tbuckley/cabot-search huggingface dataset:
Abstract 3557: Beta-hydroxybutyrate inhibits oncogenic signaling and cellular motility in pancreatic cancer cells
Authors: Surendra K. Shukla, Nina V. Chaika, Pankaj K. Singh
Journal: Cancer Research (2018)

Abstract Pancreatic ductal adenocarcinoma is a devastating malignancy with a five-year survival rate less than 7%. It is characterized by a plethora of metabolic and signaling pathways, which plays a critical role in the pathogenesis of the disease. Caloric restriction and ketogenic diets have been shown to be beneficial in the management of several kinds of malignancies including pancreatic cancer. During caloric restriction or ketogenic diet supplementation, blood level of ketone bodies (beta-hydroxy butyrate or BHB, acetoacetate, acetone) gets elevated in the body. Among, these ketone bodies, BHB, the most abundant ketone body in mammals has been shown to act as the modulator of several signaling and inflammatory pathways. We have evaluated the effect of BHB on oncogenic signaling pathways and motility of pancreatic cancer cells. We observed reduced activation of key oncogenic signaling pathways, including mTOR. We also observed inhibition of cellular motility in a dose-dependent manner. Furthermore, we observed reduced expression of c-Myc, a key oncogene and a downstream effector molecule of mTOR. Correspondingly, we also observed reduced expression of several c-Myc target genes. We have also evaluated the effect of BHB on epithelial-mesenchymal transition (EMT) markers and observed altered expression of EMT markers like N-cadherin and E-cadherin. We also evaluated the effect of BHB on the expression of inflammatory cytokines in the pancreatic cancer cells and observed that BHB treatment leads to the reduction of expression of several inflammatory cytokines including IL6 and IL1-beta. Overall, our findings suggest that BHB inhibits inflammatory signaling in pancreatic cancer cells and reduces the cellular motility by modulating the expression of EMT regulators. Citation Format: Surendra K. Shukla, Nina V. Chaika, Pankaj K. Singh. Beta-hydroxybutyrate inhibits oncogenic signaling and cellular motility in pancreatic cancer cells [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 3557.
Atherosclerosis in Patients Infected With HIV Is Influenced by a Mutant Monocyte Chemoattractant Protein-1 Allele
Authors: CarlosAlonso-Villaverde, BlaiColl, SandraParra, ManuelMontero, NahumCalvo, MònicaTous, JorgeJoven, LluisMasana
Journal: Circulation (2004)

Background— Patients infected with HIV present with premature atherosclerosis, and the 2 diseases share common pathogenic pathways. We investigated mutations in the monocyte chemoattractant protein-1 (MCP-1) and CCR-2 genes, which are known to control aspects of these pathways, to ascertain whether they are involved in atherogenesis in these patients. Methods and Results— We performed carotid and femoral artery ultrasonography to detect subclinical atherosclerosis in patients infected with HIV (n=183). MCP-1–2518G and CCR-2 64I polymorphisms were determined in the HIV group and in a population-based control group (n=348). We also determined MCP-1 circulating levels in the HIV group. The presence of MCP-1–2518G in the group of patients with subclinical atherosclerosis was significantly higher than in patients without atherosclerotic lesions (47.5% versus 18.2%, respectively; P<0.001). Furthermore, the patients with atherosclerotic lesions had higher MCP-1 plasma concentrations than did patients without les...
Abstract 356: Polyadenyaltion of canonical histone mRNA: A potential mechanism of arsenic-induced carcinogenesis
Authors: Qiao Yi Chen, Danqi Chen, Thomas Kluz, Feng Wu, Yusha Zhu, Thomas Des Marais, Jinquan Li, Xiaoru Zhang, Ashley Jordan, Hong Sun, Chunyuan Jin, Max Costa
Journal: Cancer Research (2018)

Abstract Naturally occurring inorganic arsenic has been identified as a prominent causal agent in lung, bladder, liver, and prostate cancers. Although arsenic (As) has long been known to induce carcinogenicity via epigenetic mechanisms, alteration in histone gene expression has not been explored. The replication-dependent histone genes (also known as canonical histone genes) are the only genes found in multicellular organisms whose messenger RNA (mRNA) does not terminate with a poly(A) tail at the 3' end. Instead, they contain a conserved 26-nucleotide sequence that forms a stem-loop structure, and serves as the binding site for the Stem-loop binding protein (SLBP). SLBP is critical for canonical histone pre-mRNA processing and histone mRNA translation. Our previous studies demonstrated that arsenic exposure increases polyadenylation of histone H3.1 mRNA (a canonical histone H3) and its presence outside of S phase of the cell cycle due to the loss of SLBP protein and mRNA. Here we report that ectopic expression of polyadenylated H3.1 mRNA induces cell transformation and that the transformed cells are able to form tumors in athymic nude mice. These carcinogenic effects are dependent on the level of polyadenylation of canonical H3.1 mRNA. Notably, transfection of H3.1 cDNA with a stem-loop sequence in the front of the poly(A) signal generates less polyadenylated H3.1 mRNA and thereby attenuates cell transformation. Furthermore, the increase in polyadenylated H3.1 mRNA is able to antagonize histone H3.3 (a non-canonical variant of H3) in the promoter of active genes and perturb expression of cancer-related genes. In addition transfection of H3.1 with a poly(A) tail causes mitotic block in the cell cycle as well as chromosome instability. Furthermore, acute arsenic exposure by inhalation in mice results in the loss of SLBP and gain of polyadenylated H3.1 mRNA in lung tissues. These results suggest that the polyadenylation of canonical histone mRNAs induce by Arsenic is very disruptive to cellular genomic integrity and contributes to development of human cancers. Citation Format: Qiao Yi Chen, Danqi Chen, Thomas Kluz, Feng Wu, Yusha Zhu, Thomas Des Marais, Jinquan Li, Xiaoru Zhang, Ashley Jordan, Hong Sun, Chunyuan Jin, Max Costa. Polyadenyaltion of canonical histone mRNA: A potential mechanism of arsenic-induced carcinogenesis [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 356.
Abstract 18971: Radiofrequency Renal Denervation Attenuates Fibrosis in the Setting of Heart Failure
Authors: David J Polhemus, Juan Gao, Rishi Trivedi, Amy Scarborough, Traci Goodchild, Frank Smart, Daniel Kapusta, David J Lefer
Journal: Circulation (2016)

Introduction: Chronic overactivity of the sympathetic nervous system during heart failure contributes to left ventricular (LV) dysfunction, adverse remodeling, and fibrosis. We investigated the effects of radiofrequency renal sympathetic denervation (RDN) on LV function and cardiac fibrosis in a rodent model of hypertension and ischemic heart failure. Methods: Spontaneously hypertensive rats (SHR) were subjected to 45 min. of coronary artery ligation and reperfusion (Rep) for 12 weeks. At 4 weeks post-Rep, rats underwent either bilateral radiofrequency RDN (n=8) or sham RDN (n=8) procedure using surgical technique. Two- dimensional echocardiograms were performed biweekly. At 12 weeks post-Rep, heart tissues were fixed and stained using Masson’s trichrome for assessment of cardiac fibrosis. RT-PCR was used to quantify relative gene expression of pro-fibrotic factors. Results: RDN significantly preserved LV ejection fraction at 12 weeks vs. sham (47% ± 2.4 vs. 30% ± 2.5, p < 0.05). RDN also reduced left ven...
Canonical Wnt Signaling Remodels Lipid Metabolism in Zebrafish Hepatocytes following Ras Oncogenic Insult
Authors: Yuxiao Yao, Shaoyang Sun, Jingjing Wang, Fei Fei, Zhaoru Dong, Ai-Wu Ke, Ruoyu He, Lei Wang, Lili Zhang, Min-Biao Ji, Qiang Li, Min Yu, Guo-Ming Shi, Jia Fan, Zhiyuan Gong, Xu Wang
Journal: Cancer Research (2018)

Abstract There is limited understanding of the effects of major oncogenic pathways and their combinatorial actions on lipid composition and transformation during hepatic tumorigenesis. Here, we report a negative correlation of Wnt/Myc activity with steatosis in human hepatocellular carcinoma (HCC) and perform in vivo functional studies using three conditional transgenic zebrafish models. Double-transgenic zebrafish larvae conditionally expressing human CTNNB1mt and zebrafish tcf7l2 or murine Myc together with krasv12 in hepatocytes led to severe hepatomegaly and significantly attenuated accumulation of lipid droplets and cell senescence triggered by krasv12 expression alone. UPLC-MS–based, nontargeted lipidomic profiling and transcriptome analyses revealed that Wnt/Myc activity promotes triacylglycerol to phospholipid transformation and increases unsaturated fatty acyl groups in phospholipids in a Ras-dependent manner. Small-scale screenings suggested that supplementation of certain free fatty acids (FA) or inhibition of FA desaturation significantly represses hepatic hyperplasia of double-transgenic larvae and proliferation of three human HCC cells with and without sorafenib. Together, our studies reveal novel Ras-dependent functions of Wnt signaling in remodeling the lipid metabolism of cancerous hepatocytes in zebrafish and identify the SCD inhibitor MK8245 as a candidate drug for therapeutic intervention. Significance: These findings identify FA desaturation as a significant downstream therapeutic target for antagonizing the combinatorial effects of Wnt and Ras signaling pathways in hepatocellular carcinoma. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/19/5548/F1.large.jpg. Cancer Res; 78(19); 5548–60. ©2018 AACR.
Abstract 111: The CX3CR1-Fractalkine axis drives both circulating prostate cancer cells and macrophages to the bone metastatic microenvironment
Authors: Ramanpreet Kaur, Chen Qian, Joseph Salvino, Olimpia Meucci, Alessandro Fatatis
Journal: Cancer Research (2018)

Abstract Prostate cancer (PCa) is the second most frequently diagnosed cancer and its progression into metastatic disease reduces the 5-year survival rate to 29% in diagnosed men. A better understanding of the mechanisms underpinning metastatic dissemination and the role played by the tumor microenvironment at distant sites is essential. Our lab has shown that PCa cells express the chemokine receptor CX3CR1 and seed the skeleton when attracted by bone-derived Fractalkine (FKN) (a.k.a. CX3CL1). A crucial component of the bone microenvironment consists of heterogeneous populations of tumor-associated macrophages (TAMs), which can polarize into M1 or M2 phenotypes and are likely implicated in metastatic progression. TAMs migrate in close proximity of cancer cells and release growth factors, chemokines, and other inflammatory mediators that influence tumor growth. Using cell biology tools, we show that both PCa cells and macrophages express the CX3CR1 receptor, which signal to downstream targets when engaged by FKN and is inhibited by a novel small-molecule inhibitor. We also employed a mouse model of cancer cell dissemination and metastasis to show that our novel CX3CR1 antagonist impairs tumor seeding to the skeleton. Furthermore, as macrophages also express CX3CR1, targeting this receptor may potentially hinder TAMs' accumulation into the metastatic microenvironment, depriving it of crucial pro-metastatic conditioning. In conclusion, we propose that the CX3CR1-FKN axis drives both cancer cells and TAMs to metastatic sites and that the mitigation of the functional interactions between this receptor and its unique chemokine ligand by antagonists of CX3CR1 will impair the clinical progression of PCa metastasis. Citation Format: Ramanpreet Kaur, Chen Qian, Joseph Salvino, Olimpia Meucci, Alessandro Fatatis. The CX3CR1-Fractalkine axis drives both circulating prostate cancer cells and macrophages to the bone metastatic microenvironment [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 111.
Abstract 18015: Loss of Swi/snf-complex Subunit Heart of Stone Leads to Cardiac Hyperplasia in Zebrafish
Authors: Tobias Zimmermann, Ina Berger, Steffen Just, Wolfgang Rottbauer, Tillman Dahme
Journal: Circulation (2013)

Fish and also neonatal mice possess the capacity to regenerate their hearts after myocardial damage. The adult mammalian heart only has a very limited capacity to regenerate after cardiac injury. Myocardial regeneration in zebrafish and newborn mice involves the dedifferentiation and proliferation of resident cardiomyocytes to replace the injured tissue. Unfortunately, only little is known about the factors and signaling cascades that regulate this regenerative capacity. In a forward genetics ENU-screen in zebrafish, we recently isolated the mutant heart of stone (hos). Hearts of hos mutant embryos show a severe thickening of the ventricle with almost complete obliteration of the ventricle. Based on cell count assays using histological sections we find significantly increased cell numbers in hos mutant ventricles. Based on BrdU incorporation assays as well as H3P and PCNA stainings, we find that ventricular hyperplasia in hos is caused by significantly enhanced cardiomyocyte proliferation. By positional cloning we show a splice donor site mutation within the zebrafish hos gene. hos is a subunit of the SWI/SNF chromatin remodeling complex, which is known to be involved in transcriptional regulation. The identified hos mutation specifically leads to an integration of Intron7 resulting in a reading frame shift and thereby to premature termination of hos protein translation. Injection of wild-type hos mRNA in hos mutant embryos restores the wild-type, while injection of morpholinos directed against the splice donor site of Exon7 phenocopy the hos mutant phenotype. In addition, by generating hos-null zebrafish using morpholinos directed against the translational start site of hos, we are also able to induce ventricular hyperplasia, suggesting that the hos mutation results in the complete loss of hos function. Interestingly, in contrast to hos-deficient embryos, targeted knockdown of the zebrafish SWI/SNF-complex core component BRG1 leads to severe hypoplastic hearts, indicating that hos in zebrafish might play a repressive role on SWI/SNF complex function and the control of cardiomyocyte proliferation in vivo.
Abstract 18066: Novel NLRP3 Inflammasome Inhibitor OLT1177 Reduces Infarct Size in a Mouse Model of Myocardial Ischemia Reperfusion Injury
Authors: Stefano Toldo, Adolfo G Mauro, Carlo Marchetti, Eleonora Mezzaroma, Benjamin Van Tassell, Damaris Skouras, Federica La Neve, Charles Dinarello, Antonio Abbate
Journal: Circulation (2017)

Introduction: Activation of the NLRP3 inflammasome during acute myocardial infarction (AMI) mediates further inflammatory injury after reperfusion. Several NLRP3 inflammasome inhibitors have been s...
Lanreotide Reduces Serum Free and Total Insulin-Like Growth Factor-I After Angioplasty
Authors: JanFrystyk, ChristianSkjærbæk, NielsAlexander, HåkanEmanuelsson, HarrySuryapranata, HorstBeyer, MarieFoegh, HansØrskov
Journal: Circulation (1996)

Background Several experiments point to a participating role of insulin-like growth factor-I (IGF-I) in the vascular events leading to restenosis after percutaneous transluminal coronary angioplasty (PTCA). Methods and Results We measured fasting serum total (extractable) IGF-I in 553 patients in a controlled clinical trial. Half of the patients received continuous subcutaneous infusion of the somatostatin analogue lanreotide from the day before (baseline) and for 4 days after PTCA. We also measured ultrafiltrated serum free IGF-I and IGF-II, total IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-3, and insulin in a subgroup of 18 placebo-treated and 20 lanreotide-treated patients. Total IGF-I had decreased by 7% (P<.0001) 1 day after initiation of lanreotide infusion and stayed reduced, whereas no early changes occurred in placebo-treated patients. The same pattern was observed in the subgroup. Free IGF-I decreased significantly from baseline by 22% to 27% (P<.05) in lanreotide-treated patients and increas...
Bayesian Phylogeography and Pathogenic Characterization of Smallpox Based on<i>HA</i>,<i>ATI</i>, and<i>CrmB</i>Genes
Authors: Dillon C Adam, Matthew Scotch, Chandini Raina MacIntyre
Journal: Molecular Biology and Evolution (2018)

Variola virus is at risk of re-emergence either through accidental release, bioterrorism, or synthetic biology. The use of phylogenetics and phylogeography to support epidemic field response is expected to grow as sequencing technology becomes miniaturized, cheap, and ubiquitous. In this study, we aimed to explore the use of common VARV diagnostic targets hemagglutinin (HA), cytokine response modifier B (CrmB), and A-type inclusion protein (ATI) for phylogenetic characterization as well as the representativeness of modelling strategies in phylogeography to support epidemic response should smallpox re-emerge. We used Bayesian discrete-trait phylogeography using the most complete data set currently available of whole genome (n = 51) and partially sequenced (n = 20) VARV isolates. We show that multilocus models combining HA, ATI, and CrmB genes may represent a useful heuristic to differentiate between VARV Major and subclades of VARV Minor which have been associated with variable case-fatality rates. Where whole genome sequencing is unavailable, phylogeography models of HA, ATI, and CrmB may provide preliminary but uncertain estimates of transmission, while supplementing whole genome models with additional isolates sequenced only for HA can improve sample representativeness, maintaining similar support for transmission relative to whole genome models. We have also provided empirical evidence delineating historic international VARV transmission using phylogeography. Due to the persistent threat of re-emergence, our results provide important research for smallpox epidemic preparedness in the posteradication era as recommended by the World Health Organisation.
Abstract 2298A: Enhanced consideration of context dependence reveals the scope of somatic missense drivers in human cancers
Authors: Collin J. Tokheim, Neha Nanda, Nicholas J. Roberts, Rachel Karchin
Journal: Cancer Research (2018)

Abstract Large-scale sequencing studies of patient cohorts have enabled identification of many driver genes whose somatic alterations confer a selective advantage to cancer cells. However, not every mutation in a driver gene is necessarily a driver of cancer. As mutation-based biomarkers are increasingly used to decide drug regimens and placement in clinical trials, it is important to distinguish specific driver mutations. Improved computational methods are necessary for identifying the particular mutations in a given cancer that are drivers, especially for rare mutations (&amp;lt;1% of patients). We have previously developed the CHASM algorithm to identify cancer-specific driver missense mutations. Here, we present a completely re-worked version that leverages the context-dependence of driver mutations. We show that the new CHASM2 consistently outperforms comparable methods across a wide variety of benchmarks, including in vivo and in vitro experiments. Applied to 8,657 TCGA cancer samples in 32 cancer types, CHASM2 identifies 3,527 distinct driver somatic missense mutations. Our results suggest substantial heterogeneity of the driver mutation landscape across cancer types and a strikingly large prevalence of rare driver mutations. For particular cancer types driven by common mutations, current sample sizes are already saturating driver discovery. We performed validation experiments on missense mutations of rare and intermediate frequency in the tumor suppressor gene ATM and show CHASM2 distinguishes a radiosensitive phenotype in cultured cells. To our knowledge CHASM2 is the first sufficiently powered method to predict individual driver somatic missense mutations at multiple scales – whole exome, targeted gene panel, and within a single gene. Citation Format: Collin J. Tokheim, Neha Nanda, Nicholas J. Roberts, Rachel Karchin. Enhanced consideration of context dependence reveals the scope of somatic missense drivers in human cancers [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 2298A.
Abstract 2698: Phosphoproteomics-guided anticancer drug combination design with a novel small-molecule PP2A activator
Authors: Danica D. Wiredja, Peter Liao, Jaya Sangodkar, Daniela Schlatzer, Mark R. Chance, Goutham Narla
Journal: Cancer Research (2018)

Abstract Significance: Phosphatases are cellular antagonists of kinase signaling and have a diverse range of substrates, many of which are ideal targets for small molecule-based anticancer treatment. Our lab and collaborators have generated a novel series of compounds that bind to and activate the serine/threonine protein phosphatase 2A (PP2A), and these small-molecule activators of PP2A (SMAPs) induce apoptosis and inhibit tumor growth in numerous cancer models. Based on these findings, this project aimed to identify drug combinations with our SMAP that could drive optimal anticancer activity. Methods: We first turned to global shotgun phosphoproteomics to compare the signaling response signatures of our SMAP against a combination of a MEK inhibitor (MEKi) and an AKT inhibitor (AKTi). We then applied Kinase-Substrate Enrichment Analysis (KSEA) to extract key diverging biologic patterns between these two arms, with the goal of identifying distinct pathways that are inhibited in each condition. These results, in turn, could provide insight to differences between phosphatase activation versus kinase inhibition. Results: KSEA profiling revealed distinct signaling responses between the two arms. Notably, the kinase inhibitors caused robust downregulation of the MAPK signaling pathway, whereas SMAP treatment showed limited involvement of that cascade. Thus, we hypothesized that a combination of SMAP + MEKi would yield enhanced anticancer response compared to either single agent. Subsequent murine xenograft testing demonstrated superior tumor response with SMAP + MEKi versus either compound alone. Conclusion: This project offers a phosphoproteomics-level glimpse to the signaling effects between phosphatase activation compared to kinase inhibition. The data, in turn, could be used for rational drug combination design to improve antitumor therapy. Citation Format: Danica D. Wiredja, Peter Liao, Jaya Sangodkar, Daniela Schlatzer, Mark R. Chance, Goutham Narla. Phosphoproteomics-guided anticancer drug combination design with a novel small-molecule PP2A activator [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 2698.
Modeling sporadic ALS in iPSC-derived motor neurons identifies a potential therapeutic agent
Authors: Koki Fujimori, Mitsuru Ishikawa, Asako Otomo, Naoki Atsuta, Ryoichi Nakamura, Tetsuya Akiyama, Shinji Hadano, Masashi Aoki, Hideyuki Saya, Gen Sobue, Hideyuki Okano
Journal: Nature Medicine (2018)
Abstract 15300: Genetic Determinants of Plasma Glycine Levels Are Associated With Coronary Artery Disease: Meta-Analysis of Genome-Wide Association Studies in ~105,000 Subjects of European Ancestry
Authors: Jaana A Hartiala, W.H. Wilson Tang, Zeneng Wang, Jeanette Erdmann, Stanley L Hazen, Hooman Allayee
Journal: Circulation (2016)

We recently identified a variant (rs715) in carbamoyl phosphatase 1 (CPS1) on chr2q34 that was strongly associated with plasma betaine and glycine levels, and showed a striking female-specific asso...