Arnaud , Schoepfer Christina , Silva Brandon Da , Yao Melissa , Park Youngkyu , Hollingsworth Michael A. , Tuveson David 
Published: May 2018

Abstract
Pancreatic ductal adenocarcinoma (PDA) is almost uniformly lethal and surgical intervention is the only cure. Unfortunately, most patients are ineligible for resection because of the advanced stage of disease by the time of diagnosis. This is due in part to the lack of diagnostic tools, especially for families with elevated risk. The PDA biomarker, CA19-9, is measured in the blood to follow tumor burden longitudinally, but is neither sensitive nor specific enough to be used for diagnosis. The use of CA19-9 in PDA diagnosis is problematic given the elevation of CA19-9 in benign pancreatic disease, such as pancreatitis.
While CA19-9 has been traditionally used as a diagnostic, retrospective studies reported that PDA patients who maintain a CA19-9 negative/low status have a significantly longer survival relative to those with higher CA19-9 levels in multivariate analyses. The functional significance of CA19-9 to PDA initiation, maintenance, and progression remains unclear due in part to the absence of this carbohydrate modification in mice. We found that expression of CA19-9 in the mouse pancreas is sufficient to induce pancreatitis, a benign proliferative condition that often confounds the diagnosis of PDA. Specifically, CA19-9 elevation resulted in rapid elevation of pancreatic enzymes in the blood, pancreatic infiltration of immune cells, acinar-to-ductal metaplasia and atrophy, as well as increased proliferation. Furthermore, we explored the utility of CA19-9 as a therapeutic target for both acute and chronic pancreatitis. This avenue of treatment strategy exhibits potential given that a pilot study demonstrated that turning off CA19-9 expression results in the normalization of pancreatic enzyme levels within four days following an acute episode of pancreatitis.
Future work will focus on how elevation of this glycosylation modification mediates the development of pancreatitis by identifying the signaling pathways that are altered upon CA19-9 expression. In addition, we will explore the efficacy of therapeutically targeting CA19-9 in both pancreatitis and PDA with a larger goal of delineating the role of CA19-9 in pancreatic disease.
Citation Format: Dannielle Engle, Hervé Tiriac, Arnaud Pommier, Christina Schoepfer, Brandon Da Silva, Melissa Yao, Youngkyu Park, Michael A. Hollingsworth, David Tuveson. Exploring the role of glycosylation in pancreatic disease [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A27.
Abstract A39: Modeling organelle-specific O-glycosylation in driving liver tumor growth, invasion, and metastasis
Authors: Nguyen Anh Tuan , Bard Frederic 
Published: May 2018

Abstract
Cancer progression is driven by the ability of tumor cells to invade surrounding tissues. Invasiveness correlates with perturbation of a covalent modification of cell surface proteins: O-glycosylation. However, the underlying molecular mechanisms are still unclear. Here, we show that O-glycosylation initiating enzymes are activated during liver tumor growth by intracellular relocation from Golgi to ER. In a Nras/shp53 mouse liver cancer model, coexpressing an ER-targeted glycosyl-transferase GALNT1 (ER-G1) massively increased tissue growth, invasion, and metastases. ER-G1, but not its Golgi-localized counterpart, strongly stimulates glycosylation of the key cancer matrix metalloprotease MT1-MMP, this modification being essential for collagenase activity. Conversely, expression of an ER-targeted inhibitor of GALNTs inhibits liver tumor progression in Nras/shp53-injected mice. In summary, our model comprehensively demonstrates the generation and analyses of the GALA (GALNTs Activation) pathway driving liver tumor invasiveness; thus, further characterization of glycosylation substrates will unveil mechanisms of tumor growth and help identify potential therapeutic targets in human liver cancer.
Citation Format: Anh Tuan Nguyen, Frederic Bard. Modeling organelle-specific O-glycosylation in driving liver tumor growth, invasion, and metastasis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A39.
Abstract A40: Twist1 activation in muscle progenitor cells during development or adulthood causes severe muscle loss reminiscent of human cancer cachexia
Authors: Parajuli Parash , Kumar Santosh , Loumaye Audrey , Singh Purba , Eragamreddy Sailaja , Nguyen Thien Ly , Ozkan Seval , Razzaqe Mohammed S. , Prunier Céline , Thissen Jean-Paul , Atfi Azeddine 
Published: May 2018

Abstract
Cancer cachexia is characterized by extreme skeletal muscle loss that results in high morbidity and mortality. The incidence of cachexia varies among tumor types, being lowest in sarcomas, whereas 90% of pancreatic ductal adenocarcinoma (PDAC) patients experience severe weight loss. How these tumors trigger muscle depletion is still unfolding. Serendipitously, we found that overexpression of Twist1 in mouse muscle progenitor cells, either constitutively during development or inducibly in adult animals, caused severe muscle atrophy with features reminiscent of cachexia. Using several genetic mouse models of PDAC, we detected a massive increase in Twist1 expression in muscle undergoing cachexia. In cancer patients, elevated levels of Twist1 are associated with greater degrees of muscle wasting. Both genetic and pharmacologic inactivation of Twist1 in muscle progenitor cells afforded substantial protection against cancer-mediated cachexia, which translated into meaningful survival benefits, implicating Twist1 as a possible target for attenuating muscle cachexia in cancer patients.
Citation Format: Parash Parajuli, Santosh Kumar, Audrey Loumaye, Purba Singh, Sailaja Eragamreddy, Thien Ly Nguyen, Seval Ozkan, Mohammed S. Razzaqe, Céline Prunier, Jean-Paul Thissen, Azeddine Atfi. Twist1 activation in muscle progenitor cells during development or adulthood causes severe muscle loss reminiscent of human cancer cachexia [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr A40.
Abstract B01: A genetically engineered mouse model of de novo bone metastasis
Authors: Arriaga Juan Martin , Abate-Shen Cory 
Published: May 2018

Abstract
The primary metastatic site of prostate cancer is the bone, which is associated with high morbidity and mortality. Despite this fact, very few genetically engineered mouse models recapitulate this phenotype, hindering our ability to model and understand the molecular drivers of bone metastasis. Our laboratory has generated a highly metastatic mouse model of castration-resistant prostate cancer based on the monoallelic loss of function of Nkx3.1, biallelic deletion of Pten, and oncogenic mutation of Kras in the prostate, termed the NPK model. By tracking these tumors with a bright fluorescent reporter, we now show that these tumors metastasize to bone with a penetrance of ~45% and display a bone distribution similar to that of human cancer. This model has thus allowed us to comprehensively profile the molecular alterations of bone metastatic lesions compared to the primary tumor and other metastatic sites. We found that differential gene expression profiles comparing bone metastases with primary tumors differ from those comparing lung metastases with primary tumors, suggesting that different biologic principles underlie metastasis to these two organ sites. Furthermore, gene-expression profiling demonstrated significant overlap with human bone metastases at the gene, master regulator, and pathway levels. Even though expression of the androgen receptor (AR) is maintained in the primary tumor and most lung metastases, bone lesions are AR-, without evidence of neuroendocrine (NE) differentiation, pointing to an AR-, NE- prostate cancer subtype, which is increasingly frequent in human prostate cancer. These results lay the groundwork for understanding the molecular drivers and pathways that are important for bone metastatic spread and may hopefully aid in selecting appropriate molecular targets to combat the metastatic disease.
Citation Format: Juan Martin Arriaga, Cory Abate-Shen. A genetically engineered mouse model of de novo bone metastasis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B01.
Abstract B11: Foxm1 mediates maintenance and progression of mouse lung tumor driven by oncogenic Kras
Authors: Chao Sheng-Yang , Li Chien-Cheng , Liang Sheng-Kai , Chiu Yi-Shiuan , Lin Yi-Kai , Hsu Chia-Chan , Chen Jen-Kun , Tsou Tsui-Chun , Wang I-Ching 
Published: May 2018

Abstract
Oncogenic mutation of Kras gene is one of the major causes of non-small cell lung cancer (NSCLC), and there is no effective chemotherapy agent available for targeting cancers harboring oncogenic Kras mutations. Hence, identifying new downstream molecular targets of KRAS signaling is critical for improving current therapeutic outcomes. Previous research has demonstrated that increased activity and expression of Forkhead box M1 (FOXM1) transcription factor are associated with poor prognosis in NSCLC patients. We and others have reported that FOXM1 regulates gene transcription network of cell cycle, angiogenesis, epithelial-to-mesenchymal transition (EMT), cell migration, and cancer stemness. Deletion of Foxm1 alleles in respiratory epithelial cells diminished the lung tumor initiation in SPC-rtTA/tetO-KrasG12D/Foxm1-/- mice; however, whether Foxm1 is critical for Kras mutant tumor maintenance and progression remains unclear. Herein, we report that intratracheal (IT) injected adenoviral Ad-Cre to CCSP-rtTA/tetO-KrasG12D/Foxm1fl/fl mice that bear induced KRAS mutant lung tumors, causing 75% of preexisting lung tumor regression as detected by micro-computed tomography (μCT). IT treatment with Ad-Cre that mediated genetically deletion of Foxm1 alleles in lungs, resulted in reduced proliferation of tumor cells. Moreover, in vitro disruption of FOXM1 expression by shRNA diminished cell proliferation on plate and anchorage-independent growth in soft agar of KRAS-mutated lung cancer NCI-H23 as well as KRASG12D-transformed BEAS-2B cells. Accordingly, these results demonstrated that Foxm1 is critical for oncogenic KRAS signaling pathway in both maintenance and progression of lung adenocarcinoma, suggesting that Foxm1 could be a potential therapeutic target to improve the outcome of KRAS mutant lung cancer treatment.
Citation Format: Sheng-Yang Chao, Chien-Cheng Li, Sheng-Kai Liang, Yi-Shiuan Chiu, Yi-Kai Lin, Chia-Chan Hsu, Jen-Kun Chen, Tsui-Chun Tsou, I-Ching Wang. Foxm1 mediates maintenance and progression of mouse lung tumor driven by oncogenic Kras [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B11.
Abstract B33: CRISPR/Cas9 generation of Ret and Ntrk1 fusion oncogenes and novel in vitro sgRNA screening method
Authors: Schubert Laura , Le Anh T. , Malkoski Stephen P. , Nemenoff Raphael , Doebele Robert C. 
Published: May 2018

Abstract
Chromosomal rearrangements of ALK, RET, ROS1, and NTRK1 collectively represent approximately 10% of oncogenic drivers in lung adenocarcinoma. These rearrangements result in the aberrant expression and constitutive activation of a chimeric fusion kinase, which promotes growth, proliferation and survival of the cancer cell. CRISPR/Cas9 technology can now be employed to generate these chromosomal rearrangements both in vitro and in vivo. sgRNAs can be designed to target the Cas9 endonuclease to introns within the 5′ and 3′ gene partners of the rearrangement. A unique advantage of this approach is that it is compatible with immunocompetent mouse models. We have developed a novel in vitro screening strategy to identify sgRNAs that successfully generated the intended rearrangements. Ba/F3 cells are a murine B-cell cell line whose proliferation is normally dependent on the exogenous addition of the cytokine interleukin 3 (IL3), but can be rendered IL3 independent if an oncogenic alteration is introduced. We hypothesized that IL3-independence in Ba/F3 cells could be used as a method to select for cells that had successfully created chromosomal rearrangements leading to oncogenic fusions. This strategy eliminates the need for single cell cloning to confirm that successful CRISPR genome editing has occurred. We transfected Ba/F3 cells with pairs of sgRNAs within the PX330 Cas9 containing plasmid and then withdrew IL3. Cells that became IL3 independent were tested for rearrangements. Using this screening system, we successfully generated Kif5b-Ret, Trim24-Ret, and Tpm3-Ntrk1 rearrangements in Ba/F3 cells. These rearrangements were confirmed using PCR or RT-PCR and sequencing using fusion-specific primers. Additionally, the Ret rearrangements and Ntrk1 rearrangements were far more sensitive to RET and TRK inhibitors, respectively, than parental Ba/F3 cells, further confirming that the Ba/F3 cells' growth was now dependent on signaling from the fusion kinase. RET protein expression was also detected with Western blotting in the two Ret rearranged Ba/F3 cell lines. Our future plans are to introduce adenovirus containing validated sgRNAs into immune-competent mice, and confirm that they generate tumors with the intended rearrangements.
Citation Format: Laura Schubert, Anh T. Le, Stephen P. Malkoski, Raphael Nemenoff, Robert C. Doebele. CRISPR/Cas9 generation of Ret and Ntrk1 fusion oncogenes and novel in vitro sgRNA screening method [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B33.
Abstract B38: In vivo genome editing and organoid transplantation models of colorectal cancer and metastasis
Authors: Roper Jatin , Tammela Tuomas , Cetinbas Naniye Malli , Akkad Adam , Roghanian Ali , Rickelt Steffen , Almeqdadi Mohammad , Wu Katherine , Oberli Matthias , Sánchez-Rivera Francisco , Park Yoona , Liang Xu , Eng George , Taylor Martin S. , Azimi Roxana , Kedrin Dmitriy , Neupane Rachit , Beyaz Semir , Sicinska Ewa T. , Suarez Yvelisse , Yoo James , Chen Lillian , Zukerberg Lawrence , Katajisto Pekka , Deshpande Vikram , Bass Adam , Tsichlis Philip N. , Lees Jacqueline , Langer Robert , Hynes Richard O. , Chen Jianzhu , Bhutkar Arjun J. , Jacks Tyler , Yilmaz Ömer H. 
Published: May 2018

Abstract
In vivo interrogation of the function of genes implicated in tumorigenesis is limited by the need to generate and cross germline mutant mice. Here we describe approaches to model colorectal cancer (CRC) and metastasis that rely on in situ gene editing and orthotopic organoid transplantation in mice without cancer-predisposing mutations. Autochthonous tumor formation is induced by CRISPR/Cas9-based editing of the Apc and Trp53 tumor suppressor genes in colon epithelial cells and by orthotopic transplantation of Apc-edited colon organoids. ApcΔ/Δ;KrasG12D/+;Trp53Δ/Δ (AKP) mouse colon organoids and human CRC organoids engraft in the distal colon and metastasize to the liver. Finally, we apply the orthotopic transplantation model to characterize the clonal dynamics of Lgr5+ stem cells and demonstrate sequential activation of an oncogene in established colon adenomas. These experimental systems enable rapid in vivo characterization of cancer-associated genes and reproduce the entire spectrum of tumor progression and metastasis.
Citation Format: Jatin Roper, Tuomas Tammela, Naniye Malli Cetinbas, Adam Akkad, Ali Roghanian, Steffen Rickelt, Mohammad Almeqdadi, Katherine Wu, Matthias Oberli, Francisco Sánchez-Rivera, Yoona Park, Xu Liang, George Eng, Martin S. Taylor, Roxana Azimi, Dmitriy Kedrin, Rachit Neupane, Semir Beyaz, Ewa T. Sicinska, Yvelisse Suarez, James Yoo, Lillian Chen, Lawrence Zukerberg, Pekka Katajisto, Vikram Deshpande, Adam Bass, Philip N. Tsichlis, Jacqueline Lees, Robert Langer, Richard O. Hynes, Jianzhu Chen, Arjun J. Bhutkar, Tyler Jacks, Ömer H. Yilmaz. In vivo genome editing and organoid transplantation models of colorectal cancer and metastasis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B38.
Abstract B44: Lysyl oxidases suppress pancreatic cancer progression and inhibit FAK and ERK signaling
Authors: Shields Mario , Maguin Pascal , Giuliano Christopher , Dallas Sarah , Wilkinson John Erby , Egeblad Mikala 
Published: May 2018

Abstract
Pancreatic cancer carries a dismal prognosis, as most patients present with locally advanced and metastatic disease at time of diagnosis. High levels of type I collagen extracellular matrix in pancreatic tumor specimens are associated with poor survival and resistance to therapy. Furthermore, the expression of lysyl oxidases (LOXs), enzymes that mediate cross-linking and linearization of collagen type I, correlate with poor prognosis in breast and pancreatic cancer. However, a clinical trial targeting LOX-like (LOXL) 2 in pancreatic cancer did not show any survival benefits, pointing to a limited understanding of the context in which these enzymes function in cancer progression.
To understand how collagen structure influences cancer cell behavior, we used host mice that expressed GFPtopaz fused to collagen type I and performed intravital microscopy after orthotopic injection of fluorescently labeled cancer cells (derived from the KPC mouse models of pancreatic cancer). Strikingly, we observed that invasive cancer cells migrated out of the tumors on linear type I collagen. Surprisingly, inhibition of LOX and LOXL2, using a pharmacologic inhibitor or shRNA-mediated knockdown, had the opposite results of what we expected with increased metastasis, collagen linearization, and focal adhesion kinase (FAK) activity. Indicating a mechanism independently of collagen crosslinking, LOX inhibition promoted invasion and increased FAK and Ras/ERK-MAPK signaling in vitro, when cells were grown on plastic. We demonstrated that the FAK activity was required for the increased metastasis induced by LOX inhibition, using a clinical stage pharmacologic inhibitor. Our data highlight that LOXs in pancreatic cancer play an important role in suppression of the ERK and FAK signaling pathways, and metastasis. Indeed, the earliest report of lysyl oxidase function in cancer was as a tumor suppressor in Ras transformed cells.
Citation Format: Mario Shields, Pascal Maguin, Christopher Giuliano, Sarah Dallas, John Erby Wilkinson, Mikala Egeblad. Lysyl oxidases suppress pancreatic cancer progression and inhibit FAK and ERK signaling [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B44.
Abstract IA09: Metabolic recycling in cancer
Authors: Haigis Marcia 
Published: May 2018

Abstract
Metabolic reprogramming is a hallmark of cancer that supports the rapid proliferation and survival of tumor cells. While many studies have focused on identifying pathways involved in increased fuel usage, such as glucose and glutamine uptake and metabolism, the fate of metabolic waste products has been little investigated. Ammonia is a ubiquitous by-product of cellular metabolism, long thought to be a toxic waste product. Here we will discuss ammonia recycling to support cellular biomass and proliferation in breast cancer.
Citation Format: Marcia Haigis. Metabolic recycling in cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr IA09.
Joint Effect of Carotid Plaque and C‐Reactive Protein on First‐Ever Ischemic Stroke and Myocardial Infarction?
Authors: Eltoft Agnethe , Arntzen Kjell Arne , Wilsgaard Tom , Hansen John‐Bjarne , Mathiesen Ellisiv B. , Johnsen Stein Harald 
Published: May 2018

Background

The joint effect of atherosclerosis and CRP (C‐reactive protein) on risk of ischemic stroke (
IS
) and myocardial infarction (
MI
) has been sparsely studied. The aim of this study was to explore whether
CRP
mediates the risk of events in subjects with prevalent carotid plaque, examine synergism, and test whether
CRP
and carotid plaque add to risk prediction beyond traditional risk factors.

Methods and Results

CRP
and carotid total plaque area (
TPA
) were measured in 10 109 participants in the Tromsø Study from 1994 to 2008. Incident
IS
(n=671) and
MI
(n=1079) were registered until December 31, 2013. We calculated hazard ratios (HRs) of
MI
and
IS
according to categories of
CRP
(<1, 1–3, and >3 mg/L) and plaque status (no plaque and
TPA
below and above median) in Cox proportional hazard models with time‐varying covariates. Multivariable‐adjusted
CRP
>3 versus <1 mg/L was associated with risk of
IS
(
HR
, 1.84; 95% confidence interval, 1.49–2.26) and
MI
(
HR,
1.46; 95% confidence interval, 1.23–1.73).
TPA
above median versus no plaque was associated with risk for
IS
(
HR
, 1.65; 95% confidence interval, 1.36–2.01) and
MI
(
HR
, 1.64; 95% confidence interval, 1.41–1.92). In participants with plaque, adjustment for
CRP
minimally attenuated the risk estimates. The highest incidence rates for
MI
and
IS
were seen in the group with both
CRP
>3 mg/L and TPA is above the median.
TPA
and
CRP
combined added to risk prediction beyond traditional risk factors.

Conclusions

The simultaneous presence of subclinical atherosclerosis and elevated
CRP
was associated with increased risk of
IS
and
MI
. The combined assessment of subclinical atherosclerosis and inflammatory biomarkers may improve cardiovascular disease risk stratification.
The acoustics of primary and secondary stress in Modern Hebrew
Authors: Cohen Evan-Gary , Silber-Varod Vered , Amir Noam 
Published: May 2018

Abstract
This study investigates the acoustic realization of primary and secondary stress in polysyllabic words in Modern Hebrew (MH). The study focuses on the production of target words embedded in a meaningful carrier sentence, with three primary stress types: ultimate, penultimate and antepenultimate stress. We measured the duration, intensity and F0 of each vowel. Results show that duration is the sole reliable cue for stress in MH, and that there is no phonetic realization of secondary stress in MH, and therefore no true surface alternating pattern. These findings may have phonological implications regarding the prosodic organization of language, and provide a solid basis for future studies on the perception of primary and secondary stress by speakers.