tbuckley/cabot-search huggingface dataset:
Predictors of the Long-Term Outcome After Combined Aortic and Mitral Valve Surgery
Authors: Juraj Turina, Thomas Stark, Burkhardt Seifert, Marko Turina
Journal: Circulation (1999)

Background —The influence of preoperative clinical, hemodynamic, and surgical procedures on long-term prognosis after combined aortic and mitral valve surgery is not well known. Methods and Results —One hundred seventy patients (mean age, 50.5 years; 102 men and 68 women) who underwent surgery for chronic combined aortic and mitral valvular disease between 1975 and 1989 were followed up for an average of 10.6 years. Additional repair of tricuspid valve was performed in 29 patients (17%), and aortocoronary bypass graft surgery was performed in 7 patients (4.1%). The perioperative mortality rate was 4%, and 10- and 20-year survival rates were 61% and 33%. Only 12 of 94 deaths (11%) were non–cardiac related. At 10 and 20 years, 57% and 21% of patients were free of reoperation, respectively. The main predictors of late survival in univariate analysis were age at surgery ( P =0.0002), preoperative left ventricular ejection fraction ( P =0.002), cardiac index ( P =0.007), tricuspid surgery ( P =0.03), pulmonary vascular resistance ( P =0.03), NYHA class ( P =0.04), and additional aortocoronary bypass graft surgery ( P =0.04). Duration of symptoms, gender, cause of valvular disease, and type of prosthesis were not predictive of postoperative outcome. In multivariate stepwise Cox analysis, ejection fraction ( P =0.0008), age at surgery ( P =0.0011), and tricuspid surgery ( P =0.007) were independent predictors of late survival. Conclusions —In combined aortic and mitral valve disease, preoperative myocardial function is the main predictor of long-term survival. Low operative mortality rates and good late outcome make valve replacement mandatory before deterioration of myocardial function occurs. Additional tricuspid valve disease requiring surgery significantly decreases the late survival rate.
Abstract 5608: Evaluation of retargeted T cell cytotoxicity of a bispecific antibody targeting CDH17 and CD3 in 2D- and 3D-colon cancer models
Authors: Macarena Irigoyen, Eric Dai, John Luk, Gonzalo Castillo, Don Staunton
Journal: Cancer Research (2018)

Abstract Cadherin-17 (CDH17) is an adhesion molecule that binds to self and integrin a2b1, its expression in the adult is limited to gastrointestinal tissue and is involved in cancer progression. CDH17 is expressed de novo or overexpressed in several gastro-intestinal cancers including colorectal, gastric and pancreatic, making it an ideal target for immunotherapies. A humanized bifunctional antibody was developed, ARB-201, that binds to both CDH17 and the CD3/TCR complex (CD3) with high affinity. ARB-201 induced retargeted T cell cytotoxicity was determined in a 2D and 3D model. Relative to 2D, cytotoxicity of 3D tumors may be considered more predictive of efficacy for solid tumors. DLD-1, a colorectal adenocarcinoma cell line, was targeted in the 2D and 3D T cell cytotoxicity assays. Pre-labeled DLD-1 were grown in standard 384-well microplate (2D) or Kuraray's 384-well Elplasia microplates (3D). Effector PBMCs, freshly isolated from healthy donors were added to the target DLD-1 cells containing a concentration response curve of ARB-201. Samples were evaluated for the specific cellular cytotoxicity using cell imaging. The results show at 48 hours an EC50 of 12 pM for 2D and 47 pM for the 3D model. ARB-201 induced potent T cell cytotoxicity of DLD-1. Although cytotoxicity in the 3D tumor model was relatively less, we observed an increase over time, demonstrating that ARB-201 progressively kills 3D tumor cells and possesses cytotoxic activity that may translate into clinical efficacy for solid tumors. Citation Format: Macarena Irigoyen, Eric Dai, John Luk, Gonzalo Castillo, Don Staunton. Evaluation of retargeted T cell cytotoxicity of a bispecific antibody targeting CDH17 and CD3 in 2D- and 3D-colon cancer models [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 5608.
Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations
Authors: Amit V. Khera, Mark Chaffin, Krishna G. Aragam, Mary E. Haas, Carolina Roselli, Seung Hoan Choi, Pradeep Natarajan, Eric S. Lander, Steven A. Lubitz, Patrick T. Ellinor, Sekar Kathiresan
Journal: Nature Genetics (2018)
Abstract 660: Integration of radiomics with "omic" analyses to predict survival in newly diagnosed IDH-1 wild-type glioblastoma
Authors: Paul M. Daniel
Journal: Cancer Research (2018)

Abstract Glioblastoma (GBM) is the most commonly diagnosed glioma and has the poorest median survival of all brain tumours at only 14 months. Despite intensive characterisation of this disease through ‘omic' investigations which has led to the identification of critical molecular drivers of malignancy, only a limited selection of biomarkers have proven to be clinically relevant in predicting patient survival. One reason for this lack of success is the existence of intratumoural heterogeneity, where individual tumours can harbour spatially separated molecular and phenotypic diversity, thereby limiting the insight which ‘omic' analysis of small biopsy specimens can impart. Radiomics involves high-throughput mining of quantitative image features via image acquisition, region of interest segmentation and feature extraction from standard MRI scans and relating extracted feature values to molecular, phenotypic and clinical properties. Notably, radiomics derives features from the whole tumour mass and therefore overcomes limitations associated with intratumoural heterogeneity. As such, we sought to investigate the ability for radiomics to describe tumour characteristics and integrate radiomics alongside genomics and transcriptomics to derive a prognostic model for IDH1 wild-type GBM. We observed 2 radiomic clusters in IDH1-wild-type GBM which each had an equivalent distribution of each of the four molecular subtypes. Whilst radiomic clusters themselves were not predictive of survival, three radiomic features were able to separate patients into long and short survival groups. Integration of genomic and transcriptomic features alongside radiomic analysis increased the predictive strength of our model. Finally, we found an association between longer survival in patients with IDH1 wild-type GBM and increased expression of the complement system. Our observations suggest that integration of radiomics alongside ‘omic' investigations offer a greater ability to predict survival in IDH1 wild-type GBM and suggests a role for the innate immune system in driving patient outcome. Citation Format: Paul M. Daniel. Integration of radiomics with "omic" analyses to predict survival in newly diagnosed IDH-1 wild-type glioblastoma [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 660.
Abstract 4797: In vitro and in vivo effect of ARQ 531 on Trk family kinases
Authors: Yi Yu, Gabi Schwartz, Pascal Schamber, Ron E. Savage, Sudharshan Eathiraj, Terence Hall, Brian Schwartz
Journal: Cancer Research (2018)

Abstract The tropomycin kinase (Trk) receptor family contain Trk A, B and C that are encoded by the NTRK1, NTRK2, and NTRK3 genes respectively. Trk family kinases have been shown to play a very important role in the development and physiological functions of the nervous system. Recently, chimeric Trk kinases resulted from gene fusions of NTRK genes are involved in initiation and progression of various cancers such as sarcoma, thyroid, salivary gland cancers, etc. Targeting such alteration of Trk family kinases becomes a new avenue for the therapeutic intervention. ARQ 531 has biochemical IC50 values of 1.3 nM, 1.8 nM and 1.8 nM for Trk A, B and C, respectively with targeting a unique set of other kinases. In a cell based assay, ARQ 531 inhibits kinase activity of Trk A, B and C in UOS2 cells overexpressing Trk family kinases with IC50 values of 50.5 nM, 28.0 nM and 4.1 nM respectively. Pathway analysis shows that ARQ 531 abolished autophosphorylation of TMP3-Trk A in colon cancer KM-12 cells after 2-hour treatment, concomitant with marked inhibition of pAKT, pERK and pPLCγ1. Moreover, in Trk A-overexpressing K562 cells, ARQ 531 suppressed phosphorylation of Trk A and its downstream targets AKT and MAPK. Anti-proliferative activity of ARQ 531 has been demonstrated in Ba/F3 system over-expressing fusion Tel-Trk family kinases (ETV6-NTRK1, 2 or 3), exhibiting IC50 value of 300, 481, and 341 nM for Tel-Trk A, B or C respectively. In TMP3-TrkA(TMP3-NTRK1) fusion-driven KM12 cells driven by ARQ 531 strongly suppressed cell proliferation with an IC50 value of 130 nM. Subsequently, apoptotic response was observed in KM-12 cells after treatment of ARQ 531 for 24 hours, which was demonstrated by the increase in cleaved PARP1 and cleaved caspase 3. Significant anti-tumor activity of ARQ 531 was observed in KM-12 xenograft mouse model. In conclusion, ARQ 531 is a potent Trk family kinase inhibitor and the results from preclinical study provides rationale for testing ARQ 531 in a clinical setting, particularly in cancers driven by Trk fusion kinases. Citation Format: Yi Yu, Gabi Schwartz, Pascal Schamber, Ron E. Savage, Sudharshan Eathiraj, Terence Hall, Brian Schwartz. In vitro and in vivo effect of ARQ 531 on Trk family kinases [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 4797.
Anthracycline Therapy Is Associated With Cardiomyocyte Atrophy and Preclinical Manifestations of Heart Disease
Authors: Thiago Ferreira de Souza, Thiago Quinaglia A.C. Silva, Felipe Osorio Costa, Ravi Shah, Tomas G. Neilan, Lício Velloso, Wilson Nadruz, Fabricio Brenelli, Andrei Carvalho Sposito, Jose Roberto Matos-Souza, Fernando Cendes, Otávio Rizzi Coelho, Michael Jerosch-Herold, Otavio Rizzi Coelho-Filho
Journal: JACC. Cardiovascular imaging (2018)
Biomatrix for upper and lower airway biomarkers in patients with allergic asthma
Authors: Ulrich M. Zissler, Moritz Ulrich, Constanze A. Jakwerth, Sandra Rothkirch, Ferdinand Guerth, Markus Weckmann, Matthias Schiemann, Bernhard Haller, Carsten B. Schmidt-Weber, Adam M. Chaker
Journal: Journal of Allergy and Clinical Immunology (2018)
Abstract 249: Genome-scale analysis of aberrant DNA methylation for emerging, high incidence of colorectal cancer in Taiwan
Authors: KuoHsing Chen, Liang-Chuan Lai, Hsien-Fang Chang, Yu-Liang Chao, Been-Ren Lin, Jin-Tung Liang, Ann-Lii Cheng, Eric Y. Chuang, Kun-Huei Yeh
Journal: Cancer Research (2018)

Abstract Background: The incidence of colorectal cancer (CRC) in Taiwan is increasing in decades, and the definite etiology remains elusive. This study aimed to explore the association of aberrant DNA methylations and the development of colorectal cancer in Taiwan. Materials and methods: We prospectively collected 27 CRC patients' tumors, the adjacent normal colons (frozen specimens), and clinical characteristics, including age, sex, body mass index (BMI), stage at diagnosis and medical history of diabetes mellitus and hyperlipidemia. We conducted a genome-scale analysis of DNA methylation in these 27 CRC and 5 adjacent normal colon samples by using Illumina Methylation EPIC Beadchips. We used Wilcoxon rank-sum test (p &amp;lt; 0.05) and β value difference (≧ 0.25 or ≦ -0.25) to evaluate the methylation differences between CRC and adjacent normal colon samples. Results: Overall, 7,672 differentially methylated genes (DMGs) were found between 27 CRCs and 5 adjacent normal colons. Principle component analysis demonstrated that a distinct cluster of adjacent normal colon and CRC tissue samples. Pathway analysis (β value difference ≧ 0.4 or ≦ -0.4) showed that ERK/MAPK signaling, GP6 signaling, CREB signaling in neurons, CDK5 and IGF-1 pathways were the top 5 pathways that were involved by DMGs. Subgroup analysis revealed most DMGs (N = 5,228) are shared by all 3 subgroups, however, patients who had metabolic syndrome had fewest subgroup-specific DMGs between tumors and adjacent normal colons, compared to patients who had no metabolic syndrome with normal weight or overweight (BMI &amp;lt; 25 or ≧ 25). Conclusion: We demonstrated a genome-scale difference of aberrant DNA methylation in colorectal cancer in an East Asian population. These data will be validated further in a larger cohort. Citation Format: KuoHsing Chen, Liang-Chuan Lai, Hsien-Fang Chang, Yu-Liang Chao, Been-Ren Lin, Jin-Tung Liang, Ann-Lii Cheng, Eric Y. Chuang, Kun-Huei Yeh. Genome-scale analysis of aberrant DNA methylation for emerging, high incidence of colorectal cancer in Taiwan [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 249.
Abstract 4728: Iron regulation of innate immune pathogen-associated molecular pattern receptors
Authors: Evan Stater
Journal: Cancer Research (2018)

Abstract Pathogen-associated molecular pattern (PAMP) receptors are key triggers of the pro-inflammatory immune effector functions of the cells of the innate immune system. Ectopic PAMP activation is a contributing factor to both cancer development and pathology, as well as host anti-tumor immune responses. Iron, an essential mineral in biological systems, has a similar dualistic role in cancer. We have shown that iron acts as a key modulator of intracellular signaling cascades downstream from PAMP activation. Cellular iron enrichment enhances the transcriptional activity of a pathogen-induced transcription factor downstream of PAMPs in an immortalized human macrophage cell line treated with a PAMP receptor-specific agonist ligand. Cell surface expression of the receptor was not affected by the iron enrichment; therefore, any modulation of receptor signaling by iron is likely downstream of the receptor. Furthermore, iron supplementation in vitro increases expression of immunity-related genes regulated by the pathogen-induced transcription factor; by contrast, treatment with iron-chelating reagents reduces expression of these genes. These results suggest that the iron content of the tumor microenvironment may have a regulatory role in pathological immunoregulation. In particular, the iron-retaining phenotype of many tumor cells may serve a novel pathological function, inhibiting PAMP-regulated anti-tumoral effector functions of tumor-infiltrating macrophages cells by iron deprivation. Citation Format: Evan Stater. Iron regulation of innate immune pathogen-associated molecular pattern receptors [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 4728.
Depth of Propofol Sedation and Postoperative Delirium
Authors: Elizabeth L. Whitlock, Emily Finlayson
Journal: JAMA Surgery (2018)

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Abstract 5713: Promising predictive biomarkers for immunotherapy in metastatic melanoma
Authors: Marta Nyakas, Elin Aamdal, Tormod Guren, Steinar Aamdal, Kari Dolven Jacobsen, Paal Brunsvig, Kristin Austlid Tasken, Gunhild Mælandsmo, Arne Yndestad, Bente Halvorsen, Paal Aukrust, Thor Ueland
Journal: Cancer Research (2018)

Abstract Aim: to explore biomarkers in order to predict outcome in patients with metastatic melanoma who have had immunotherapy with ipilimumab in a real-world setting. Metastatic melanoma is a very aggressive, incurable cancer with historically few therapeutic options and poor survival. Immunotherapy represents a revolution for metastatic melanoma treatment but there is a lack of biomarkers to predict treatment response. Material and methods: In the Norwegian National Phase 4 Multicenter Study, IPI4, 150 patients were included to receive ipilimumab (anti-CTLA3). A subgroup of 73 patients (4 screening failure) was included at Oslo University Hospital -The Norwegian Radium Hospital. Serum was available from 56 patients of this subgroup and were examined before and during ipilimumab treatment concerning possible predictive biomarkers. Expression of a panel of 17 inflammatory markers reflecting different inflammatory pathways including extra cellular matrix remodeling and fibrosis, vascular inflammation, notch signaling, inflammation in general and monocyte/macrophage activation were measured at baseline and at the 2nd and/or 3rd treatment with ipilimumab. Results: During an average 33.7 months follow-up, 33 (59%) patients died. Six promising candidates (endostatin, osteoprotegerin, C-reactive protein, pulmonary and activation-regulated chemokine and galectin-3 binding-protein) were higher in non-survivors. In particular, high endostatin and galectin-3 binding protein levels were independently associated with poor long time survival also in adjusted analysis (age, gender, lactate dehydrogenase). A 1 standard deviation (SD) increase in Gal3BP gave a 1.8 x times higher risk of death (95% CI 1.10-2.95, p=0.019) while a 1 SD increase in endostatin was associated with a 2x higher risk of death (95% CI 1.12-3.64, p=0.020) in the final model. Conclusion: Endostatin and galectin-3 binding protein may represent biomarkers for prognosis during immunotherapy with ipilimumab and should be further evaluated. Citation Format: Marta Nyakas, Elin Aamdal, Tormod Guren, Steinar Aamdal, Kari Dolven Jacobsen, Paal Brunsvig, Kristin Austlid Tasken, Gunhild Mælandsmo, Arne Yndestad, Bente Halvorsen, Paal Aukrust, Thor Ueland. Promising predictive biomarkers for immunotherapy in metastatic melanoma [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 5713.
Abstract A67: Effects of the atypical PKC-ι inhibitor ICA-1 on ovarian cancer proliferation and survival
Authors: Tracess Smalley, Mildred Acevedo-Duncan
Journal: Clinical Cancer Research (2018)

Abstract Ovarian cancer is the most lethal gynecologic cancer diagnosis. There is no efficient screening process for ovarian cancers and the average stage of diagnosis is stage III. Atypical PKCs (PKC-ζ and PKC-ι/λ) have been shown to be overexpressed in various malignant cells lines and to be linked to pathways for cellular proliferation and survival. Estrogen is also highly linked to carcinogenesis. In this investigation, ovarian cell lines (HEY, COV644, T80) were treated with the atypical PKC-ι inhibitor ICA-1 in two different systems, with and without estrogen, and assayed to determine the effects on proliferation and cellular survival. These assays included protein quantification, cell proliferation, and wound healing. Our preliminary data suggest that PKC-ι is a novel target in carcinogenesis and inhibition of this protein decreases the rate of proliferation. Our results also suggest that estrogen has a great effect on cell proliferation, even in estrogen receptor-negative cells. Citation Format: Tracess Smalley, Mildred Acevedo-Duncan. Effects of the atypical PKC-ι inhibitor ICA-1 on ovarian cancer proliferation and survival. [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 A67.
NSun2 Deficiency Protects Endothelium From Inflammation via mRNA Methylation of ICAM-1
Authors: YuhongLuo, JuanFeng, QingboXu, WengongWang, XianWang
Journal: Circulation Research (2016)

Rationale:Vascular endothelial inflammation, including the expression of intercellular adhesion molecule 1 (ICAM-1), is a key event in vascular diseases. However, the mechanisms underlying the regulation of ICAM-1 are largely unknown. Objective:To investigate the mechanisms on the regulation of ICAM-1 by NOP2/Sun domain family, member 2 (NSun2)-mediated mRNA methylation and the impact of NSun2–ICAM-1 regulatory process in vascular inflammation and allograft arteriosclerosis. Methods and Results:By using in vitro, in cells, and in vivo methylation assays, we showed that the tRNA methyltransferase NSun2 methylated the ICAM-1 mRNA. Methylation by NSun2 promoted the translation of ICAM-1, thereby increasing the adhesion of leukocytes to endothelial cells. Tumor necrosis factor-α or homocysteine activated the methyltransferase activity of NSun2 by repressing the phosphorylation of NSun2 by Aurora-B. The levels of ICAM-1 induction and of leukocyte adhesion to vascular endothelium observed with homocysteine trea...
Abstract 2668: Regio- and stereospecific synthesis of oridonin D-ring aziridinated analogues for the treatment of triple-negative breast cancer via mediated irreversible covalent warheads
Authors: Ye Ding, Dengfeng Li, Chunyong Ding, Zhiqing Liu, Eric A. Wold, Na Ye, Haiying Chen, Mark A. White, Qiang Shen, Jia Zhou
Journal: Cancer Research (2018)

Abstract The covalent drugs dramatically resurge in recent years due to the comprehensive optimization of the structure-activity relationship (SAR) and structure-reactivity relationship (SRR). Natural product oridonin with an impressive pharmacological profile through its covalent enone warhead on the D-ring has attracted substantial SAR studies to appreciate its potential in the development of new molecular entities for the treatment of various human cancers and inflammation. Herein, for the first time we report the excessive reactivity of this covalent warhead and mediation of the covalent binding capability through a Rh2(esp)2-catalyzed mild and concise regio- and stereospecific aziridination approach. Intriguingly, new analogue YD0514 with a more drug-like irreversible covalent warhead has been identified to significantly induce apoptosis and inhibit colony formation against triple-negative breast cancer with comparable to enhanced antitumor effects in vitro and in vivo, while displaying lower toxicity to normal human mammary epithelial cells in comparison with oridonin. Citation Format: Ye Ding, Dengfeng Li, Chunyong Ding, Zhiqing Liu, Eric A. Wold, Na Ye, Haiying Chen, Mark A. White, Qiang Shen, Jia Zhou. Regio- and stereospecific synthesis of oridonin D-ring aziridinated analogues for the treatment of triple-negative breast cancer via mediated irreversible covalent warheads [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 2668.