tbuckley/cabot-search huggingface dataset:
Abstract 2212: Risk prediction for Barrett's esophagus and esophageal adenocarcinoma: Incorporation of epidemiologic risk factors and 23 confirmed genetic loci
Authors: Jing Dong, Aaron Thrift
Journal: Cancer Research (2018)

Abstract Background &amp; Aims: We developed comprehensive risk prediction models for Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC) that incorporate a polygenic risk score (PRS) and non-genetic factors. Methods: We used pooled data from 3,288 BE, 2,511 EAC, and 2,177 controls from BEACON, the United Kingdom Barrett's Esophagus Gene Study, and United Kingdom Stomach and Oesophageal Cancer Study. A PRS was created from 23 BE/EAC risk loci. We developed and compared risk models with various combinations of non-genetics factors and the PRS. We assessed their predictive accuracy using the area under the receiver operating characteristic curve (AUC). Results: Individuals in the highest quartile of the PRS had 2-fold higher risks of BE (odds ratio [OR], 2.22; 95% confidence interval [CI], 1.89-2.60) and EAC (OR, 2.46; 95% CI, 2.07-2.92) compared to those in the lowest quartile of the PRS. Risk models including only demographic/lifestyle factors (age, sex, smoking, body mass index, and nonsteroidal anti-inflammatory drugs) or only gastroesophageal reflux disease (GERD) symptoms had AUCs ranging from 0.637 to 0.667. The AUCs for models adding demographic/lifestyle factors to GERD symptoms were 0.793 and 0.745 for BE and EAC, respectively. Small absolute improvement in AUCs for each model was observed when including the PRS in the model (AUCs range, 0.656-0.799). Including the PRS in the model of non-genetic factors provided 3.0% and 5.6% improvement in the net reclassification index for BE and EAC, respectively. Conclusions: Although adding the PRS improved discrimination and net reclassification, the absolute magnitude of improvement is not sufficient to justify its clinical use. Citation Format: Jing Dong, Aaron Thrift. Risk prediction for Barrett's esophagus and esophageal adenocarcinoma: Incorporation of epidemiologic risk factors and 23 confirmed genetic loci [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 2212.
Abstract 1217: The association between birth order and childhood brain tumors: A systematic review and meta-analysis
Authors: Mai V. Nguyen, Mo Thi Tran, Chi TDu Tran, Quang H. Tran, Thuy Thi-Van Tuong, Linh C. Le, Paolo Boffetta, Hung N. Luu
Journal: Cancer Research (2018)

Abstract Background: The incidence of childhood brain tumors (CBT) has increased worldwide, likely resulting from the improvements of early diagnostics. The only known risk factors for CBT are the Li-Fraumeni syndrome and iodization. While both genetic and environmental factors are suggested roles in CBT, birth characteristics, including birth order, maternal age, and mode of delivery, might present the interactions between genetic susceptibility and perinatal environmental causes. Birth order has been hypothesized to play an important role in CBT carcinogenesis due to its possible role as proxy for 1) early infection exposure and 2) hormone levels since first pregnancy differs endocrinologically from later pregnancies. We conducted a systematic review and meta-analysis to clarify the association between birth order and CBT. Methods: We followed established guidelines to systematically search OvidMedline, PubMed, and the Cochrane Library for English-language studies (both case-control and cohort designs) published prior to November 2017. Meta-analysis provided pooled risk estimates and their 95% confidence intervals (CI) for birth order and CBT. Funnel plots were used to identify sources of heterogeneity and publication bias. Results: We identified 16 case-control studies with a total sample of 32,439 cases and 166,144 controls. Compared to first birth order, the meta-odds ratio (mOR) for second birth order was 1.04 (95% CI 1.01-1.07), and that for third birth order was 0.98 (95% CI: 0.90-1.06). We also identified 3 cohorts comprising a total of 1,208 cases. The meta-hazard ratio (mHR) for second or higher birth order compared to first birth order was 1.00 (95% CI: 0.96-1.05). Conclusions: We found no overall association between birth order and CBT in both case-control and cohort study designs; the small association observed for second birth order in case-control studies deserves further consideration. Limited statistical power might have hampered the results of the other analyses. Citation Format: Mai V. Nguyen, Mo Thi Tran, Chi TDu Tran, Quang H. Tran, Thuy Thi-Van Tuong, Linh C. Le, Paolo Boffetta, Hung N. Luu. The association between birth order and childhood brain tumors: A systematic review and meta-analysis [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 1217.
Some Coronary Risk Factors Related to the Insulin Resistance Syndrome and Treatment With Gemfibrozil
Authors: LeenaTenkanen, MattiMänttäri, VesaManninen
Journal: Circulation (1995)

Background Coronary risk factors related to the insulin resistance syndrome tend to cluster in the same individual. Our previous studies have shown that the dyslipidemia characteristic of this syndrome—low HDL cholesterol and high triglyceride (TG) levels—responds well to treatment with gemfibrozil. Most factors related to insulin-resistance syndrome decrease fibrinolytic capacity, whereas a recent study showed that gemfibrozil improves it and thus may attenuate thrombotic events. To discover whether subjects with clustering of factors related to this resistance might in particular benefit from gemfibrozil, we reanalyzed the Helsinki Heart Study data. Methods and Results We used Cox regression models to explore the effects of gemfibrozil among overweight subjects with additional coronary risk factors in this hypercholesterolemic male population of 2046 subjects randomized to gemfibrozil and 2035 to placebo. The effect of gemfibrozil was largely confined to overweight subjects: among those with body mass i...
Abstract 19783: The Impact of Cardiac Sympathetic Nerve Activity Evaluated by Cardiac I-123 Metaiodobenzylguanidine Scintigraphy on the Chronotropic Incompetence
Authors: ToshihikoGoto, KazuakiWakami, KentoMori, KentaHachiya, NoriyukiIkehara, HiroshiFujita, HidekatsuFukuta, NobuyukiOhte
Journal: Circulation (2015)

Introduction: Chronotropic incompetence (CI), defined as the inability of the heart to increase its rate commensurate with increased activity, produces exercise intolerance, and is an independent predictor of overall mortality. Cardiac sympathetic nerve (SNS) activity has been suggested to have a relation to CI. However, the mechanisms for CI have not been fully elucidated. Thus, we investigated the cardiac SNS activity in patients with CI using cardiac I-123 metaiodobenzylguanidine (MIBG) scintigraphy. Methods: Sixteen patients with CI and 17 subjects who served as controls were enrolled in this study (age 77.5±9.2years; male 57.6%). Patients with CI were defined as who were implanted with pacemaker due to sick sinus syndrome. Results: There were no significant differences in age, sex, or left ventricular ejection fraction (66.3±14.3 vs 58.3±22.2%, ns) between patients with CI and controls. Plasma BNP level was also similar between two groups (79.0[IQR, 41.0-175.3] vs 90.9[IQR, 35.5-185.3]pg/mL, ns). The...
Abstract 1863: Ursolic acid sensitizes rhTRAIL-resistant triple negative breast carcinoma to rhTRAIL-induced apoptosis
Authors: Jasmine Manouchehri, Michael Kalafatis
Journal: Cancer Research (2018)

Abstract Recombinant human tumor necrosis factor-related apoptosis-inducing ligand (rhTRAIL) possesses the ability to induce apoptosis in cancer cells independent of their p53 status while exhibiting minimal toxicity to normal, non-transformed cells, and thus, it is a promising anti-cancer therapeutic. However, rhTRAIL-induced apoptosis is not as effective in a majority of breast cancers due to the up-regulation of anti-apoptotic proteins, down-regulation of pro-apoptotic proteins, and/or down-regulation of death receptors (DRs) 4 and 5. A combinatorial approach of rhTRAIL with the “mother nature”-derived compound ursolic acid (UA) has been applied to sensitize rhTRAIL-resistant triple negative breast carcinoma. UA is derived from the leaves and berries of various plants and found in the coatings of fruits and does not exhibit toxicity to normal, non-transformed cells. UA has been revealed to possess the ability to up-regulate DR5 and diminish the expression of anti-apoptotic proteins survivin and FLIP in cancer cells and thereby, making UA an encouraging choice to be utilized as a sensitizing agent. The aim of this study was to determine the capacity of UA to sensitize rhTRAIL-resistant triple negative breast cancer (TNBC) BT-20 and HCC1937 cells to rhTRAIL-induced apoptosis and elucidate the underlying mechanisms for UA's sensitization. The combinatorial treatment of UA and rhTRAIL augmented the induction of apoptosis when compared to single agent UA and rhTRAIL treatments as detected by Annexin V/PI assays and through by the execution of the extrinsic pathway as marked by the activation of caspase 8, activation of the executioner caspases 3 and 7, and eventual PARP cleavage (a hallmark of apoptosis). The underlying mechanisms for UA's sensitization of rhTRAIL-resistant TNBCs were established to be through the down-regulation of the anti-apoptotic protein FLIP and through the up-regulation of DR4 and DR5. Overall, these findings reveal that UA is an efficacious sensitizing agent for rhTRAIL-resistant TNBCs. Citation Format: Jasmine Manouchehri, Michael Kalafatis. Ursolic acid sensitizes rhTRAIL-resistant triple negative breast carcinoma to rhTRAIL-induced apoptosis [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 1863.
Abstract 4918: Pharmacokinetics and toxicity studies of AT1965, a B-cell activating immunotherapy
Authors: Aniruddha Sengupta, Mallik Samarla, Manoj Pandey, Arindam Sarkar, Monideepa Roy, Shiladitya Sengupta
Journal: Cancer Research (2018)

Abstract Introduction: Cancer immunotherapy is the emerging paradigm in the search for a cure for cancer. AT1965 is a novel therapeutic that demonstrates remarkable anti-tumor activity across different preclinical tumor models, mediated through the activation of B-cells. In this study, we have evaluated the metabolism, pharmacokinetics (PK) and toxicity of AT1965 in rodent and non-rodent species. Methods: AT1965 metabolism was studied in rodent, canine and primate liver microsomes. The PK of AT1965 was determined in 4T1 tumor bearing female Balb/c mice; female Sprague Dawley rats and female Beagle dogs at a variety of doses and schedules following single intravenous (i.v) injections. The extent and duration of the exposure was monitored over 120 hours in mice and rats, and till 192 hours in dogs, post dosing. Concentrations of AT1965 in plasma samples were determined either by LC-MS/MS or Atomic Absorption Spectroscopy. The toxicity of AT1965 in male and female Sprague Dawley Rats following single dose i.v. administration of 43.7, 87.4 and 174.8 mg/kg dosage of AT1965 were examined. During toxicity studies, clinical health status was observed daily for 14 days after treatment, followed by necropsy. Results: AT1965 metabolism evaluated in mouse, rat, dog, monkey and human liver microsomes indicated high stability across all species. PK studies reveal that AT1965 exhibited a high exposure, slow systemic clearance and a proportional increase in dose normalized exposure across species. The elimination half-life (T1/2) varied from 34-40 hours in tumor-bearing mice to 29-44 hours in rats and ~ 66 hours in dogs. The excretion of AT1965 was predominantly through hepatobiliary route, with minimal renal clearance. Single i.v. administered acute dose toxicity studies for AT1965 reveal 87.4 mg/kg and 174.8 mg/kg as MTD and toxic doses respectively in rats. Conclusion: The excellent pharmacokinetic profile of AT1965 showing high exposure and enhanced elimination half-life tested across species, in addition to striking antitumor activity coupled with low toxicity in multiple rodent tumor models, provide a compelling rationale for the development of AT1965 as a novel immunotherapeutic agent in the clinic. Citation Format: Aniruddha Sengupta, Mallik Samarla, Manoj Pandey, Arindam Sarkar, Monideepa Roy, Shiladitya Sengupta. Pharmacokinetics and toxicity studies of AT1965, a B-cell activating immunotherapy [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 4918.
Abstract 2262: Inference of kinase activity for cancer phosphoproteomics using substrate prediction scores
Authors: Peter Liao, Jennifer Yori, Ruth Keri, Mehmet Koyuturk, Jill Barnholtz-Sloan
Journal: Cancer Research (2018)

Abstract Background: Quantification of global protein phosphorylation abundance levels with residue-level resolution is feasible with mass spectrometry and phosphopeptide enrichment methods. Researchers have inferred kinase activity from phosphoproteomics data using a variety of methods to extract interpretable and biologically relevant information, but analysis of phosphoproteomics data is limited by the fact that detected phosphorylation sites often have unknown function and relevance. Methods: We developed a novel method for aggregating and interpreting phosphoproteomics data that combines kinase prediction scores from NetworKIN with experimental summary statistics to estimate abundance changes in predicted kinase substrates. By weighting student t-statistic scores by kinase prediction scores and summing cumulative scores across all phosphopeptides detected in a given screen, we generated kinase activity scores that reflect the overall direction, magnitude and significance of observed changes in predicted kinase substrates. These kinase scores were assessed using permutation testing to determine their significance versus changes that would be expected from random chance. To evaluate our method, we applied it to a shotgun phosphoproteomic dataset generated to study phosphorylation responses to rapamycin, dasatinib and combination treatment in MDA-MB-231 breast cancer cells. Results: We were able to confirm phosphoproteomic perturbations in expected “hallmark” kinase activities using prediction-based kinase activity inference scores, including decreased phosphorylation of Src and Abl substrates in response to dasatinib treatment, as well as decreases in p70S6K substrate phosphorylation in response to rapamycin. Compared to KSEA, we identified changes in substrate abundance for a variety of potential downstream kinases including DNAPK, PAK2, CDK3, and multiple members of the MAPK family that were observed to be downregulated in single-agent and in combination treatment. Conclusions: Our novel method provides a representation of phosphoproteomic changes based on abundance of predicted kinase substrates. Using predicted substrates allows for a global view of phosphoproteomic changes that extends beyond the relatively small number of known kinase-substrate relationships. Using a drug combination with potential application in breast cancer as an example, we demonstrate that this method can be used to identify phosphoproteomic changes and can potentially be used to rationally design and investigate novel drug combinations. Citation Format: Peter Liao, Jennifer Yori, Ruth Keri, Mehmet Koyuturk, Jill Barnholtz-Sloan. Inference of kinase activity for cancer phosphoproteomics using substrate prediction scores [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 2262.
Abstract 16961: A Novel Large Animal Model of Chronic Kidney Disease-induced Heart Failure With Preserved Ejection Fraction (HFpEF)
Authors: Angela M Castellanos, Bryon A Tompkins, Victoria Florea, Makoto Natsumeda, Kevin Collon, Jose Rodriguez, Marcos Rosado, Wayne Balkan, Joshua M Hare, Ivonne H Schulman
Journal: Circulation (2016)

Introduction: Large animal models are invaluable to gain a better understanding of the complexity of HFpEF and current small animal models are not representative of the syndrome in patients. HFpEF ...
Abstract 13743: Prognostic Values of Ratio of Serum Eicosapentaenoic Acid to Arachidonic Acid on Clinical Outcome after Endovascular Therapy in Patients with Peripheral Artery Disease due to Femoropopliteal Artery Lesions
Authors: KeiichiHishikari, ShigekiKimura, YosukeYamakami, KeisukeKojima, TakatoshiShigeta, YuichiroSagawa, HirohumiOtani, TomoyoSugiyama, TaishiKuwahara, HiroyukiHikita, AtsushiTakahashi, MitsuakiIsobe
Journal: Circulation (2014)

Background: Peripheral artery disease (PAD) patients have a substantially increased risk of mortality and cardiovascular morbidity than those without PAD. However, risk prediction tools have not been established among patients with PAD to identify who is likely destined for adverse clinical outcome. Eicosapentaenoic acid to arachidonic acid (EPA/AA) ratio has emerged as predictor of mortality endpoints in vascular diseases, especially, coronary artery disease and cerebrovascular disease. In contrast, the prognostic value of EPA/AA ratios in patients with PAD is unclear. We sought to examine whether assessment of serum ratio of EPA/AA in patients with PAD due to femoropopliteal artery lesions can predict clinical outcome after endovascular therapy (EVT). Methods: We obtained serum EPA/AA ratio in 132 consecutive patients with PAD due to femoropopliteal artery lesions before EVT. We analyzed the incidence of major adverse event (MAE) including major adverse limb event (MALE) and any-cause death. The clinica...
Abstract 3791: Triggering receptor expressed in myeloid cells 1 (TREM1) is a predictive marker for breast cancer therapeutics
Authors: Ashok K. Pullikuth, Julia Chifman, Eric D. Routh, Jeff Chou, Guangxu Jin, Michael A. Black, Lance D. Miller
Journal: Cancer Research (2018)

Abstract Triggering receptor expressed on myeloid cells-1 (TREM1) is a cell surface immunoglobulin that amplifies pro-inflammatory responses in myeloid cell populations and has been implicated in carcinogen-induced liver cancer. However, its role in breast cancer is unknown. In a recent screen to identify gene expression patterns associated with breast cancer outcomes, we identified a significant and reproducible positive association between TREM1 expression and breast cancer recurrence in two large breast cancer cohorts comprising 1,984 and 616 patients (p&amp;lt;0.001 and p=0.003, respectively). TREM1 expression was significantly associated with recurrence in both basal-like (p&amp;lt;0.001) and luminal tumor subtypes (Luminal A, p=0.047; Luminal B, p=0.022) and remained significant (p&amp;lt;0.001) in a multivariate Cox regression model, independent of histologic grade, tumor size, nodal status, patient age, treatment and molecular subtype. In pre-treatment biopsies of patients treated with neoadjuvant chemotherapy, high TREM1 expression was associated with a significant decrease in pathologic complete response (pCR) rate (p&amp;lt;0.001), especially in those tumors estimated to have high levels of lymphocytic infiltrate that otherwise associated with an increased pCR rate, consistent with an immune regulatory function for TREM1. Bioinformatics analysis of genes reproducibly correlated with TREM1 expression in breast tumors revealed significant enrichment in myeloid immune cell populations (p&amp;lt;0.001) in general, and neutrophils (p&amp;lt;0.001), M0 macrophages (p&amp;lt;0.001) and M2 macrophages (p&amp;lt;0.001), in particular. Immunohistochemical analysis of breast tumor tissues confirmed colocalization of TREM1 protein expression with the pan-macrophage marker, CD68. These findings, together with the established role for TREM1 in promoting inflammation, fit a model where tumor-infiltrating TREM1-positive myeloid cells impact breast cancer outcomes by promoting immune evasion. Citation Format: Ashok K. Pullikuth, Julia Chifman, Eric D. Routh, Jeff Chou, Guangxu Jin, Michael A. Black, Lance D. Miller. Triggering receptor expressed in myeloid cells 1 (TREM1) is a predictive marker for breast cancer therapeutics [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 3791.
Assessment of the Accuracy of Disease Coding Among Patients Diagnosed With Sarcoma
Authors: Heather G. Lyu, Leah A. Stein, Lily V. Saadat, Sheila N. Phicil, Adil Haider, Chandrajit P. Raut
Journal: JAMA Oncology (2018)

Assessment of the Accuracy of Disease Coding Among Patients Diagnosed With SarcomaThe rarity of sarcoma makes performing appropriately powered studies challenging and increases the significance of accurate data collection.Tumor registries and population-based databases are increasingly used to determine sarcoma incidence, treatment patterns, and outcomes. [1]2][3] The utility of these databases is contingent on meticulous data collection.Although the validity of large databases has been questioned, 4 little is documented about the initial coding process.This study characterizes inaccuracies in coding practices that result in incorrect sarcoma surgical diagnostic codes and tumor registry data at a high-volume health care center.Identification of coding practice errors has implications for the validity of larger oncology databases.