tbuckley/cabot-search huggingface dataset:
Abstract 4777: Antitumor effect of neratinib in lung cancers harboring <i>HER2</i> oncogene alterations
Authors: Yusuke Ogoshi, shinichi Toyooka, Jyunichi Soh, hiromasa Yamamoto, Kazuhiko Shien, Hidejiro torigoe, Hiroki sato, Takahiro Yoshioka, Kei Namba, Yuta Takahashi, Eisuke Kurihara
Journal: Cancer Research (2018)

Abstract Background The HER2-targeted therapy for non-small cell lung cancer (NSCLC) harboring HER2 oncogene alterations is one of promising strategy to improve the clinical outcome of treatment for NSCLC. In this study, we investigated the antitumor effect of neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI) in NSCLC cells harboring HER2 alterations including mutation and amplification. Materials and Methods We examined the sensitivity of neratinib against normal bronchial epithelial cells BEAS-2B which ectopically overexpressing wild-type or mutant HER2. Furthermore, we examined the antitumor activity of neratinib in addition to afatinib in several NSCLC cell lines harboring HER2 or EGFR alterations in in vitro and in vivo experiments, and investigated the association between their genetic alterations and sensitivity to neratinib treatment. Results BEAS-2B cells ectopically overexpressing wild-type HER2 or mutants (A775insYVMA, G776VC, G776LC, P780insGSP, V659E, G660D, and S310F) showed constitutive autophosphorylation of HER2 and activation of downstream signaling by Western blotting. These BEAS-2B cells were sensitive to neratinib, but insensitive to erlotinib, a first generation EGFR-TKI. Neratinib also showed antiproliferative effects on both HER2-altered (H2170, Calu-3, and H1781) and EGFR-mutant (HCC827, PC9, and HCC4006) NSCLC cell lines. Neratinib administration showed strong antitumor effect on tumor growth in mouse xenograft model using HER2-altered lung cancer cell lines. Conclusions Our study strongly suggests that neratinib is a promising therapeutic option for the treatment of HER2-altered NSCLC. Citation Format: Yusuke Ogoshi, shinichi Toyooka, Jyunichi Soh, hiromasa Yamamoto, Kazuhiko Shien, Hidejiro torigoe, Hiroki sato, Takahiro Yoshioka, Kei Namba, Yuta Takahashi, Eisuke Kurihara. Antitumor effect of neratinib in lung cancers harboring HER2 oncogene alterations [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 4777.
Abstract 11396: Myocardial Afadin Attenuates Chronic Pressure Overload-Induced Cardiac Damage via Transforming Growth Factor β Receptor-Mediated Signaling
Authors: Hisakazu Ogita, Dimitar P Zankov
Journal: Circulation (2016)

Afadin, an adaptor protein of cell adhesion molecules nectins, plays a key role in embryonic morphogenesis and tissue organization together with or independent of nectins. However, little is understood how myocardial afadin pathophysiologically functions in the heart. In cardiomyocytes, afadin is reported to localize at the intercalated disks. We, in this study, generated conditional knockout mice lacking myocardial afadin (afadin-cKO mice) by the Cre/loxP system. The proportion of born afadin-cKO mice complied with the Mendel’s law and their appearance was undistinguishable from the littermate control mice. Heart rate, blood pressure, and cardiac dimension and contractility showed similar results between afadin-cKO and control mice. Gross heart morphology, heart weight, histology, and intercalated disks structure in afadin-cKO mice did not differ from those in control mice. We then used a model of chronic pressure overload for 8 weeks created by transverse aortic constriction (TAC) operation. This pressure overload significantly induced systolic dysfunction, enhanced fibrogenesis and apoptosis in afadin-cKO mice comparing with control mice. Myocardial afadin deletion aggravated macrophage infiltration early after TAC procedure. Loss of afadin suppressed transforming growth factor (TGF) β receptor-mediated signaling: phosphorylation of Smad2 and TAK1. Afadin was also found to interact with TGFβ receptor I at the intercalated disks, which was confirmed by co-immunoprecipitation experiments and confocal microscopy. This interaction may contribute to enhancement of TGFβ receptor-mediated signaling initiated by TAC procedure, and prevent cardiac damage. In contrast, administration of SB431542, a pharmacological antagonist of TGFβ receptor I, augmented mononuclear infiltration in the hearts of TAC-operated control mice. In conclusion, afadin is a critical molecule of cardiac protection against chronic pressure overload. The beneficial effects are likely to be a result of afadin interaction with TGFβ receptor.
Abstract 1904: Polyprenoic acid, the first-discovered hepatocyte nuclear factor 4 alpha agonist, inhibits multistep liver carcinogenesis
Authors: Taro Yamashita, Hikari Okada, Masao Honda, Shuichi Kaneko
Journal: Cancer Research (2018)

Abstract Hepatocyte nuclear factor 4 alpha (HNF4α) is one of the most ancient nuclear receptors known as a master regulator of hepatocytes in lipids, carbohydrates, and drug metabolism. It also works as a tumor suppressor to regulate cell cycle in hepatocellular carcinoma (HCC), but the ligand activating HNF4α has not yet been discovered thus far. Here we evaluated the effect of polyprenoic acid (PA), formerly known as an acyclic retinoid, on HNF4α activation in dysplastic nodule and HCC in vitro and in vivo. PDGF-C transgenic (Tg) mice was evaluated by Gd-EOB-DTPA-enhanced MRI to examine the effect of PA on HCC development in vivo. Whole exome sequence analysis was performed using Illumina Hiseq 2000 system. Contrast enhanced CT scan data of patients enrolled in previous phase II/III randomized placebo-controlled study were collected and analyzed (n = 124 for PA and 127 for placebo). PA treatment regressed the liver dysplastic nodule and a subset of HCCs in PDGF-C Tg mice evaluated by MRI. This tumor regression was accompanied with the reduction of accumulated gene mutations, inactivation of cell cycle, and transcriptional activation of HNF4α-target genes. The binding of PA on ligand binding domain of HNF4α was shown by docking simulation in silico and immunoprecipitation-mass spectrometry analysis in vitro. Transcriptional activation of HNF4α by PA was also verified using a luciferase reporter assay and binding of HNF4α on DNA binding elements. PA treatment in HCC cells immediately resulted in the degradation of HNF4α by ubiquitin-proteasome system with activation of DNA damage responses when cultured in lipid depleted medium. In vivo knockdown of HNF4A cancelled the effect of PA on regression of liver tumor growth in PDGF-C Tg mice. PA treatment (600 mg/day) suppressed the HCC development from dysplastic nodule compared with placebo in human with statistical significance (HR 0.41; 95% CI, 0.17~0.98, P = 0.046). Taken together, our data indicated that PA is the first-discovered HNF4α ligand to activate its function. PA activates the DNA damage responses and suppresses the accumulation of gene mutations especially in dysplastic nodule, warranting the future prospective study to evaluate the effect of PA on suppression of HCC development from dysplastic nodules in human. Citation Format: Taro Yamashita, Hikari Okada, Masao Honda, Shuichi Kaneko. Polyprenoic acid, the first-discovered hepatocyte nuclear factor 4 alpha agonist, inhibits multistep liver carcinogenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1904.
Percutaneous Coronary Angioplasty Compared With Exercise Training in Patients With Stable Coronary Artery Disease
Authors: RainerHambrecht, ClaudiaWalther, SvenMöbius-Winkler, StephanGielen, AxelLinke, KatrinConradi, SandraErbs, RegineKluge, KaiKendziorra, OsamaSabri, PeterSick, GerhardSchuler
Journal: Circulation (2004)

Background— Regular exercise in patients with stable coronary artery disease has been shown to improve myocardial perfusion and to retard disease progression. We therefore conducted a randomized study to compare the effects of exercise training versus standard percutaneous coronary intervention (PCI) with stenting on clinical symptoms, angina-free exercise capacity, myocardial perfusion, cost-effectiveness, and frequency of a combined clinical end point (death of cardiac cause, stroke, CABG, angioplasty, acute myocardial infarction, and worsening angina with objective evidence resulting in hospitalization). Methods and Results— A total of 101 male patients aged ≤70 years were recruited after routine coronary angiography and randomized to 12 months of exercise training (20 minutes of bicycle ergometry per day) or to PCI. Cost efficiency was calculated as the average expense (in US dollars) needed to improve the Canadian Cardiovascular Society class by 1 class. Exercise training was associated with a higher...
Abstract IA13: Dynamic cell populations are responsible for sarcoma propagating potential
Authors: Jackie Tang, Kirsch David, Benjamin Alman
Journal: Clinical Cancer Research (2018)

Abstract Self-renewal can maintain tumor viability and play a role in recurrence and metastasis, yet little is known about the control of self-renewal in sarcomas. We previously found that cells that exclude Hoechst dye (side population or SP cells) are enriched for tumor propagating potential in serial transplantations in a variety of sarcoma types, and thus might be enriched for renewal capacity. Here we used a mouse in which soft tissue sarcomas were driven by Trp53 deletion and Kras overexpression to trace individual clones of cells. Expression of a confetti allele or expression of barcoding in the Rosa26 locus was used to trace clones. Tumors were observed in situ in the mice, and in serial translations. Intravital microscopy in transplantations of tumors from mice expressing the confetti allele was also undertaken. While there were multiple fluorescent colors in the primary tumors, over time a dominant clone was apparent. This usually arises from a small population of cells in the early tumor. This finding was verified with serial intravital microscopy, as well as tracing the clones using barcoding. SP cells were sorted from the tumors and found to be significantly enriched for tumor propagating potential as demonstrated using serial transplantations. Over multiple transplantations, the fluorescent color expressed by cells that sorted to the SP, and were enhanced for tumor propagating potential, changed. This suggests that the tumor propagating population is dynamic, rather than being limited to a specific clone. Barcoding in additional experiments showed the same result. This was further verified by genetically expressing different-colored fluorescent markers in SP and non-SP cells. While at a given time the SP expressed one fluorescent color, over serial transplantations, they expressed different colors. Taken together, this shows that the small subpopulation of cells that are enhanced for tumor propagating potential are not derived from the same clone, but a dynamic population that changes over time. Similar to findings in human sarcoma SP cells, RNA sequencing data showed that the murine SP cells were enhanced for Wnt and Notch signaling, even in different clones over time from the same initial population. Blocking these pathways suppresses the tumor propagating potential. Thus, epigenetic changes that activate Wnt and Notch in dynamic cell populations derived from different clones in the initial tumor are likely responsible for enhancing tumor propagating potential and for cells to achieve an SP cell phenotype. Citation Format: Jackie Tang, Kirsch David, Benjamin Alman. Dynamic cell populations are responsible for sarcoma propagating potential [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr IA13.
The Effects of Cholesterol-Derived Oncometabolites on Nuclear Receptor Function in Cancer
Authors: Sandrine Silvente-Poirot, Florence Dalenc, Marc Poirot
Journal: Cancer Research (2018)

Epidemiologic studies are controversial concerning the roles played by cholesterol in cancer risk and development, possibly as it is not cholesterol per se that is pathologic in cancers. Indeed, recent data reveal that the cholesterol metabolism in cancer cells can generate endogenous oncopromoter metabolites at higher levels compared with normal tissues and/or can be deregulated in the production of endogenous oncosuppressor metabolites in an opposite way. These metabolites are oxysterols, which are cholesterol oxygenation products generated by enzymatic and/or autoxidation processes. All these oxysterols are new classes of estrogen, glucocorticoid, or liver X nuclear receptor ligands, and their protumor action on their cognate receptors could explain some drug resistance, while treatment with antitumor metabolites could complement their deficiency in cancers and restore their action on their nuclear receptor. Given that hypercholesterolemia and high intakes of cholesterol-rich foods or processed foods can generate these oxysterols, their importance in cancer risk or development in overweight and obese people is to be considered. The discovery of these cholesterol-derived metabolites and the identification of the nuclear receptors mediating their pro- or antitumor activities are important findings, which should have major implications in the diagnosis, prevention, and treatment of different cancers and open new areas of research. Cancer Res; 78(17); 4803-8. ©2018 AACR.
α1AMPK deletion in myelomonocytic cells induces a pro-inflammatory phenotype and enhances angiotensin II-induced vascular dysfunction
Authors: Thomas Jansen, Swenja Kröller-Schön, Tanja Schönfelder, Marc Foretz, Benoit Viollet, Andreas Daiber, Matthias Oelze, Moritz Brandt, Sebastian Steven, Miroslava Kvandová, Sanela Kalinovic, Jeremy Lagrange, John F Keaney, Thomas Münzel, Philip Wenzel, Eberhard Schulz
Journal: Cardiovascular Research (2018)

Immune cell function involves energy-dependent processes including growth, proliferation, and cytokine production. Since the AMP-activated protein kinase (AMPK) is a crucial regulator of intracellular energy homeostasis, its expression and activity may also affect innate and adaptive immune cell responses. Therefore, we aimed to investigate the consequences of α1AMPK deletion in myelomonocytic cells on vascular function, inflammation, and hypertension during chronic angiotensin II (ATII) treatment.We generated a mouse strain with α1AMPK deletion in lysozyme M+ myelomonocytic cells. Compared to controls, chronic ATII infusion (1 mg/kg/day for 7 days) lead to increased vascular oxidative stress and aggravated endothelial dysfunction in LysM-Cre+ x α1AMPKfl/fl mice. This was accompanied by an increased aortic infiltration of CD11b+F4/80+ macrophages and enhanced pro-inflammatory cytokine release (tumour necrosis factor-alpha, interferon-gamma, and interleukin-6). Mechanistically, we found that increased expression of C-C chemokine receptor 2 (CCR2) in α1AMPK deficient myelomonocytic cells facilitated their recruitment to the vascular wall. In addition, expression of the ATII receptor type 1a and the oxidative burst was increased in these cells, indicating an increased susceptibility towards pro-oxidant stimuli.In summary, α1AMPK deletion in myelomonocytic cells aggravates vascular oxidative stress and dysfunction by enhancing their recruitment to the vascular wall and increasing their susceptibility towards pro-oxidant stimuli. Our observations suggest that metabolic control in myelomonocytic cells has profound implications for their inflammatory phenotype and may trigger the development of vascular disease.
Abstract 3111: Expansion of mouse prostate epithelial stem cells in serum-free ProstaCult Organoid Growth Medium
Authors: John Stingl, David Rowbotham, Terry E. Thomas, Allen C. Eaves, Sharon A. Louis
Journal: Cancer Research (2018)

Abstract Growing prostate epithelial cells as organoids in a three-dimensional (3D) cell culture environment represents a more physiological model system than conventional 2D adherent cell culture systems for studying many different aspects of prostate epithelial cell biology. Two types of prostate epithelial organoids have been previously described: large hollow cystic organoids, and smaller solid organoids (Karthaus et al, Cell 2014). Both types of organoids are composed of androgen receptor (AR)-expressing luminal cells and keratin (K) 5-expressing basal cells, but only vary in the proportion of each cell type, with the cystic organoids enriched for luminal cells and solid organoids enriched for basal cells. We are currently developing ProstaCult™ Organoid Growth Medium, a serum-free medium for the long-term propagation of both types of organoids from mouse prostate tissue. To initiate the cultures, mouse prostates are enzymatically dissociated sequentially in collagenase type II, trypsin and dispase to generate a single cell suspension, and 5x103 the liberated cells are then embedded in Corning® Matrigel® and cultured in ProstaCult™ Organoid Growth Medium. Approximately 10±2% (mean±sem; n=6) of the seeded cells will proliferate and generate approximately equivalent numbers of cystic and solid organoids, which can be dissociated and passaged every 7 days as a single cell suspension. Typical total epithelial cell expansion observed during media development ranges from 21-240-fold per passage for a minimum of 4 passages. Experiments are ongoing to determine the long-term passageability of organoids maintained in ProstaCult™ Organoid Growth Medium. Organoids that are generated at multiple passages are composed of a polarized epithelium with AR+K18+ luminal cells and K5+ basal cells. These results demonstrate that ProstaCult™ Organoid Growth Medium efficiently generates and expands prostate epithelial organoids. Citation Format: John Stingl, David Rowbotham, Terry E. Thomas, Allen C. Eaves, Sharon A. Louis. Expansion of mouse prostate epithelial stem cells in serum-free ProstaCult Organoid Growth Medium [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 3111.
Prolonged Kinetics of Recovery of Oxygen Consumption After Maximal Graded Exercise in Patients With Chronic Heart Failure
Authors: AlainCohen-Solal, ThierryLaperche, DanielMorvan, MichelGeneves, BernardCaviezel, RenéGourgon
Journal: Circulation (1995)

Background Patients with chronic heart failure (CHF) often complain of prolonged dyspnea after exercise. The determinants of oxygen consumption after exercise in these patients are unknown. We hypothesized that the kinetics of oxygen consumption recovery after graded exercise was prolonged in parallel with the recovery of muscle energy stores, was not affected by the exercise level, and could be used to assess the circulatory response to exercise. Methods and Results Seventy-two patients with CHF in Weber’s class A (n=28), B (n=21), and C/D (n=23) and 13 healthy subjects performed maximal upright bicycle exercise with breath-by-breath respiratory gas analysis. Kinetics of recovery of ventilation (Ve), oxygen consumption (Vo2), and CO2 production (Vco2) after exercise were characterized by T1/2, the time to reach 50% of the peak value. T1/2 Vo2 (seconds) increased with the severity of CHF (97±17 for CHF A [P<.05 versus CHF B, P<.05 versus CHF C/D], 119±22 for CHF B [P<.05 versus control subjects, P<.05...
Associations between cardiovascular disease, cancer, and very low high-density lipoprotein cholesterol in the REasons for Geographical and Racial Differences in Stroke (REGARDS) study
Authors: Peter Penson, D Leann Long, George Howard, Virginia J Howard, Steven R Jones, Seth S Martin, Dimitri P Mikhailidis, Paul Muntner, Manfredi Rizzo, Daniel J Rader, Monika M Safford, Amirhossein Sahebkar, Peter P Toth, Maciej Banach
Journal: Cardiovascular Research (2018)

Abstract Aims Relatively little is known about the health outcomes associated with very low plasma concentrations of high-density lipoprotein cholesterol (HDL-C) mainly because of the small numbers of individuals with such extreme values included in clinical trials. We, therefore, investigated the association between low and very low HDL-C concentration at baseline and incident all-cause-mortality, death from malignant disease (i.e. cancer), and with fatal or non-fatal incident coronary heart disease (CHD) in individuals from the Reasons for Geographical And Racial Differences in Stroke (REGARDS) study. Methods and results Analysis was based on 21 751 participants from the REGARDS study who were free of CHD, other cardiovascular disease, and cancer at baseline and were categorized by baseline HDL-C into &lt;30 mg/dL (very low), 30–&lt;40 mg/dL (low), and ≥40 mg/dL (reference). A series of incremental Cox proportional hazards models were employed to assess the association between the HDL-C categories and outcomes. Statistical analysis was performed using both complete case methods and multiple imputations with chained equations. After adjustment for age, race, and sex, the hazard ratios (HRs) comparing the lowest and highest HDL-C categories were 1.48 [95% confidence interval (CI) 1.28–1.73] for all-cause mortality, 1.35 (95% CI 1.03–1.77) for cancer-specific mortality and 1.39 (95% CI 0.99–1.96) for incident CHD. These associations became non-significant in models adjusting for demographics, cardiovascular risk factors, and treatment for dyslipidaemia. We found evidence for an HDL paradox, whereby low HDL (30–&lt;40 mg/dL) was associated with reduced risk of incident CHD in black participants in a fully adjusted complete case model (HR 0.63; 95% CI 0.46–0.88) and after multiple imputation analyses (HR 0.76; 95% CI 0.58–0.98). HDL-C (&lt;30 mg/dL) was significantly associated with poorer outcomes in women for all outcomes, especially with respect to cancer mortality (HR 2.31; 95% CI 1.28–4.16) in a fully adjusted complete case model, replicated using multiple imputation (HR 1.81; 95% CI 1.03–3.20). Conclusion Low HDL-C was associated with reduced risk of incident CHD in black participants suggesting a potential HDL paradox for incident CHD. Very low HDL-C in women was significantly associated with cancer mortality in a fully adjusted complete case model.
Trends in Out-of-Hospital Deaths Due to Coronary Heart Disease in Sweden (1991 to 2006)
Authors: KerstinDudas, GeorgLappas, SimonStewart, AnnikaRosengren
Journal: Circulation (2011)

Background—Case fatality associated with a first coronary event is often underestimated when only those who survive to reach a hospital are considered. Few studies have examined long-term trends in case fatality associated with a major coronary event that occurs out of the hospital. Methods and Results—Record linkage documented all case subjects 35 to 84 years of age in Sweden during 1991 to 2006 with a first major coronary event (out-of-hospital coronary death or hospitalization for acute myocardial infarction). Of the 384 597 cases identified, 111 319 (28.9%) died out of the hospital, and another 36 552 (9.5%) died in the hospital or within 28 days of hospitalization. From 1991 to 2006, out-of hospital deaths as a proportion of all major coronary events declined from 30.5% to 25.6% (adjusted mean annual decrease 2.2%, 95% confidence interval 2.1% to 2.4%), however, with a larger decline in 28-day case fatality in hospitalized cases (adjusted mean annual decrease 5.8%, 95% confidence interval 5.5% to 6.0...