bluuebunny/crossref_metadata_2025_split huggingface dataset:
Muscle afferent excitability testing in spinal root-intact rats: dissociating peripheral afferent and efferent volleys generated by intraspinal microstimulation
Authors: Tomatsu Saeka , Kim Geehee , Confais Joachim , Seki Kazuhiko 
Published: December 2016

Presynaptic inhibition of the sensory input from the periphery to the spinal cord can be evaluated directly by intra-axonal recording of primary afferent depolarization (PAD) or indirectly by intraspinal microstimulation (excitability testing). Excitability testing is superior for use in normal behaving animals, because this methodology bypasses the technically challenging intra-axonal recording. However, use of excitability testing on the muscle or joint afferent in intact animals presents its own technical challenges. Because these afferents, in many cases, are mixed with motor axons in the peripheral nervous system, it is crucial to dissociate antidromic volleys in the primary afferents from orthodromic volleys in the motor axon, both of which are evoked by intraspinal microstimulation. We have demonstrated in rats that application of a paired stimulation protocol with a short interstimulus interval (ISI) successfully dissociated the antidromic volley in the nerve innervating the medial gastrocnemius muscle. By using a 2-ms ISI, the amplitude of the volleys evoked by the second stimulation was decreased in dorsal root-sectioned rats, but the amplitude did not change or was slightly increased in ventral root-sectioned rats. Excitability testing in rats with intact spinal roots indicated that the putative antidromic volleys exhibited dominant primary afferent depolarization, which was reasonably induced from the more dorsal side of the spinal cord. We concluded that excitability testing with a paired-pulse protocol can be used for studying presynaptic inhibition of somatosensory afferents in animals with intact spinal roots.NEW & NOTEWORTHY Excitability testing of primary afferents has been used to evaluate presynaptic modulation of synaptic transmission in experiments conducted in vivo. However, to apply this method to muscle afferents of animals with intact spinal roots, it is crucial to dissociate antidromic and orthodromic volleys induced by spinal microstimulation. We propose a new method to make this dissociation possible without cutting spinal roots and demonstrate that it facilitates excitability testing of muscle afferents.
Abstract A04: Identification of novel pancreatic cancer-specific biomarkers with organoid models
Authors: Engle Dannielle , Tiriac Herve , Keith Rivera , Ludwig Michael , Hwang Chang-il , Yu Kenneth , Pappin Darryl , Tuveson David 
Published: December 2016

Abstract
Pancreatic ductal adenocarcinoma (PDA) is almost uniformly lethal and surgical intervention is the only cure. Unfortunately, the majority of patients are ineligible for resection because of the advanced stage of disease by the time of diagnosis. This is due in part to that lack of diagnostic tools, especially for families with elevated risk. Although considered an intractable and aggressive malignancy, progression from the initiating events to overt cancer requires approximately 12 years, and advancement to metastatic disease takes another 5 – 7 years. This latency indicates that there is a window for early detection and intervention. 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. In particular, the use of CA19-9 in PDA diagnosis is problematic given the elevation of CA19-9 in benign conditions, such as pancreatitis, that have a higher incidence than PDA. To improve the diagnostic performance of CA19-9, we identified tissue- and cancer-specific protein carriers of the CA19-9 carbohydrate modification using murine and human organoid model systems of pancreatic cancer disease progression. To induce CA19-9 expression in murine organoids, two human gylcosyl transferases that were deficient in mice were ectopically expressed. CA19-9 protein carriers specific to malignancy were identified relative to normal, proliferating ductal cells. Some CA19-9 carriers that were shared between normal and malignant pancreatic ductal organoids were also detected in the sera of patients with benign pancreatic disease, highlighting their inability to distinguish malignancy from pancreatitis. Importantly, several of the tumor-specific novel CA19-9 carriers identified in organoids also discriminated between benign and malignant disease in human patient sera, and are nominated for clinical validation. Overall, organoid model systems allow identification of biomarkers that discriminate between normal proliferation and malignant conditions of multiple gastrointestinal tissues, providing a robust platform for biomarker discovery.
Citation Format: Dannielle Engle, Herve Tiriac, Rivera Keith, Michael Ludwig, Chang-il Hwang, Kenneth Yu, Darryl Pappin, David Tuveson.{Authors}. Identification of novel pancreatic cancer-specific biomarkers with organoid models. [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 A04.
Abstract A07: Identification of endocrine/metabolic biomarkers associated to early PDC in a transgenic mouse model
Authors: Pasquale Valentina , Dugnani Erica , Liberati Daniela , Marra Paolo , Canu Tamara , Esposito Antonio , Piemonti1 Lorenzo 
Published: December 2016

Abstract
Background: Pancreatic ductal adenocarcinoma (PDC) is a deadly disease, even surgery contributes little to survival if PDC is not diagnosed at an initial stage. Glucose homeostasis alteration associated to PDC was described to identify an high risk population for screening. Moreover the weight loss often manifests several months before cachexia. The crosstalk between metabolism and cancer could be a key to early diagnosis. Our aim is to find endocrine/metabolic biomarkers of early PDC development in a gold standard murine model.
Materials and Methods: Candidate markers were investigated using LSL-KrasG12D/+;LSL-Trp53R172H/+;Pdx-1-Cre (KPC) mouse, a genetically-engineered model that develops PDC with 100% penetrance. KPC has been fed with standard diet (SD) or high fat diet (HFD) introducing a further risk factor for diabetes and metabolic alterations. To overcome the problem of asynchronous development of PDC in KPC, 7T-MRI was used to classify mice in actual pathological stage: normal (S1); cystic degeneration (S2); small tumor (S3) and advanced pancreatic cancer (S4). We performed metabolic test (OGTT) and serum endocrine/metabolic profile (xMAP technology and clinical biochemistry) in n=27 KPC (and control mice PDX-1 Cre) fed with HFD vs n=26 KPC (and control mice PDX-1 Cre) fed with SD. To prioritize markers we computed the ROC curve analysis.
Results: i) Glucose metabolism: KPC were normoglycemic regardless of the diet; the AUC in OGTT increases in KPC fed with HFD (HFD vs SD: S1 p&lt;0,001, S2 p&lt;0,001, S3 p=0,002, Cre p&lt;0,001) ii) Serum levels of 29 endocrine/metabolic biomarkers were assessed during disease progression. The more relevant results are: increase of PYY (p&lt;0,003) and decrease of leptin (p&lt;0,02), GIP (p&lt;0.005) albumin (p&lt;0.001) both in HFD and SD fed KPC (Cre vs S2); increase of amylase in stage 1 HFD-fed KPC (p=0,037). Moreover PYY was able to discriminate control from stage 2 KPC with an AUC=0,929 in the ROC curve analysis (p&lt;0,001).
Conclusions: Unlike human, in the mouse model the development of PDC is not associated with an hyperglycemic status, regardless of the diet. However KPC fed with HFD experience a mild impairment of glucose metabolism (as well as in control mice) and a mild pancreatic damage. Our results identify Leptin, PYY, GIP and albumin as markers of early stage PDC in a preclinical model with a diagnostic potential to be validated in human patients.
Citation Format: Valentina Pasquale, Erica Dugnani, Daniela Liberati, Paolo Marra, Tamara Canu, Antonio Esposito, Lorenzo Piemonti1.{Authors}. Identification of endocrine/metabolic biomarkers associated to early PDC in a transgenic mouse model. [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 A07.
Abstract A34: Oncogenic KRAS regulates pancreatic cancer cell signaling via stromal reciprocation
Authors: Tape Christopher , Ling Stephanie , Dimitriadi Maria , McMahon Kelly , Worboys Jonathan , Leong Hui S. , Norrie Ida , Miller Crispin , Poulogiannis George , Lauffenburger Douglas , Jorgensen Claus 
Published: December 2016

Abstract
Pancreatic Ductal Adenocarcinoma is characterized by a reactive stroma, which modifies tumor progression and response to therapy. Oncogenic mutations regulate signaling both within tumor cells and adjacent stromal cells. However, defining whether oncogenes can regulate tumor cell signaling and phenotypic behavior via stromal cells is of importance to understand mechanisms of disease progression and response to therapy. Here we show that oncogenic KRAS (KRASG12D) regulates pancreatic cancer cell signaling via stromal stellate cells. By combining cell-specific proteome labeling with multivariate phosphoproteomics, we analyzed heterocellular KRASG12D signaling in Pancreatic Ductal Adenocarcinoma (PDA) cells. Tumor cell KRASG12D engages heterotypic stellate cells, which subsequently instigate reciprocal signaling in the tumor cells. Reciprocal signaling employs additional kinases and doubles the number of regulated signaling nodes from cell-autonomous KRASG12D. Consequently, reciprocal KRASG12D produces a tumor cell phosphoproteome and total proteome that is distinct from cell-autonomous KRASG12D alone. Reciprocal signaling regulates tumor cell proliferation, apoptosis, and increases mitochondrial capacity via an IGF1R/AXL-AKT axis. These results demonstrate that oncogene signaling should be viewed as a heterocellular process and that our existing cell-autonomous perspective underrepresents the extent of oncogene signaling in cancer.
Citation Format: Christopher Tape, Stephanie Ling, Maria Dimitriadi, Kelly McMahon, Jonathan Worboys, Hui S. Leong, Ida Norrie, Crispin Miller, George Poulogiannis, Douglas Lauffenburger, Claus Jorgensen.{Authors}. Oncogenic KRAS regulates pancreatic cancer cell signaling via stromal reciprocation. [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 A34.
Abstract A37: Targeting RAGE in pancreatic cancer using monoclonal antibodies
Authors: Swami Priyanka , Indurthi Venkata , Vetter Stefan W. , Leclerc Estelle 
Published: December 2016

Abstract
Recent studies suggest that the Receptor for Advanced Glycation End Products (RAGE) and its ligands (S100P or HMGB1) are important contributors to the progression of pancreatic cancer. Being a cell surface receptor, RAGE possesses a large extracellular domain that binds its activating ligands. We reasoned that monoclonal antibodies that block the interaction between RAGE and its ligands could impact the progression of pancreatic cancer. We have generated a panel of antibodies recognizing different domains of the receptor and are currently testing their inhibitory effects, in pancreatic cancer cells and in small animal models.
Citation Format: Priyanka Swami, Venkata Indurthi, Stefan W. Vetter, Estelle Leclerc.{Authors}. Targeting RAGE in pancreatic cancer using monoclonal antibodies. [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 A37.
Abstract A51: Notch4 acts as an oncogenic signal in pancreatic tumorigenesis
Authors: Qiu Wanglong , Suh David D. , Tsay Natasha M. , Chadi Simona , Chambers Adam R. , Sims Peter A. , Shawber Carrie J. , Kitajewski Jan , Remotti Helen E. , Su Gloria H. 
Published: December 2016

Abstract
The Notch signaling network is an evolutionarily conserved intercellular signaling pathway which regulates interactions between adjacent cells. The Notch family receptor and its signaling pathways are involved in the development of numerous tissues in multicellular organisms. Recent studies from our Acvr1bflox/flox;LSL-KrasG12D;Pdx1-Cre mice suggest that Notch4 plays an oncogenic role in dictating cell fate and contributes to pancreatic tumorigenesis, particularly in the development of pancreatic intraductal papillary mucious neoplasms (IPMNs). The perinuclear localization of the activated Notch4 (but not other Notch members) intracellular domain (ICD) in the apical cytoplasm of neoplastic cells appeared to be associated with the expansion of the IPMN lesions. The unique role of Notch4 signaling pathway in IPMN development was also confirmed by unbiased RNA-Seq analyses. The deletion of Notch4 in the p16flox/flox;LSL-KrasG12D;Pdx1-Cre mice prolonged survival, further supporting its oncogenic role in pancreatic tumorigenesis.
Citation Format: Wanglong Qiu, David D. Suh, Natasha M. Tsay, Simona Chadi, Adam R. Chambers, Peter A. Sims, Carrie J. Shawber, Jan Kitajewski, Helen E. Remotti, Gloria H. Su.{Authors}. Notch4 acts as an oncogenic signal in pancreatic tumorigenesis. [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 A51.
Abstract A72: Phase 1 study of nivolumab (nivo) + nab-paclitaxel (nab-P) ± gemcitabine (G) in pancreatic cancer (PC): safety evaluation of patients treated with nivo + nab-P in arm A
Authors: Hochster Howard S. , Wainberg Zev A. , Gutierrez Martin , Waterhouse David , Chiorean E Gabriela , George Ben , Ko Amy , Manax Victoria , Stergiopoulos Sotirios , O'Dwyer Peter 
Published: December 2016

Abstract
Background: Cytotoxic chemotherapy activates the immune system through multiple mechanisms, including stress signaling, antigen release by dying tumor cells, and modulation of immune cell populations. Nivo, an anti–PD-1 antibody, has demonstrated activity in other solid tumors but has not yet demonstrated activity in PC. The combination of nab-P + G is approved by the US Food and Drug Administration as first-line therapy for metastatic PC (MPC). nab-P does not require corticosteroid pretreatment, which makes it a suitable combination partner with nivo to test for safety and efficacy in PC. Here we report interim results from the first of 2 PC cohorts of a Phase 1 study of nivo + the standard dose and schedule of nab-P.
Methods: The 2 PC cohorts (arms A and B) were to be initiated sequentially. In arm A, patients with locally advanced PC (LAPC) or MPC who had received 1 prior chemotherapy regimen received nab-P 125 mg/m2 on days 1, 8, and 15 of a 28-day cycle (qw 3/4) in combination with nivo 3 mg/kg on days 1 and 15 of the 28-day cycle starting with cycle 1. The primary objective of part 1 was to identify dose-limiting toxicities (DLTs). Patients treated with ≥ 2 cycles of nivo + nab-P or who discontinued due to a DLT prior to completing 2 cycles of nivo + nab-P were considered DLT evaluable. If arm A is deemed safe per DLT evaluation, arm B will enroll chemotherapy-naive patients, who will receive G 1000 mg/m2 qw 3/4 in addition to nivo + nab-P.
Results: Between February 24 and December 3, 2015, 11 patients were enrolled in arm A. Most patients were &lt; 75 years of age (82%) and male (55%). No DLTs were observed, and no grade 3/4 AEs occurred in &gt; 1 patient. Among 8 response-evaluable patients, 1 had a partial response and 4 achieved stable disease. Eight patients discontinued treatment due to disease progression.
Conclusions: In arm A of the PC cohort, the addition of nivo to nab-P did not appear to increase safety/tolerability concerns. Based on safety observed in arm A, arm B will enroll patients with MPC for first-line treatment with nivo + nab-P + G. ClinicalTrials.gov: NCT02309177.
Citation Format: Howard S. Hochster, Zev A. Wainberg, Martin Gutierrez, David Waterhouse, E Gabriela Chiorean, Ben George, Amy Ko, Victoria Manax, Sotirios Stergiopoulos, Peter O’Dwyer.{Authors}. Phase 1 study of nivolumab (nivo) + nab-paclitaxel (nab-P) ± gemcitabine (G) in pancreatic cancer (PC): safety evaluation of patients treated with nivo + nab-P in arm A. [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 A72.
Abstract A77: Screening of conditionally reprogrammed patient-derived carcinoma cells identifies ERCC3-MYC interactions as a target in pancreatic cancer
Authors: Astsaturov Igor , Jablonski Sandra A. , Zhou Yan , Serebriiskii Ilya , Keren Paz , Weiner Louis M. , Golemis Erica , Khazak Vladimir 
Published: December 2016

Abstract
Methods: Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy that affects 44,000 individuals yearly in the US. The list of agents active against PDAC is limited. We explored in an unbiased fashion the clinically available drugs to identify novel cytotoxics using new physiological models for PDAC including cells rapidly expanded in vitro from surgical or xenografted tumors (PDX).
Results: Not unexpectedly, only a small minority of agents showed activity against pancreatic carcinoma cells in vitro. Among these, transcriptional repressors and drugs interfering with protein folding and biosynthesis ranked as most cytotoxic. Triptolide, a covalent inhibitor of the ERCC3, a bifunctional regulator of transcription and DNA repair, was most consistently effective in vitro and highly effective in vivo, causing prolonged complete regression in multiple PDX models. Importantly, triptolide showed superior activity in MYC-amplified PDX models, suggesting a critical role for ERCC3 in this subset. Triptolide elicited rapid and profound depletion of MYC oncoprotein, a transcriptional co-factor for ERCC3. Expression of ERCC3 was MYC-dependent, while resistance to triptolide was associated with elevated ERCC3 and MYC expression. Furthermore, high ERCC3 mRNA level was associated with decreased survival of PDAC patients.
Conclusions: These findings provide preclinical evidences for transcriptional vulnerability in PDAC via ERCC3 targeting and a new mechanistic approach for disruption of MYC-dependent pancreatic cancers.
Citation Format: Igor Astsaturov, Sandra A. Jablonski, Yan Zhou, Ilya Serebriiskii, Paz Keren, Louis M. Weiner, Erica Golemis, Vladimir Khazak.{Authors}. Screening of conditionally reprogrammed patient-derived carcinoma cells identifies ERCC3-MYC interactions as a target 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 A77.
Abstract B19: Kras mutation imparts neoplastic potential on duct cells but not acinar cells in a mouse model of obstructive chronic pancreatitis
Authors: Pan Fong C. , Kim Jessica N. , Shi Chanjuan , Washington Mary K. , Sander Maike , Gannon Maureen , Beauchamp Robert D. , Wright Christopher V. , Means Anna L. 
Published: December 2016

Abstract
Understanding the progression of human pancreatic cancer is difficult due to the late stage of diagnosis of this deadly disease. We must therefore rely upon robust model systems to understand how pancreatic cancer arises, how its acute and chronic phases of progression are regulated, and how best to identify and treat it, hopefully still in the early stage. Models of pancreatic ductal adenocarcinoma (PDAC) that accurately reflect human disease are still being developed. To mimic human disease, PDAC must arise from mutations occurring in adult animals and with etiologies relevant to humans. We developed a new mouse model that incorporates obstructive chronic pancreatitis with tissue-specific, adult-onset expression of mutant Kras. We found that KrasG12D expression in duct cells but not in acinar cells led to progression of metaplastic ducts to eventual dysplasia and cancer. In early-stage disease, Kras mutation in acinar cells led to increased acinar-to-ductal metaplasia but did not downregulate p53, thus leading to reduced cell survival. Ducts naturally express much lower p53 levels, however, and there was increased survival of KrasG12D-mediated, duct-derived metaplastic cells. Furthermore, acinar cells upregulated Pdx1 during acinar-to-ductal metaplasia while duct cells did not do so during their metaplastic transition. Without chronic pancreatitis, Kras mutation in acinar cells causes abundant Pancreatic Intraepithelial Neoplasm (PanIN)-like lesions. However, overexpression of Pdx1 in acinar cells in this context permitted acinar-to-ductal metaplasia but prevented PanIN-like lesion formation, suggesting that Pdx1 can repress neoplastic progression. In summary, in the setting of obstructive chronic pancreatitis, ducts are the principal source of cancer development via reduced Pdx1 and p53 levels and increased cell survival.
Citation Format: Fong C. Pan, Jessica N. Kim, Chanjuan Shi, Mary K. Washington, Maike Sander, Maureen Gannon, Robert D. Beauchamp, Christopher V. Wright, Anna L. Means.{Authors}. Kras mutation imparts neoplastic potential on duct cells but not acinar cells in a mouse model of obstructive chronic pancreatitis. [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 B19.