tbuckley/cabot-search huggingface dataset:
Abstract 16430: Early Urine Sodium Response After Ambulatory Diuretic Bolus to Avoid Heart Failure Hospitalization
Authors: LauraBurpee, AkshayDesai, JenniferSmallwood, MichelleYoung, LynneStevenson, IreneCooper, KristinaNavarro-Velez, ElaineShea, CraigStevens, CindyWeiffenbach, JoanneWeintraub, MandeepMehra
Journal: Circulation (2014)

Introduction: Ambulatory heart failure management may increasingly include administration of intravenous diuretics in an outpatient setting, but it is difficult to know when response will be adequate to avoid hospitalization. Hypothesis: We assessed whether a high initial urine sodium (Na) after an intravenous diuretic bolus would predict net urine output > 1 liter after 3 hours of diuretic infusion, performed in an ACTIVE (Ambulatory Cardiac Triage, InterVention, and Education) unit where a nurse and pharmacist also provided heart failure education. Methods and Results: The unit accepted patients with chronic heart failure referred with symptomatic fluid overload without severe decompensation, and prescribed loop diuretic bolus and infusion dosed from an internal algorithm based on daily oral dose. Urine output was > 1 liter after 3 hours in 77% of patients with urine Na response > 100 mmol/L, in 69% with urine Na 61-100, and only 23% with initial urine Na < 60 mmol/L. Baseline renal function was better ...
Abstract 1444: RhoC regulation of inflammatory breast cancer metabolism
Authors: Laura E. Goo, Joel A. Yates, Liwei Bao, Zhifen Wu, Sofia D. Merajver
Journal: Cancer Research (2018)

Abstract Inflammatory breast cancer (IBC) is an extremely aggressive and lethal type of cancer due to its ability to rapidly metastasize. Our previous reports have shown that the metabolic characteristics of IBC are altered from those of normal breast epithelial cells. Specifically, the levels of the metabolite N-acetylaspartate (NAA) are very high in the IBC-derived triple negative cell line SUM149 relative to the triple negative cancer cell line MDA-MB-231. Recent studies have also correlated high levels of tumoral NAA with significantly lower survival rates in ovarian cancer. N-acetylaspartate (NAA) is the second most abundant metabolite in the brain, only exceeded by glutamate. NAA is synthesized from aspartate and acetyl-CoA by the enzyme Asp-NAT, which is encoded for by the gene NAT8L. The catabolism of NAA to aspartate and acetate is carried out by the enzyme aspartoacyclase (ASPA). In the central nervous system (CNS), altered levels of NAA have been historically used as a marker for neurodegenerative diseases such as Canavan disease, a fatal genetic disorder caused by a deleterious mutation in the ASPA gene. However, the fundamental role of NAA, especially in the context of cancer remains elusive. We seek to understand and describe the role of NAA in the adapted metabolic pathways of inflammatory breast cancer that enable proliferation and metastasis of the disease. Our previous work revealed that the pro-metastatic small GTPase RhoC acts as a regulator of NAA metabolism in SUM149 cells. Knockdown of RhoC using shRNA significantly decreases NAT8L expression. RhoC and RhoA knockout cell lines have been generated using CRIPSR-Cas9 in both SUM149 and MDA-MB-231 cells to further distinguish the relationship between NAA and RhoC in these different cell lines. We have conducted metabolic studies to determine the relative abundance of common metabolites, including NAA, throughout glycolysis, the pentose-phosphate pathway, and the tricarboxylic acid cycle. We have performed similar metabolomics using xenograft mice implanted with these CRISPR knockout cell lines to determine in vivo recapitulation of the NAA phenotypes. Our work ultimately hopes to identify promising therapeutic pathways of NAA as well as further characterize NAA's role as a potential oncometabolite. Citation Format: Laura E. Goo, Joel A. Yates, Liwei Bao, Zhifen Wu, Sofia D. Merajver. RhoC regulation of inflammatory breast cancer 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 1444.
Abstract 588: Neutrophil to lymphocyte ratio as strongest predictor of early death in metastatic triple negative breast cancer
Authors: Gabriel A. De la Cruz Ku, Zaida Morante, Joseph Pinto, Jhajaira Araujo, Daniel Enriquez, Eduardo Eyzaguirre, Antonella Saavedra, Maria Lujan, Renato Luque, Cesar Rázuri, Hugo Fuentes, Silvia Neciosup, Henry Gómez Moreno
Journal: Cancer Research (2018)

Abstract Background: Metastatic triple-negative breast cancer (mTNBC) is a heterogeneous disease with poor prognosis where recent studies suggest that the immune system plays a critical role the mechanisms of disease progression and metastasis. In the other hand, a high Neutrophil to Lymphocyte Ratio (NLR) is associated with poor survival in patients diagnosed with several types of cancer. Our aim was to evaluate the prognostic value of NLR in mTNBC. Methods: We retrospectively reviewed 130 patients diagnosed with mTNBC between 2000-2014 at “Instituto Nacional de Enfermedades Neoplasicas”. NLR group was divided in &amp;lt;2.5 and ≥2.5. Sites of metastasis were identified by TAC or magnetic resonance imaging. Survival rates were estimated by the Kaplan-Meier method and differences were calculated by Log-rank test. The Cox Regression was used for prognostic factors. Results: The median age was 50 years (range: 23-92 years). From our study population, 41.2% were premenopausal, and just 10 patients (9.5%) had a breast-ovary cancer familiar background, 62.5% were diagnosed at clinical stage T3-T4 and 86.1% had lymph node involvement. From 130 patients, 41 and 64 had NLR &amp;lt;2.5 and ≥2.5, respectively, while there was no association between characteristics and NLR, only patients with malnutrition had NLR ≥2.5 (9.1% vs 40.8%, p=0.002) and solid organ involvement (62.4% vs 81.3%, p=0.04). Furthermore, lung and bone were the most frequent sites of metastasis. Those patients with lower ratio (&amp;lt;2.5) had better response to chemotherapy (p &amp;lt;0.001). With a median follow-up of 6.25 years, at 1-year OS was lower among patients with NLR ≥2.5 (59% vs 20%, HR: 2.77, 95%CI:1.77-4.33, p&amp;lt;0.001). In addition, at univariate analysis malnutrition also showed an impact on OS (HR: 1.79, 95%CI: 1.20-2.67, p=0.005). At multivariate analysis, between age, T stage, N stage, NLR and solid organ involvement, just NLR was the best and only predictor of worse OS (HR: 3.12, 95%CI:1.94-5.03, p&amp;lt;0.001). Conclusion: In mTNBC, an NLR ≥2.5 was a strong and accessible biomarker of poor OS. Lower values of NLR could help us to predict chemotherapy response. Citation Format: Gabriel A. De la Cruz Ku, Zaida Morante, Joseph Pinto, Jhajaira Araujo, Daniel Enriquez, Eduardo Eyzaguirre, Antonella Saavedra, Maria Lujan, Renato Luque, Cesar Rázuri, Hugo Fuentes, Silvia Neciosup, Henry Gómez Moreno. Neutrophil to lymphocyte ratio as strongest predictor of early death in metastatic triple negative 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 588.
Enhanced autophagy contributes to protective effects of IL-22 against acetaminophen-induced liver injury
Authors: Ruidong Mo, Rongtao Lai, Jie Lu, Yan Zhuang, Tianhui Zhou, Shaowen Jiang, Peipei Ren, Ziqiang Li, Zhujun Cao, Yuhan Liu, Lichang Chen, Lifu Xiong, Peng Wang, Hui Wang, Wei Cai, Xiaogang Xiang, Shisan Bao, Qing Xie
Journal: Theranostics (2018)

Acute or acute-on-chronic liver failure is a leading cause of death in liver diseases without effective treatment. Interleukin-22 (IL-22) is currently in clinical trials for the treatment of severe alcoholic hepatitis, but the underlying mechanisms remain to be explored. Autophagy plays a critical role in alleviating liver injury. The aim of the current study is to explore the role of autophagy in IL-22-mediated hepato-protective effect against acetaminophen (APAP)-induced liver injury. Methods: A model of acute liver injury induced by APAP was used in vivo. IL-22 was administrated to the APAP-treated mice. Hepatocytes were pre-incubated with IL-22, followed by exposure to APAP for in vitro analyses. Results: IL-22 administration significantly reduced serum ALT and AST, hepatic reactive oxygen species, and liver necrosis in APAP-challenged mice. APAP treatment increased hepatic autophagosomes, which was further intensified by IL-22 co-treatment. Hepatic LC3-II was moderately upregulated after APAP administration without obvious alteration of phosphorylation of AMP-activated kinase (p-AMPK). IL-22 pretreatment significantly upregulated hepatic LC3-II and p-AMPK in APAP-treated mice. IL-22 also alleviated APAP-induced cytotoxicity and upregulated LC3-II and p-AMPK expression in cultured hepatocytes treated with APAP in vitro. When p-AMPK was blocked with compound C (an AMPK inhibitor), IL-22-mediated LC3-II conversion and protection against APAP-induced cytotoxicity was weakened. Conclusions: Enhanced AMPK-dependent autophagy contributes to protective effects of IL-22 against APAP-induced liver injury.
AB1301 Cardiovascular risk age and vascular age estimations in predicting cardiovascular events in rheumatoid arthritis patients
Authors: G. Wibetoe, J. Sexton, E. Ikdahl, S. Rollefstad, G. Kitas, P. van Riel, S. Gabriel, T.K. Kvien, K. Douglas, A. Sandoo, E.E. Arts, S. Wållberg-Jonsson, S. Rantapää Dahlqvist, G. Karpouzas, P.H. Dessein, L. Tsang, H. El-Gabalawy, C.A. Hitchon, V. Pascual-Ramos, I. Contreas-Yaňes, P.P. Sfikakis, M.A. González-Gay, I.J. Colunga-Pedraz, D.A. Galarza-Delgado, J.R. Azpiri-Lopez, C.S. Crowson, A.G. Semb
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Rheumatoid arthritis (RA) patients are at high risk of cardiovascular disease (CVD). Risk age estimations are recommended as adjuncts to assessment of absolute 10 year risk of fatal CVD events. Two risk age models based on the Systematic Coronary Risk Evaluation (SCORE) algorithm have been developed; the cardiovascular risk age and the vascular age. <h3>Objectives</h3> We aimed to compare the discriminative ability of cardiovascular risk age and vascular age among RA patients and in subgroups of RA patients. <h3>Methods</h3> Patients with RA were included from an international consortium, aged 30–70 years at baseline. Those with prior CVD, diabetes and/or users of lipid-lowering and/or antihypertensive therapy at baseline were excluded. Cardiovascular risk age was estimated based on chronologic age, smoking status, total cholesterol and systolic blood pressure at baseline. Vascular age was derived from the 10 year risk of CVD according to the SCORE algorithm, with or without high density lipoprotein cholesterol, using the equations for low and high risk countries. Performance of each risk age model in predicting CVD events was assessed by c-statistics. <h3>Results</h3> <sup>Among 1867</sup> patients included, 74% were female, median (inter-quartile range) age and disease duration were 52.0 (44.0, 59.9) and 0.6 (0.1, 6.4) years, 72.5% were rheumatoid factor positive, 24.7% were using glucocorticoids and 10.3% were using biologics at baseline. Overall, 144 CVD events occurred. Median follow-up time was 5.0 (2.6, 9.3) years. C-indices across risk models ranged from 0.71 to 0.73 with standard errors of 0.03. Across prediction models, the lowest observed concordance was found among women and in glucocorticoid users and in those with new-onset disease (≤1 year). Additional analyses including RA patients on cardio preventive therapy yielded slightly lower c-indexes. Since SCORE was developed for use in Europe, we performed analyses on European RA patients, which yielded similar results. Certain characteristics were associated with low concordance, but standard errors were high (data not shown). <h3>Conclusions</h3> The cardiovascular risk age and vascular age models have comparable performance in predicting CVD in RA patients. The influence of RA disease characteristics on the predictive ability of these prediction models remains inconclusive. <h3>Disclosure of Interest</h3> None declared
Abstract 5853: Targeting NAD+/PARP DNA repair pathway as a novel therapeutic approach to <i>SDHB</i>-mutated cluster I pheochromocytoma and paraganglioma
Authors: Ying Pang, Yanxin Lu, Veronika Caisova, Yang Liu, Petra Bullova, Thanh-Truc Huynh, Zdenek Frysak, Igor Hartmann, David Taïeb, Karel Pacak, Chunzhang Yang
Journal: Cancer Research (2018)

Abstract Background: Cluster I pheochromocytomas and paragangliomas (PCPGs) tend to develop malignant transformation, tumor recurrence, and multiplicity. Transcriptomic profiling suggests that cluster I PCPGs and other related tumors exhibit distinctive changes in the tricarboxylic acid (TCA) cycle, the hypoxia signaling pathway, mitochondrial electron transport chain, and methylation status, suggesting that therapeutic regimen might be optimized by targeting these signature molecular pathways. Experimental design: We investigated molecular signatures in clinical specimens from cluster I and II PCPGs, with a focus on the therapeutic resistance mechanisms. Further, we tested the applicability of a combination therapy including an FDA approved PARP inhibitor olaparib (Ola) and temozolomide (TMZ) in both in vitro cellular model and an in vivo allograft animal model. Results: Our findings showed that cluster I PCPGs develop a distinctive dependency on mitochondrial complex I, evidenced by the upregulation of complex I components and enhanced NADH dehydrogenation. Mechanistically, alteration in mitochondrial function resulted in strengthened NAD+ metabolism, which provides essential cofactor for PARP catalytic activity, prompting base excision repair and chemo resistance. Combining PARP inhibitor Ola with TMZ not only improved cytotoxicity but also reduced metastatic lesions, with prolonged overall survival in a mouse model with PCPG allograft. Conclusions: Our results suggest that the NAD+/PARP pathway is a crucial targetable therapeutic resistance mechanism in SDHB-mutated PCPG. Combination therapy using TMZ and Ola could become an effective strategy against these and other advanced cluster I tumors. Disclosure Statement: The authors have nothing to disclose. Citation Format: Ying Pang, Yanxin Lu, Veronika Caisova, Yang Liu, Petra Bullova, Thanh-Truc Huynh, Zdenek Frysak, Igor Hartmann, David Taïeb, Karel Pacak, Chunzhang Yang. Targeting NAD+/PARP DNA repair pathway as a novel therapeutic approach to SDHB-mutated cluster I pheochromocytoma and paraganglioma [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 5853.
Abstract 2351: Transcriptome-wide association study reveals candidate causal genes for lung cancer
Authors: Alisson Clemenceau, Maxime Lamontagne, Robert Carreras Torres, Ma'en Obeidat, Wim Timens, Philippe Joubert, Christopher I. Amos, James D. McKay, Yohan Bossé
Journal: Cancer Research (2018)

Abstract Genome-wide association studies have identified robust susceptibility loci associated with lung cancer. As part of the OncoArray-TRICL consortium, we have recently completed the largest GWAS on lung cancer including 29,266 cases and 56,450 controls of European descent. The goal of this study is to integrate the complete GWAS results with a large-scale expression quantitative trait loci (eQTL) mapping study in human lung tissues (n=1,038) to identify candidate causal genes for lung cancer. Transcriptome-wide association study (TWAS) was used to integrate GWAS and lung eQTL signals and identify genes whose levels of expression in lung tissue are causally related to lung cancer. TWAS was performed on six histologic and smoking subgroups, namely overall lung cancer, adenocarcinoma, squamous cell carcinoma, small cell carcinoma, never-smokers, and ever-smokers. As expected, the main TWAS signal for all histologic subtypes and ever-smokers was on chromosome 15q25. The genes most strongly associated with lung cancer at this locus were IREB2 (PTWAS=4.97E-104), and to a lower extent, CHRNA5 (PTWAS=5.26E20) and HYKK (PTWAS=2.04E-17). TWAS identified causal genes were different from those reported in GWAS, including JAML on 11q23.3 in overall lung cancer (PTWAS=1.39E-6) and adenocarcinoma (PTWAS=2.09E-8), NOTCH4 on 6p21.32 in squamous cell carcinoma (PTWAS=1.24E-12), ZNRD1 on 6p22.1 in overall lung cancer (PTWAS=3.41E-14) and ever-smokers (PTWAS=1.29E-9), HIST1H2BD on 6p22.2 for small cell carcinoma (PTWAS=1.54E-6), and NEXN on 1p31.1 in never-smokers (PTWAS=2.64E-5). In addition, a new small cell carcinoma susceptibility locus was identified on 4q32.2 and associated with the expression levels of TMA16 (PTWAS=4.2E-6). In conclusion, lung tissue TWAS on lung cancer, histologic subtypes and smoking subgroups revealed novel causal genes in GWAS-nominated loci. A new locus for small cell carcinoma (4q32.2-TMA16) was also identified and will require further validation. Citation Format: Alisson Clemenceau, Maxime Lamontagne, Robert Carreras Torres, Ma'en Obeidat, Wim Timens, Philippe Joubert, Christopher I. Amos, James D. McKay, Yohan Bossé. Transcriptome-wide association study reveals candidate causal genes for lung 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 2351.
Abstract 14453: Multi-institutional Implementation of a Novel Tablet-Based Platform for Home Monitoring Infants With Single Ventricle Cardiac Disease: Cardiac High Acuity Monitoring Program (CHAMP)
Authors: Matthew D Files, Kendra Waldburger, Lori Erickson, John Apperson, Richard Stroup, Amy Ricketts, Bryan Beaven, Suma Goudar, Amy S Lay, Girish Shirali
Journal: Circulation (2016)

Introduction: Infants with single ventricle cardiac disease require a series of palliative surgeries culminating in Fontan circulation. The “interstage period” between the first and second surgeries is characterized by medical fragility with mortality rates of 2-20%. Most programs use paper-based home monitoring to improve survival and growth, and to alert families and care teams to physiologic compromise. However, paper-based monitoring places the burden on families to report their child’s clinical status. Hypothesis: We hypothesized that mobile technology could alert the care team more rapidly, and that short videos would provide additive clinical data. After CHAMP was implemented locally, we hypothesized that multi-institutional implementation of CHAMP would require significant restructuring of the care teams to ensure appropriate responsiveness to instant alerts, videos and clinical concerns. Methods: The CHAMP platform was constructed for multi-center deployment using the Microsoft Azure cloud in a H...
Abstract 4028: Molecular mechanisms of magnolin resistance in ovarian cancer cells
Authors: Sun-Mi Yoo, Cheol-Jung Lee, Seung-Min Kim, Seon-Yeon Cho, Juhee Park, Yong-Yeon Cho
Journal: Cancer Research (2018)

Abstract Mitogen-activated protein kinase (MAPK) and PKB signaling pathways are highly activated in many human solid cancers and play a key role in carcinogenesis, tumor growth and cancer cell survival. Although regulation mechanisms of each signaling pathway are well-elucidated, interrelationship between both signaling pathways in cancer growth has not been understood. In this study, we found that magnolin, ERK1 and ERK2 inhibitor with 16 nM and 68 nM of IC50 value, suppressed cell proliferation and colony growth of ovarian cancer cells. In signaling pathway analysis, we found that TOV-112 and SKOV3 showed differential responsiveness by EGF stimulation. The differential responsiveness was caused by differential activation signaling through MAPK and PKB signaling pathway. Notably, TOV-112D sensitized by magnolin treatment in cell proliferation and colony growth in soft agar by alteration of cell cycle regulation, but not in SKOV3 cells. Notably, phosphorylation of ATF-1, a downstream target of RSK2, at Ser63 was inhibited in TOV-112 by magnolin treatment, resulted in cellular senescence. However, SKOV3 was vice versa. We further found that magnolin fraction suppressed TOV-112D cancer growth in xenograft animal model. Taken together, we concluded that signaling alteration might involve in magnolin resistance in SKOV3. Keywords: MAP kinase, molecular targets, ovarian cancer, cancer growth Citation Format: Sun-Mi Yoo, Cheol-Jung Lee, Seung-Min Kim, Seon-Yeon Cho, Juhee Park, Yong-Yeon Cho. Molecular mechanisms of magnolin resistance in ovarian 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 4028.
Abstract 2600: Resistance biomarkers in patients with head and neck squamous cell carcinoma treated with cetuximab
Authors: Maud Kamal, Olivia Leblanc, Sophie Vacher, Charlotte Lecerf, Emmanuelle Jeannot, Jerzy Klijanienko, Frederique Berger, Caroline Hoffmann, Valentin Calugaru, Nathalie Badois, Anne Chilles, Maria Lesnik, Samar Krhili, Thomas Jouffroy, Ivan Bieche, Christophe Le Tourneau
Journal: Cancer Research (2018)

Abstract BACKGROUND: Cetuximab, a monoclonal antibody targeting EGFR, improves overall survival in the locally advanced setting in combination with radiotherapy and in first-line recurrent setting in combination with chemotherapy in HNSCC patients. No predictive biomarker of efficacy of cetuximab in these settings. We aimed at identifying biomarkers of sensitivity/resistance to cetuximab. PATIENTS AND METHODS: HNSCC patients treated with cetuximab at Institut Curie, for which complete clinicopathological data and formalin-fixed, paraffin-embedded (FFPE) tumor tissue were available and collected before cetuximab treatment, were included in this retrospective study. Immunohistochemistry analyses of PTEN and EGFR were performed to assess expression levels. PIK3CA and KRAS mutations were analyzed using high resolution melting (HRM) and Sanger sequencing. The predictive value of these alterations on progression-free survival (PFS) was evaluated. RESULTS: PIK3CA and KRAS/HRAS mutations were associated with poor PFS in HNSCC patients treated with cetuximab in first-line recurrence setting but not in patients treated with cetuximab in combination with radiotherapy. PTEN loss of expression had a negative prognostic impact in HNSCC patients treated with cetuximab and radiotherapy, while EGFR high expression was not found to be a sensitivity biomarker for cetuximab in our patient population. CONCLUSIONS: PIK3CA and RAS mutations were resistance biomarkers of cetuximab in first-line recurrent setting, whereas PTEN loss was a resistance biomarker of cetuximab when given in combination with radiotherapy. Citation Format: Maud Kamal, Olivia Leblanc, Sophie Vacher, Charlotte Lecerf, Emmanuelle Jeannot, Jerzy Klijanienko, Frederique Berger, Caroline Hoffmann, Valentin Calugaru, Nathalie Badois, Anne Chilles, Maria Lesnik, Samar Krhili, Thomas Jouffroy, Ivan Bieche, Christophe Le Tourneau. Resistance biomarkers in patients with head and neck squamous cell carcinoma treated with cetuximab [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 2600.