tbuckley/cabot-search huggingface dataset:
Abstract 5091: Maintaining long-term stromal depletion therapy for pancreatic cancer
Authors: Sam R. Grimaldo, Mahsa Khatibeghdami
Journal: Cancer Research (2018)

Abstract A hallmark feature of pancreatic cancer is a dense fibrotic stroma that surrounds the tumor and sequesters blood vessel growth. The lack of blood vessels results in poor perfusion, causing most therapies to fail. Antistromal therapy via targeting the sonic hedgehog (SHH) pathway is a controversial approach to improving drug distribution for pancreatic cancer. While this approach has been shown to be initially effective, over time stroma depletion results in the return of an aggressive cancer. Long-term stromal depletion creates a microenvironment that permits angiogenesis and fuels the return of an aggressive cancer. It is unknown if inhibiting angiogenesis will improve the long-term success of antistromal therapy. We are pursuing two therapeutic strategies that couple an antiangiogenic component with SHH therapy. These therapeutic strategies will be tested in one of the two novel inducible models we have developed, including the standard iKPC model and an SHH-deleted model iKPC-SHH. Preliminary survival analysis shows overall survival of 8 months and 5 months for the iKPC and iKPC-SHH, respectively. Furthermore, increased CD31 blood vessel staining is seen in the iKPC-SHH model, suggesting increased angiogenesis. Using the standard iKPC we will pursue a co-treatment approach with gemcitabine and the SHH inhibitor, itraconazole, to evaluate the effect on median survival. Itraconazole was chosen from a screen of ten SHH inhibitors and found to have a highest efficacy on vascular endothelial cell (IC50 0.02υM). Thereby we expect this molecule to target both the SHH pathway and blood vessels. The second approach we are pursuing is to determine if the antiangiogenic drug, sunitinib, improves median survival in the iKPC-SHH. The iKPC-SHH serves as a surrogate of antistromal therapy and allows for a focused investigation with antiangiogenic compounds. Sunitinib was chosen from the class of antiangiogenic pharmacologics for its direct efficacy on primary pancreatic tumor cells (IC50 2.4υM); thereby it is expected to target blood vessels and tumor cells in vivo. While both treatments approaches are ongoing. current data show that itraconazole co-treatments are living over 7.5 months in the (noninducible) KPC model. Previous reports with an SHH inhibitor in the KPC model showed a survival at approximately 3-4 months. Thereby our initial data show promise that inhibiting angiogenesis can improve the long-term efficacy of antistromal therapy. Citation Format: Sam R. Grimaldo, Mahsa Khatibeghdami. Maintaining long-term stromal depletion therapy for pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5091.
Abstract 4658: Novel paclitaxel medical nanoparticle formulation for breast cancer
Authors: Pallabita Chowdhury, Sumeet S. Chauhan, Prashanth K. Nagesh, Elham Hatami, Bilal B. Hafeez, Sheema Khan, Meena Jaggi, Murali M. Yallapu
Journal: Cancer Research (2018)

Abstract Objectives: Paclitaxel (Ptxl) is currently the most common first-line therapeutic option for breast cancer (BrCa). However, adverse side effects and problems associated with chemo-resistance, limits its use in clinical settings. Nanoparticle mediated delivery can improve Ptxl delivery and its activity at the tumor site, and considered to be an attractive strategy for BrCa therapy. Therefore, we aim to generate a novel Ptx medical nanoparticle formulation (PMNPs) using a polyphenol as a carrier, and evaluate its efficacy against BrCa cells. Methods: Physico-chemical characterization of this PMNPs was performed using TEM, DLS, FT-IR, TGA, X-RD, and SAXS methods. Its internalization and cellular availability was examined using HPLC method. Cell proliferation and colony formation assays were utilized to evaluate therapeutic efficacy of this unique nanoformulation in clinically relevant cell line models (MCF7 and MDA-MB-231). Additionally, molecular effects of this formulation on apoptosis, anti-apoptosis, and drug resistant associated proteins were evaluated using immunoblotting assays. A tubulin stabilization study was performed using confocal immunofluorescence microscopy analysis. Results: The PMNPs formulation showed optimal particle size and zeta potential, which can be efficiently internalized in BrCa cells. PMNPs exhibited potent anti-cancer efficacy via induction of the expression of apoptosis associated proteins (Bax and Bad, cleaved PARP, and caspase 3) and downregulation of anti-apoptotic proteins (Bcl-2 and Bcl-xL) in BrCa ell lines. Further, the expression of chemoresistance-associated proteins were also decreased with the treatment of PMNPs. Conclusion: PMNPs formulation can efficiently be internalized in BrCa cells and induce enhanced therapeutic potential of Ptxl. Development of a targeted drug delivery system would not only reduce the dose of paclitaxel required to kill cancer cells but also minimize long-term paclitaxel associated systemic toxicity and drug-resistance. Citation Format: Pallabita Chowdhury, Sumeet S. Chauhan, Prashanth K. Nagesh, Elham Hatami, Bilal B. Hafeez, Sheema Khan, Meena Jaggi, Murali M. Yallapu. Novel paclitaxel medical nanoparticle formulation for breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4658.
Abstract 2237: Diclofenac as a dual inhibitor of cyclooxygenase and aldo-keto-reductase 1B10 inhibits pancreatitis-enhanced carcinogenesis in <i>LSL-Kras</i> <i>G12D</i> <i>-Pdx-1-Cre</i>mice
Authors: Jie Liao, Leyu Sun, Haonan Li, Rong Xia, Xiaoming You, Dandan Xu, Guang-Yu Yang
Journal: Cancer Research (2018)

Abstract Diclofenac is one of non-steroid anti-inflammatory drugs and is recently identified as a competitive inhibitor of aldo-keto reductase family 1B10 (AKR1B10). AKR1B10 is an NADPH-dependent enzyme that exhibits lipid substrate specificity, especially for farnesyl and geranylgeranyl involved in protein prenylation (such as for Kras) and plays an oncogenic role in pancreatic carcinogenesis. In the present study, we determined the chemopreventive effects and mechanism of diclofenac on inhibiting pancreatitis-carcinogenesis in LSL-KrasG12D/Pdx1-Cre mice (called Pankras mice), particularly on Kras prenylation. Pancreatitis was induced by single i.p. injection of Cearulein (250ug/Kg body weight) for 5-week old mice, and one week after caerulein treatment, Pankras mice were fed an AIN-93M diet or a diet with 5 or 20ppm diclofenac (n=12 mice/group) for 7 months. The results showed that Diclofenac significantly reduced the severity of chronic pancreatitis, as measured by the extent of acini loss, inflammatory cell infiltration and stromal fibrosis. The progression of low-grade mPanIN I to high-grade mPanIN II/III and to invasive carcinoma was significantly suppressed and the tumor incidence significantly reduced to 50% and 17% in the mice treated with either 5ppm or 20 diclofenac compared to 86% in Pankras mice. Inhibition of membrane-bound mutant Kras (prenylated) and its transmitted phosphorylation of mitogen-activated protein kinase's kinase/extracellular signal-regulated kinases were demonstrated in pancreatic tissues by western blot assay. Analysis of the eicosanoid profile revealed a significant reduction of prostaglandin E2. These results indicate that diclofenac is a highly potential agent for preventing chronic pancreatitis and carcinogenesis, mainly via targeting mutant Kras and inflammation (Supported by NIH R01 CA164041). Citation Format: Jie Liao, Leyu Sun, Haonan Li, Rong Xia, Xiaoming You, Dandan Xu, Guang-Yu Yang. Diclofenac as a dual inhibitor of cyclooxygenase and aldo-keto-reductase 1B10 inhibits pancreatitis-enhanced carcinogenesis in LSL-KrasG12D-Pdx-1-Cremice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2237.
Alginate encapsulation as long-term immune protection of allogeneic pancreatic islet cells transplanted into the omental bursa of macaques
Authors: Matthew A. Bochenek, Omid Veiseh, Arturo J. Vegas, James J. McGarrigle, Meirigeng Qi, Enza Marchese, Mustafa Omami, Joshua C. Doloff, Joshua Mendoza-Elias, Mohammad Nourmohammadzadeh, Arshad Khan, Chun-Chieh Yeh, Yuan Xing, Douglas Isa, Sofia Ghani, Jie Li, Casey Landry, Andrew R. Bader, Karsten Olejnik, Michael Chen, Jennifer Hollister-Lock, Yong Wang, Dale L. Greiner, Gordon C. Weir, Berit Løkensgard Strand, Anne Mari A. Rokstad, Igor Lacik, Robert Langer, Daniel G. Anderson, Jose Oberholzer
Journal: Nature Biomedical Engineering (2018)
Activation of Apoptosis Signal-Regulating Kinase 1 in Injured Artery and Its Critical Role in Neointimal Hyperplasia
Authors: YasukatsuIzumi, ShokeiKim, MinoruYoshiyama, YasuhiroIzumiya, KaoruYoshida, AtsushiMatsuzawa, HidenoriKoyama, YoshikiNishizawa, HidenoriIchijo, JunichiYoshikawa, HiroshiIwao
Journal: Circulation (2003)

Background— Apoptosis signal-regulating kinase 1 (ASK1), recently identified as one of the mitogen-activated protein kinase kinase kinases, is activated by various extracellular stimuli and involved in a variety of cellular function. Therefore, we first examined the role of ASK1 in vascular remodeling. Methods and Results— We used rat balloon injury model and cultured vascular smooth muscle cells (VSMCs). Arterial ASK1 activity was rapidly and dramatically increased after balloon injury. To specifically inhibit endogenous ASK1 activation, dominant-negative mutant of ASK1 (DN-ASK1) was transfected into rat carotid artery before balloon injury. Gene transfer of DN-ASK1 significantly prevented neointimal formation at 14 days after injury. Bromodeoxyuridine labeling index at 7 days after injury showed that DN-ASK1 remarkably suppressed VSMC proliferation in both the intima and the media. We also examined the role of ASK1 in cultured rat VSMCs. Infection with DN-ASK1 significantly attenuated serum-induced VSMC...
HCN3 Contributes to the Ventricular Action Potential Waveform in the Murine Heart
Authors: StefanieFenske, RobertMader, AndreasScharr, ChristosPaparizos, XiaochunCao-Ehlker, StylianosMichalakis, LiorShaltiel, MarthaWeidinger, JulianeStieber, SusanneFeil, RobertFeil, FranzHofmann, ChristianWahl-Schott, MartinBiel
Journal: Circulation Research (2011)

Rationale:The hyperpolarization-activated current Ih that is generated by hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) plays a key role in the control of pacemaker activity in sinoatrial node cells of the heart. By contrast, it is unclear whether Ih is also relevant for normal function of cardiac ventricles. Objective:To study the role of the HCN3-mediated component of ventricular Ih in normal ventricular function. Methods and Results:To test the hypothesis that HCN3 regulates the ventricular action potential waveform, we have generated and analyzed a HCN3-deficient mouse line. At basal heart rate, mice deficient for HCN3 displayed a profound increase in the T-wave amplitude in telemetric electrocardiographic measurements. Action potential recordings on isolated ventricular myocytes indicate that this effect was caused by an acceleration of the late repolarization phase in epicardial myocytes. Furthermore, the resting membrane potential was shifted to more hyperpolarized potentials ...
Abstract LB-244: Overcoming resistance to DNA targeted agents by epigenetic activation of Schlafen 11 (SLFN11) expression with class I histone deacetylase inhibitors
Authors: Azam Ghafoor, Sai-Wen Tang, Anish Thomas, Junko Murai, Jane B. Trepel, Susan E. Bates, Vinodh N. Rajapakse, Yves Pommier
Journal: Cancer Research (2018)

Abstract Purpose: Schlafen 11 (SLFN11), a putative DNA/RNA helicase is a dominant genomic determinant of response to DNA damaging agents and is frequently not expressed in cancer cells. Whether histone deacetylase (HDAC) inhibitors can be used to release SLFN11 and sensitize SLFN11-inactivated cancers to DNA-targeted agents is tested here. Experimental Design: SLFN11 expression was examined in The Cancer Genome Atlas (TCGA), in cancer cell line databases and in patients treated with romidepsin. Isogenic cells overexpressing or genetically inactivated for SLFN11 were used to investigate the effect of HDAC inhibitors on SLFN11 expression and sensitivity to DNA damaging agents. Results: SLFN11 expression is suppressed in a broad fraction of common cancers and cancer cell lines. In cancer cells not expressing SLFN11, transfection of SLFN11 sensitized the cells to camptothecin, topotecan, hydroxyurea and cisplatin but not to paclitaxel. SLFN11 mRNA and protein levels were strongly induced by class I (romidepsin, entinostat), but not class II (roclinostat) HDAC inhibitors in a broad panel of cancer cells. SLFN11 expression was also enhanced in peripheral blood mononuclear cells of patients with circulating cutaneous T-cell lymphoma treated with romidepsin. Consistent with the epigenetic regulation of SLFN11, camptothecin and class I HDAC inhibitors were synergistic in many of the cell lines tested. Conclusion: This study reports the prevalent epigenetic regulation of SLFN11 and the dominant stimulatory effect of HDAC inhibitors on SLFN11 expression. Our results provide a rationale for combining class I HDAC inhibitors and DNA damaging agents to overcome epigenetic inactivation of SLFN11-mediated resistance to DNA-targeted agents. Citation Format: Azam Ghafoor, Sai-Wen Tang, Anish Thomas, Junko Murai, Jane B. Trepel, Susan E. Bates, Vinodh N. Rajapakse, Yves Pommier. Overcoming resistance to DNA targeted agents by epigenetic activation of Schlafen 11 (SLFN11) expression with class I histone deacetylase inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-244.
Abstract 2347: High-throughput scRNA-seq analysis using Celsee Nano-prep 250K sequencing chip on Celsee C-PREP GENESIS
Authors: Vishal Premdev Sharma, William Chiro Chow, Brian Boniface, Kyle Gleason, Austin Payne, Priya Gogoi, Kalyan Handique
Journal: Cancer Research (2018)

Abstract For effective targeted therapeutics, it is critical to identify cancer mutations in cells that are often regional and heterogenic. Recent advances in single-cell mRNA sequencing (scRNA-seq) have made it possible to study intratumor heterogeneity and its role in cancer progression, metastasis, and treatment resistance. Next-generation sequencing (NGS)-based studies have identified critical genetic alterations in a variety of malignancies. However, the current workflow of existing technologies leads to significant loss of cells and thus loss of critical information. In this study we present a technology that decreases cell loss and increases efficiency of scRNA-seq. C-PREP GENESIS is a fully automated, random-access, multiple-sample processor for single-cell sequencing preparation. C-PREP GENESIS allows automated fluid dispensing and controlled pumping through Nanochips. The instrument utilizes unitized reagent cartridge for dispensing reagents for wash, lysis, cDNA synthesis and oil (for partitioning). With its automated thermocycling (4oC- 100oC), it can achieve the single cell to cDNA synthesis on beads with unique cell barcode and UMI tags in under 2 hours with an efficiency of ~80% of the 50,000 single cells captured on the nano-PREP 250K sequencing chip. The cDNA can then be retrieved from the chip for downstream library preparation. Alternatively, users can perform a targeted library prep PCR on the same instrument. Here we present scRNA-seq analysis of single cells obtained from patient tumor biopsy samples and cancer tissue culture single cells to discuss the critical mutations observed in single cells of the heterogenic tumor populations. Citation Format: Vishal Premdev Sharma, William Chiro Chow, Brian Boniface, Kyle Gleason, Austin Payne, Priya Gogoi, Kalyan Handique. High-throughput scRNA-seq analysis using Celsee Nano-prep 250K sequencing chip on Celsee C-PREP GENESIS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2347.
Abstract 11585: Long-term Survival of Stroke and Acute Delirium Following Cardiac Surgery is Compromised: Validation of a Prediction Model for Neurological Outcomes
Authors: Priyadharshanan Ariyaratnam, Mahmoud Loubani, Ajith Vijayan
Journal: Circulation (2015)

Introduction: Neurological complications following cardiac surgery have a high in-hospital mortality and morbidity associated with it. Unlike the USA, the UK does not have a scoring system to predict such complications. Furthermore, little long-term data exists for survival from stoke, transient ischaemic attacks (TIAs) and acute delirium following cardiac surgery. We therefore looked at the long-term effects of neurological complications as well as developed and validated a scoring system to predict post-operative stroke. Methods: Retrospective analysis of data collected prospectively on our cardiac database between July 1999 and March 2015. A multivariate logistic regression model was used to create a prediction model and the model was then validated. Long-term survival was evaluated using the Kaplan-Meier method. Results: In total, 13,655 consecutive patients underwent cardiac surgery using cardiopulmonary bypass. Permanent stroke occurred in 1.1% of patients, acute delirium in 2.2% and TIAs in 1.1%. The validation for the final logistic regression model for permanent stroke showed a c-index of 0.717. Permanent stroke (38% vs 3%), TIA (6% vs 3%) and acute delirium (8% vs 3%) patients were significantly more likely (p&lt;0.05) to have a higher in-hospital mortality compared to non-neurological complication patients. These neurological complications were significantly more likely to have longer hospital stays and rehabilitation (p&lt;0.05). The long-term survival (2, 5, 10 &amp; 15 years) was significantly less (p&lt;0.05, log-rank) in those who survived stroke, TIA and acute delirium at hospital discharge compared to those discharged who did not sustain these pathologies (Figure 1). Conclusion: We have developed a risk score to predict these neurological outcomes which will help identify those patients at the highest risk so they can be thoroughly counselled and optimised pre-operatively and that our annual resource allocation can be planned.
Abstract 15968: Use of Prescription Smoking Cessation Medications After Myocardial Infarction in Community Practice
Authors: Neha J Pagidipati, Anne Hellkamp, Laine Thomas, Martha Gulati, Eric Peterson, Tracy Wang
Journal: Circulation (2016)

Introduction: Hospitalization for an acute myocardial infarction (MI) is an ideal opportunity to initiate smoking cessation interventions. Prescription medications such as bupropion and varenicline...
Abstract IA12: Acquired chemotherapy resistance in high-grade serous ovarian cancer patients
Authors: Elizabeth L. Christie, Jessica Beach, Dariush Etemadmoghadam, Dale Garsed, Ann-Marie Patch, Sian Fereday, Swetansu Pattnaik, Samuel Brady, Andrea Bild, David D.L. Bowtell
Journal: Clinical Cancer Research (2018)

Abstract High-grade serous ovarian cancer (HGSC) was one of the first cancer types subjected to comprehensive genomic analysis, and over the last 5-7 years gene expression and DNA sequence data have been generated from hundreds of samples. A large majority of this data has been obtained from surgical samples collected following primary debulking surgery or following a few cycles of neoadjuvant chemotherapy. By contrast, comparatively little data exist from patients who have been extensively treated with chemotherapy or newer targeted agents, such as antiangiogenics or PARP inhibitors (PARPi). Of particular interest are samples collected from patients whose cancer was initially responsive to treatment but has become resistant to therapy (acquired resistance) at the time of collection. The presentation will describe data obtained from whole-genome (N=73 samples, 36 patients) and targeted (N=65 samples, 48 patients) sequence analysis of recurrent or end-stage HGSC samples, focusing in particular on two mechanisms of acquired resistance–fusions involving the ABCB1 gene and reversion of germline BRCA1/2 mutations. ABCB1 encodes the multidrug resistance transporter MDR1, also known as P-glycoprotein. Data will be presented on the frequency and mechanisms of ABCB1 deregulation in recurrent HGSC, and approaches to clinical intervention in fusion-positive patients. Reversions in BRCA1/2 appear to render tumors that were defective in homologous recombination (HR) repair, HR proficient and therefore may have important implications for likely treatment response. The presentation will also discuss approaches to evaluating reversion status in patients with mutation in BRCA1/2. Citation Format: Elizabeth L. Christie, Jessica Beach, Dariush Etemadmoghadam, Dale Garsed, Ann-Marie Patch, Sian Fereday, Swetansu Pattnaik, Australian Ovarian Cancer Study, Samuel Brady, Andrea Bild, David D.L. Bowtell. Acquired chemotherapy resistance in high-grade serous ovarian cancer patients. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA12.
Genetic polymorphisms of the OPG gene associated with breast cancer.
Authors: Gunter Assmann, Ingolf Juhasz-Boess, Frank Gruenhage, Stefan Graeber, Stefan Wieczorek, Michael Pfreundschuh, Erich-Franz Solomayer, Jasmin Teresa Ney
Journal: Journal of Clinical Oncology (2012)

1523 Background: The receptor activator of NfkappaB (RANK) and osteoprotegerin (OPG) cascade system have been reported to play a role in the pathogenesis of breast cancer (BC). Genetic variations in the genes coding for RANK, RANK ligand (RANKL), and OPG are supposed to play a role in the susceptibility of breast cancer. Methods: In the present case-control study genomic DNA was obtained from 307 BC patients (age: median 56) and 396 healthy female controls (healthy blood donors, HC; age median: 45). We studied six single nucleotide polymorphisms (SNPs) in the genes coding for RANK (2 SNPs, rs1805034, rs35211496), OPG (2 SNPs, rs3102735, rs2073618), and RANKL (2 SNPs, rs9533156, rs2277438) using TaqMan assay-guided PCR for the respective SNPs. The genotype and allelic frequencies comparing BC with HC were analyzed with χ2 test for 2x3 and 2x2 tables, respectively. Results: The genotype distributions as well as the allelic frequencies of the SNP rs3102735 in the OPG gene differed significantly (p=0.006 and p=0.019, respectively) between BC patients and HC; the genotypes containing the minor allele were more frequent in BC patients (table). In the OPG SNP rs2073618 the minor allele C was significantly less frequent in BC patients compared to HC (43.8 vs. 49.7%; OR: 0.788; p=0.031). In addition, BC patients carried less frequently the homozygous genotype of the minor allele compared to major allele (18.6 vs. 23.9%, p=0.083). No significant risk was detected for the other SNPs investigated in this study. Conclusions: This is the first study reporting a significant association of the SNP rs3102735 in the OPG gene with the susceptibility to develop BC in the Caucasian population. The minor allele C of OPG SNP rs2073618, however, seems to be protective against BC disease. The impact of the OPG SNP rs3102735 (location: 5`near region, chromosome 8q24) and of the OPG SNP rs2073618 (a missense SNP, leading to amino acid exchanges Leu3Asn) on the pathogenesis of BC are unclear. [Table: see text]