tbuckley/cabot-search huggingface dataset:
Abstract 5479: Targeting fructose-induced metabolic reprogramming in liver metastasis
Authors: Xiling Shen
Journal: Cancer Research (2018)

Abstract Primary tumors gradually accumulate genetic alterations and are influenced by their microenvironment until they acquire the ability to metastasize to distant organs. Typical of this process, colorectal cancer (CRC) progresses through an adenoma-to-carcinoma sequence that eventually leads to metastasis, preferentially (~70% patients) to the liver. At this phase, the disease becomes challenging to treat and eventually develops resistance to most forms of combination therapy, making CRC metastasis a leading cause of cancer-related deaths. Patients with inoperable liver metastasis respond poorly to chemotherapeutic intervention and have a median survival of 6 to 9 months. Liver lesions have also been shown to seed tertiary tumors in the lungs of patients. Current chemotherapy for advanced CRC does not target liver metastases specifically. This is partly based on observations that CRC metastases are not consistently associated with any specific genetic mutations and they generally resemble cells in the primary tumor. However, emerging evidence suggests that nongenetic alterations, such as epigenetic and metabolic reprogramming, may promote cancer metastasis, including CRC. Targeting such mechanisms may provide a way to enhance therapeutics against metastasis. In this study, pair-wise analysis of 90 matched samples (normal colon, primary CRC, liver metastasis) from 30 Stage IV CRC patients and an in vivo CRC metastasis model via cecum transplantation suggests that CRC liver metastases alter activity levels of certain metabolic pathways. LC-MS based metabolomics systematically mapped the altered metabolic pathways in CRC liver metastasis. In particular, via hypoxia-responsive GATA6 and fructose-responsive ChREBP, liver metastases upregulate ALDOB, an enzyme involved in fructose metabolism, given that 70% of fructose is metabolized in the liver. Intrahepatic implantation indicates that the liver environment causes CRC cells to upregulate ALDOB. Metabolomics and 13C-labeled fructose tracing studies indicate that ALDOB promotes fructose metabolism to fuel glycolysis, gluconeogenesis and the pentose phosphate pathway. Fructose also triggered downstream signaling to enhance lipid synthesis. ALDOB silencing or dietary fructose restriction suppresses growth of CRC liver metastases, but not primary tumors or lung metastases, highlighting the importance of tumor environment. Our findings suggest that metastatic cells can take advantage of abundant metabolites in their new microenvironment, and manipulation of involved pathways impacts the course of metastatic growth. Citation Format: Xiling Shen. Targeting fructose-induced metabolic reprogramming in liver metastasis [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 5479.
Abstract 16902: Efficacy and Safety of Rivaroxaban versus Warfarin in Patients Taking Non-dihydropyridine Calcium Channel Blockers: Results From the ROCKET AF Trial
Authors: Jeffrey B Washam, Anne S Hellkamp, Yuliya Lokhnygina, Jonathan P Piccini, Scott D Berkowitz, Christopher C Nessel, Richard C Becker, Guenter Breithardt, Keith A Fox, Jonathan L Halperin, Graeme J Hankey, Kenneth W Mahaffey, Daniel E Singer, Manesh R Patel
Journal: Circulation (2015)

Background: Non-dihydropyridine calcium channel blockers (non-DHP CCBs) are agents commonly used for ventricular rate control in patients with atrial fibrillation (AF). The agents have the property of combined cytochrome 3A4 and P-glycoprotein (P-gp) inhibition which may lead to increased drug exposure for oral anticoagulants that are substrates for these pathways. We investigated the safety and efficacy of rivaroxaban versus warfarin according to use of these agents. Objectives: This post-hoc analysis examined patient characteristics and compared outcomes between rivaroxaban and warfarin using Cox proportional hazards modeling according to the use of non-DHP CCBs at baseline in ROCKET AF (n=14,264). Methods and Results: At the time of randomization, 1308 patients (9.2%) were taking a non-DHP CCBs. Patients taking a non-DHP CCB were more likely to be female (45% vs. 39%), have diabetes (43% vs. 40%), and have a medical history of COPD (21% vs. 9%) while they were less likely to have a medical history of heart failure (49% vs. 64%), myocardial infarction (14% vs.18%) and had a lower mean CHADS 2 score (3.3 vs. 3.5). Non-DHP CCB use was not associated with an increased risk of stroke or non-CNS embolism (P=0.11) or the composite outcome of non-major clinically relevant or major bleeding (P=0.087). No significant difference was observed in the primary efficacy (stroke or non-CNS embolism; adjusted interaction P value=0.38) or primary safety outcome (non-major clinically relevant bleeding or major bleeding; adjusted interaction P value=0.14) between rivaroxaban and warfarin with non-DHP CCB use (Table). Conclusion: Non-DHP CCBs are commonly used medications for rate control in patients with AF. In spite of having the properties of combined P-gp and moderate CYP3A4 inhibition, use of these agents was not associated with a significant change in the efficacy or safety of rivaroxaban compared with warfarin in the ROCKET AF trial.
Abstract LB-205: hnRNPM-IRES-mediated translation promotes colon cancer tumorigenesis
Authors: Tsung-Ming Chen, Ming-Chih Lai, Yi-Han Li, Shaw-Jenq Tsai, H. Sunny Sun
Journal: Cancer Research (2018)

Abstract Internal Ribosome Entry Site (IRES)-mediated translation is known to play a vital role for cell survival under stress conditions, yet the crucial players involved in this translational reprogramming remain largely unidentified. This study aims to elucidate the missing piece of pathway underlying the hypoxia-induced, IRES-mediated translational activation in the cancer genome. By using the proteomic profiling approach, we discovered hnRNPM as a new IRES interacting factor to activate translation in colon cancer cells. Mechanistic studies revealed that hypoxia increases hnRNPM binding onto mRNA and promotes translation of a set of critical genes relating to cell survival and metabolism. Transcriptomics and translatomics analyses discovered a unique set of hnRNPM-target mRNAs with increased ribosome occupancy under hypoxia to provoke tumorigenesis. Clinical specimen and mouse carcinogenesis model showed that hnRNPM overexpression accompanies colorectal cancer development and positively correlated with hypoxia biomarker. Collectively, these data highlight the novel role of hnRNPM-IRES-mediated translation in transforming hypoxia-induced proteome toward malignancy and demonstrate significant implications for targeting hnRNPM in future anticancer therapy. Citation Format: Tsung-Ming Chen, Ming-Chih Lai, Yi-Han Li, Shaw-Jenq Tsai, H. Sunny Sun. hnRNPM-IRES-mediated translation promotes colon cancer tumorigenesis [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-205.
Abstract 1674: Novel direct AMPK activator suppresses non-small cell lung cancer through inhibition of lipid metabolism
Authors: Xi Chen, Chun Xie, Xing Xing Fan, Ze Bo Jiang, Vincent Wong, Jia Hui Xu, Xiao Jun Yao, Liang Liu, Elaine L. Leung
Journal: Cancer Research (2018)

Abstract Lung cancer is the leading cause of cancer mortality. While non-small cell lung cancer (NSCLC) is the most common histological type of lung cancer and dominates almost 85% of all lung cancer cases. Conventional therapy, such as surgery, chemotherapy, or radiotherapy, scarify normal cells during the curing progress are becoming unfavorable. To avoid harmful side-effect on normal cell, target-based therapy is the mainstream of modern cancer therapy. For example, gefitinib is a clinically-marketed drug which acts as tyrosine kinase inhibitor to inhibit epidermal growth factor receptor (EGFR) activating signaling pathway. For the NSCLC patients who harbor activating substitution from leucine to arginine at amino acid 858 (L858R) point mutation and in-frame exon 19 deletion on EGFR, response well to gefitinib and these two common mutation are used a biomarkers for gefitinib prescription. However, gefitinib-resistance commonly happens due to further substitution mutation from threonine to methionine at amino acid position 790 (T790M) occurred after one year or less gefitinib treatment. Therefore, developing new treatment strategy to tackle gefitinib-resistance is urgently. Abnormal energy metabolism is accepted as new cancer hallmark. Recently, a metabolism rate-limiting enzyme 5'-adenosine menophosphate-activated protein kinase (AMPK) has become a promising anti-cancer target. In this study, we have applied computational docking to perform in silico virtual screening, and we have identified a novel direct AMPK agonist, D561-0775 from a compound library. Using enzyme activation assay, we demonstrated that D561-0775 activates directly on AMPK α subunit. In addition, D561-0775 exhibited significant inhibitory effect on gefitinib-resistant NSCLC cell lines but is less cytotoxicity on normal lung fibroblast cells. D561-0775 also activates AMPK/mTOR signaling pathway, resulting in induction of apoptosis, cell cycle arrest, suppressing glycolysis and cholesterol synthesis in gefitinib-resistant H1975 lung cancer cells. Taken together, D561-0775 has provided clue on a new chemical structure that could be developed as cancer drug for gefitinib-resistant NSCLC patients through inhibition lipid metabolism by directly targeting at AMPK directly. Acknowledgments: This work was supported by Macau Science and Technology Development Fund (Project No: 021/2013/A1, 074/2011/A3 &amp; 082/2013/A3) Citation Format: Xi Chen, Chun Xie, Xing Xing Fan, Ze Bo Jiang, Vincent Wong, Jia Hui Xu, Xiao Jun Yao, Liang Liu, Elaine L. Leung. Novel direct AMPK activator suppresses non-small cell lung cancer through inhibition of lipid metabolism [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 1674.
CD40 Signaling and Plaque Instability
Authors: UweSchönbeck, PeterLibby
Journal: Circulation Research (2001)

Abstract— Today, multiple lines of evidence support the view of atherosclerosis as a chronic inflammatory disease and implicate components of the immune system in atherogenesis. Recent work has documented overexpression of the potent immune mediator CD40 and its counterpart CD40 ligand (CD40L) in experimental and human atherosclerotic lesions. Notably, interruption of CD40/CD40L interactions not only diminished the formation and progression of mouse atheroma, but also fostered changes in lesion biology and structure, which are associated in humans with “plaque stabilization.” In accordance with the hypothesis that CD40 signaling promotes plaque instability, in vitro studies demonstrated that ligation of CD40 on atheroma-associated cell types, namely endothelial cells, smooth muscle cells, and macrophages, mediates functions considered crucial to the process of atherogenesis, such as the expression of cytokines, chemokines, growth factors, matrix metalloproteinases, and procoagulants. The combination of th...
Nicotine Is a Potent Blocker of the Cardiac A-Type K+ Channels
Authors: HuizhenWang, HongShi, LimingZhang, MarcPourrier, BaofengYang, StanleyNattel, ZhiguoWang
Journal: Circulation (2000)

Background—Nicotine is a main constituent of cigarette smoke and smokeless tobacco, known to increase the risk of sudden cardiac death. This study aimed at establishing ionic mechanisms underlying potential electrophysiological effects of nicotine. Methods and Results—Effects of nicotine on Kv4.3 and Kv4.2 channels expressed in Xenopus oocytes were studied at the whole-cell and single-channel levels. The effects of nicotine on the transient outward K+ current (Ito) were studied by use of whole-cell patch-clamp techniques in canine ventricular myocytes. Nicotine potently inhibited Kv4 current. The concentration for half-maximal inhibition (IC50) was 40±4 nmol/L, and the current was abolished by 100 μmol/L nicotine. The IC50 for block of native Ito was 270±43 nmol/L. The steady-state activation properties of Kv4.3 and Ito were unaltered by nicotine, whereas positive shifts of the inactivation curves were observed. Of the total inhibition of Kv4.3 and Ito by nicotine, 40% was due to tonic block and 60% was a...
Angiotensin II Activates the Smad Pathway in Vascular Smooth Muscle Cells by a Transforming Growth Factor-β–Independent Mechanism
Authors: JuanRodríguez-Vita, ElsaSánchez-López, VanesaEsteban, MónicaRupérez, JesúsEgido, MartaRuiz-Ortega
Journal: Circulation (2005)

Background— Angiotensin II (Ang II) participates in vascular fibrosis. Transforming growth factor-β (TGF-β) is considered the most important fibrotic factor, and Smad proteins are essential components of the TGF-β signaling system. Our aim was to investigate whether Ang II activates the Smad pathway in vascular cells and its potential role in fibrosis, evaluating connective tissue growth factor (CTGF) and extracellular matrix (ECM) proteins. Methods and Results— Systemic infusion of Ang II into Wistar rats increased aortic Smad2, phosphorylated-Smad2, and Smad4 expression, associated with CTGF upregulation. In growth-arrested vascular smooth muscle cells, Ang II treatment for 20 minutes caused Smad2 phosphorylation, nuclear translocation of phosphorylated-Smad2 and Smad4, and increased Smad DNA-binding activity. Ang II also caused Smad overexpression and Smad-dependent gene transcription. The AT1 antagonist losartan diminished Ang II-induced Smad activation. The blockade of endogenous TGF-β did not modify...
Abstract 14527: Temporal Changes in Cardiac Troponin I and Risk ofCardiovascular Events in the General Population: The Nord-Trøndelag Health Study
Authors: Magnus N Lyngbakken, Helge Røsjø, Oddgeir L Holmen, Håvard Dalen, Kristian Hveem, Torbjørn Omland
Journal: Circulation (2017)

Introduction: Concentrations of cardiac troponin are strongly associated with risk of heart failure (HF), myocardial infarction (MI), and cardiovascular death (CVD) in the general population. Tempo...
Abstract P253: Body Mass Index and Heart Failure among Patients with Type 2 Diabetes
Authors: GangHu, PeterKatzmarzyk, RonaldHorswell, YujieWang, JoleneJohnson, WeiqiLi
Journal: Circulation (2015)

Background: Epidemiologic data on the association between body mass index (BMI) and heart failure (HF) risk among diabetic patients is rare. Aim: To investigate the association between BMI and HF risk among patients with type 2 diabetic in the Louisiana State University Hospital-based Longitudinal study (LSUHLS). Methods: We performed a prospective cohort study of risk for HF among 31,155 patients of type 2 diabetes (11,468 men and 19,687 women). Cox proportional hazards regression models were used to estimate the association of different levels of BMI with HF risk. Results: During a mean follow-up of 7.8 years, 5,834 subjects developed HF (2,379 men and 3,455 women). The multivariable-adjusted (age, race, smoking, income and type of insurance) hazard ratios of HF associated with BMI levels (18.5-22.9, 23-24.9, 25-29.9 [reference group], 30-34.9, 35-39.9, and ≥40 kg/m2) at baseline were 0.95, 1.00, 1.00, 1.16, 1.64, and 2.02 (Ptrend <0.001) for men, and 1.16, 1.16, 1.00, 1.23, 1.55, and 2.01 (Pnon-linear ...
Gene Transfer of Dominant-Negative Mutants of Extracellular Signal–Regulated Kinase and c-Jun NH2-Terminal Kinase Prevents Neointimal Formation in Balloon-Injured Rat Artery
Authors: YasukatsuIzumi, ShokeiKim, MasashiNamba, HideoYasumoto, HitoshiMiyazaki, MasaakiHoshiga, YasufumiKaneda, RyuichiMorishita, YumeiZhan, HiroshiIwao
Journal: Circulation Research (2001)

Abstract—We previously reported that extracellular signal–regulated kinase (ERK) and c-Jun NH2-terminal kinase (JNK), belonging to mitogen-activated protein kinases, are rapidly activated in balloon-injured artery. Therefore, we examined the role of these kinase activations in neointimal formation by using an in vivo gene transfer technique. We made the dominant-negative mutants of ERK (DN-ERK) and JNK (DN-JNK) to specifically inhibit endogenous ERK and JNK activation, respectively. Before balloon injury, these mutants were transfected into rat carotid artery using the hemagglutinating virus of Japan liposome method. In vivo transfection of DN-ERK and DN-JNK significantly suppressed the activation of ERK and JNK, respectively, after balloon injury, confirming successful expression of the transfected genes. Neointimal formation at 14 and 28 days after injury was prevented by gene transfer of DN-ERK or DN-JNK. Furthermore, bromodeoxyuridine labeling index and total cell–counting analysis at 7 days showed th...
Abstract 2896: A genome-wide CRISPR/Cas9 pooled screen identifies EML4-ALK variant-specific synthetic lethal partners of HSP90 inhibitors
Authors: Marco P. Licciardello, Paul A. Clarke, Paul Workman
Journal: Cancer Research (2018)

Abstract The chromosomal rearrangement generating the EML4-ALK fusion protein occurs in 5–7% of patients with non-small-cell lung cancer (NSCLC). Distinct breakpoints give rise to variants with different EML4 fragments and an invariable ALK kinase domain. Patients treated with ALK tyrosine kinase inhibitors, such as crizotinib or alectinib, inevitably develop resistance to the drugs and need alternative therapies. EML4-ALK v1 and v3a/b, the most common variants of the fusion oncogene, display distinct cellular localization and different sensitivity to the inhibition of HSP90 chaperoning activity. In the clinic, HSP90 inhibitors have shown encouraging results in EML4-ALK+ NSCLC patients, but the responses have been heterogeneous. Currently, there is no EML4-ALK variant-based classification of patients and this might have contributed to confounding results in clinical trials. Moreover, the identification of additional biomarkers of sensitivity could further improve patient stratification and suggest potential combinatorial regimes. As chaperones are molecular hubs enriched for synthetic lethal partners, we performed a CRISPR/Cas9-based pooled screen in human NSCLC cell lines carrying different EML4-ALK variants in the presence of non-lethal concentrations of an HSP90 inhibitor. In the screen, we found already described as well as previously unreported EML4-ALK variant-specific synthetic lethal interactions. We are currently dissecting the mechanism behind these interactions, and evaluating their therapeutic potential for EML4-ALK+ NSCLC patients. Citation Format: Marco P. Licciardello, Paul A. Clarke, Paul Workman. A genome-wide CRISPR/Cas9 pooled screen identifies EML4-ALK variant-specific synthetic lethal partners of HSP90 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 2896.
Abstract 55: Intrinsic molecular characteristics of bone marrow-disseminated tumor cells
Authors: Manabu Maeshiro, Satoru Shinriki, Takuya Nakamura, Hirofumi Jono, Hideki Nakayama, Yukio Ando, Hirotaka Matsui
Journal: Cancer Research (2018)

Abstract Dormant or slow-cycling disseminated tumor cells (DTC) in bone marrow (BM) are known to persist in patients with various types of cancer including head and neck squamous cell carcinoma (HNSCC). BM-DTC has been thought to have possible metastatic stem cell traits although functional and clonal analysis of BM-DTC remain elusive. Recently, we reported that the intrinsic TGF-β2-triggered SDF-1-CXCR4 signaling axis was crucial for drug resistance dependent on a slow-cycling state in BM-DTC but not in lung metastatic cells. This study aimed to elucidate intrinsic molecular characteristics in BM-DTC. We used the human HNSCC cell line HEp3-originated sublines [i.e. parental line (P-HEp3), BM-DTC-derived (BM-HEp3), and lung metastases-derived sublines (Lu-HEp3)]. Our transcriptome analyses for these sublines revealed that slow-cycling and drug-resistant BM-HEp3 cells had unique gene expression signatures. In addition, our investigation for phosphorylation of 39 kinases associated with tumor progression showed enhanced activation of only Src in BM-HEp3 compared with P- and Lu-HEp3. Importantly, Src inhibition by dasatinib in these sublines led to a remarkable reduction in cell viability only in BM-HEp3. These data suggest that intrinsic molecular characteristics of BM-DTC are distinct from primary and lung metastatic tumor cells. Src activation may be important for survival of dormant or slow-cycling BM-DTC. Further studies should contribute to better understanding of biology of minimal residual disease in BM and metastatic initiation. Citation Format: Manabu Maeshiro, Satoru Shinriki, Takuya Nakamura, Hirofumi Jono, Hideki Nakayama, Yukio Ando, Hirotaka Matsui. Intrinsic molecular characteristics of bone marrow-disseminated tumor 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 55.
A Polysome-Based microRNA Screen Identifies miR-24-3p as a Novel Promigratory miRNA in Mesothelioma
Authors: Stefania Oliveto, Roberta Alfieri, Annarita Miluzio, Alessandra Scagliola, Raissa S. Secli, Pierluigi Gasparini, Stefano Grosso, Luciano Cascione, Luciano Mutti, Stefano Biffo
Journal: Cancer Research (2018)

Abstract The expression of miRNAs in cancer has been widely studied and has allowed the definition of oncomirs and oncosuppressors. We note that it is often underestimated that many mRNAs are expressed, but translationally silent. In spite of this, systematic identification of miRNAs in equilibrium with their target mRNAs on polysomes has not been widely exploited. To identify biologically active oncomirs, we performed a screen for miRNAs acting on the polysomes of malignant mesothelioma (MPM) cells. Only a small percentage of expressed miRNAs physically associated with polysomes. On polysomes, we identified miRNAs already characterized in MPM, as well as novel ones like miR-24-3p, which acted as a promigratory miRNA in all cancer cells tested. miR-24-3p positively regulated Rho-GTP activity, and inhibition of miR-24-3p reduced growth in MPM cells. Analysis of miR-24-3p common targets, in two mesothelioma cell lines, identified a common subset of downregulated genes. These same genes were downregulated during the progression of multiple cancer types. Among the specific targets of miR-24-3p was cingulin, a tight junction protein that inhibits Rho-GTP activity. Overexpression of miR-24-3p only partially abrogated cingulin mRNA, but completely abrogated cingulin protein, confirming its action via translational repression. We suggest that miR-24-3p is an oncomir and speculate that identification of polysome-associated miRNAs efficiently sorts out biologically active miRNAs from inactive ones. Significance: Subcellular localization of miRNAs may predict their role in cancer and identify novel oncogenic miRNAs involved in cancer progression. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/20/5741/F1.large.jpg. Cancer Res; 78(20); 5741–53. ©2018 AACR.