tbuckley/cabot-search huggingface dataset:
Abstract 2503: Rational design of small-molecule immune checkpoints' inhibitors
Authors: Khaled Barakat
Journal: Cancer Research (2018)

Abstract Blocking the PD-1/PD-L1 and CTLA-4 pathways recently emerged as a ‘game changer' in cancer immunotherapy, leading to the selection of monoclonal-antibodies (MABs) targeting PD-1 as ‘drug of the year' for 2013. Although these antibodies restored exhausted T cells' function to recognize and kill tumor cells, these MABs have numerous disadvantages. These include their very high cost and very severe side effects. Our team has been focused on designing small molecule inhibitors for this pathway. Compared to available MAB therapies, our small molecules may offer a more affordable, more easily administered and better controlled treatment for a variety of cancers. Here, we demonstrate our efforts toward this goal and summarize our data on our promising compounds targeting the PD-1/PD-L1 and CTLA-4 pathways. Citation Format: Khaled Barakat. Rational design of small-molecule immune checkpoints' inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2503.
Adrenomedullin Gene Transfer Induces Therapeutic Angiogenesis in a Rabbit Model of Chronic Hind Limb Ischemia
Authors: NoriyukiTokunaga, NoritoshiNagaya, MikiyasuShirai, EtsuroTanaka, HatsueIshibashi-Ueda, MarikoHarada-Shiba, MunetakeKanda, TakefumiIto, WataruShimizu, YasuhikoTabata, MasaakiUematsu, KazuhiroNishigami, ShunjiSano, KenjiKangawa, HidezoMori
Journal: Circulation (2004)

Background— Earlier studies have shown that adrenomedullin (AM), a potent vasodilator peptide, has a variety of cardiovascular effects. However, whether AM has angiogenic potential remains unknown. This study investigated whether AM gene transfer induces therapeutic angiogenesis in chronic hind limb ischemia. Methods and Results— Ischemia was induced in the hind limb of 21 Japanese White rabbits. Positively charged biodegradable gelatin was used to produce ionically linked DNA-gelatin complexes that could delay DNA degradation. Human AM DNA (naked AM group), AM DNA-gelatin complex (AM-gelatin group), or gelatin alone (control group) was injected into the ischemic thigh muscles. Four weeks after gene transfer, significant improvements in collateral formation and hind limb perfusion were observed in the naked AM group and AM-gelatin group compared with the control group (calf blood pressure ratio: 0.60±0.02, 0.72±0.03, 0.42±0.06, respectively). Interestingly, hind limb perfusion and capillary density of isc...
Abstract P009: Dietary Exposure to Polychlorinated Biphenyls and Incidence of Myocardial Infarction in Men - A Population-Based Prospective Cohort Study
Authors: AgnetaÅkesson, CharlotteBergkvist, MarikaBergkvist, AndersGlynn, BettinaJulin, AlicjaWolk
Journal: Circulation (2015)

Introduction: Fish consumption may promote cardiovascular health. The role of major food contaminants present in fish, such as polychlorinated biphenyls (PCBs) is, however, largely unexplored. Experimental studies indicate that PCBs cause endothelial cell dysfunction, hyperlipidemia and hypertension and cross-sectional associations have been observed between PCB-biomarkers and several intermediate risk factors for cardiovascular disease. PCBs accumulate and magnify in the food chain and fatty fish is a dominating source of exposure in populations with a relatively high fish intake. We assessed the hypothesis that dietary PCB exposure is associated with increased risk of myocardial infarction (MI) and that the exposure may mask a protective association with marine omega-3 fish fatty acids intake. Methods: Validated food frequency questionnaire-based estimates of dietary PCB exposure was obtained at baseline (1997) in 36,759 men from the population-based Cohort of Swedish Men, free of cancer, cardiovascular...
Abstract 15919: Beta Blockers Confer a Survival Benefit in Patients With Myocardial Infarction
Authors: Sanjay Verma, Karen Wells, Ed L Peterson, L K Williams, Brian Surjanhata, David E Lanfear
Journal: Circulation (2013)

BACKGROUND: The studies demonstrating mortality benefits of beta blockers (BB) after myocardial infarction (MI) were conducted before the era of percutaneous intervention and widespread use of statins. Recent high-profile literature examined BB use in patients with prior MI and found no benefit in composite cardiovascular outcomes or mortality. However, this work did not account for medication changes over time, patient non-adherence, or race-BB interaction. We evaluated the association of death and rehospitalization with time-varying BB exposure in patients with MI. METHODS: This retrospective cohort study included all patients who presented with MI at a single health care system who also had health insurance under our covered entity from January 1, 1997 to June 30, 2011. Pharmacy claims were used to estimate BB exposure over six-month rolling windows, calculated as the continuous multiple-interval medication availability. The primary endpoint was all-cause death, and the secondary endpoint was all-cause...
A Surgical Case of Expanding Bilateral Coronary Aneurysms Regarded as Immunoglobulin G4-Related Disease
Authors: YasuyukiBito, YasuyukiSasaki, HidekazuHirai, MitsuharuHosono, AtsushiNakahira, YasuoSuehiro, DaisukeKaku, YukoKubota, MakotoMiyabe, ShigefumiSuehiro
Journal: Circulation (2014)
Impact of biological therapy on work outcomes in patients with axial spondyloarthritis: results from the British Society for Rheumatology Biologics Register (BSRBR-AS) and meta-analysis
Authors: Joanna Shim, Gareth T Jones, Ejaz M I Pathan, Gary J Macfarlane
Journal: Annals of the Rheumatic Diseases (2018)

Objectives To quantify, among patients with axial spondyloarthritis (axSpA), the benefit on work outcomes associated with commencing biologic therapy. Methods The British Society for Rheumatology Biologics Register in Axial Spondyloarthritis (BSRBRAS) recruited patients meeting Assessment of SpondyloArthritis International Society criteria for axSpA naïve to biological therapy across 83 centres in Great Britain. Work outcomes (measured using the Work Productivity and Activity Impairment Index) were compared between those starting biological therapy at the time of recruitment and those not. Differences between treatment groups were adjusted using propensity score matching. Results from BSRBR-AS were combined with other studies in a meta-analysis to calculate pooled estimates. Results Of the 577 participants in this analysis who were in employment, 27.9% were starting biological therapy at the time of recruitment. After propensity score adjustment, patients undergoing biological therapy, at 12-month follow-up, experienced significantly greater improvements (relative to non-biological therapy) in presenteeism (−9.4%, 95% CI −15.3% to –3.5%), overall work impairment (−13.9%, 95% CI −21.1% to –6.7%) and overall activity impairment (−19.2%, 95% CI −26.3% to –12.2%). There was no difference in absenteeism (−1.5%, 95% CI −8.0 to 4.9). Despite these improvements, impact on work was still greater in the biological treated cohort at follow-up. In the meta-analysis including 1109 subjects across observational studies and trials, treatment with biological therapy was associated with significantly greater improvements in presenteeism, work impairment and activity impairment, but there was no difference in absenteeism. Conclusions There is consistent evidence that treatment with biological therapy significantly improves work productivity and activity impairment in people with axSpA. However, there remain substantial unmet needs in relation to work.
Abstract 1891: Cross-resistance and synergy between idelalisib and bendamustine in chronic lymphocytic leukemia
Authors: Sara E. F. Kost, Ali Saleh, Edgard M. Mejia, Marina Mostafizar, Eric D. J. Bouchard, Versha Banerji, Aaron J. Marshall, Spencer B. Gibson, Sachin Katyal, James B. Johnston
Journal: Cancer Research (2018)

Abstract Idelalisib (IDE) is an inhibitor of the δ isoform of PI3 kinase and has shown high activity in chronic lymphocytic leukemia (CLL) either when given alone or in combination with bendamustine (BEN) /rituximab (BR). In the present study, we have determined whether there is cross-resistance between BEN and IDE in primary CLL cells in vitro and whether synergy is observed upon combining these agents. In primary CLL cells in vitro, cross-resistance was not observed between BEN and IDE suggesting different modes of cytotoxicity. In contrast to BEN, sensitivity to IDE was not influenced by prior clinical treatment or the presence of a del 17p. Marked synergy in cytotoxicity was seen between BEN and IDE, which was paralleled by changes in γ-H2AX staining. These findings suggest that the synergistic antitumor effect was related to enhanced DNA damage by the drug combination. The degree of cytotoxic synergy varied and synergy was observed in some cases that were resistant to BEN or IDE, and those with del 17p. Synergy between BEN and IDE was also seen in the B cell lines, BJAB and I83, and in healthy donor peripheral blood mononuclear cells indicating that the phenomenon was not CLL-specific. To simulate the microenvironment, CLL cells were pre-stimulating with CD40L and IL4 prior to drug treatment. Interestingly this treatment caused the cells to become resistant to IDE, but BEN sensitivity was unaffected. However, combining BEN and IDE produced greater synergy than observed when cells were incubated without IL4/CD40. To examine the role of PI3Kδ for synergy, B cells from C57 BL/6 mice, both wild type and with non-functioning PI3Kδ protein, were exposed to BEN and/or IDE. Cells with the non-functioning PI3Kδ protein were more resistant to IDE than the wild-type cells and showed lesser synergy confirming the importance of this protein for the synergistic effect. In summary, these results confirm that IDE can be active against BEN-resistant CLL cells, while BEN may remain active against IDE-resistant samples, demonstrating different modes of anti-tumor activity. However, the unique yet inconsistent synergy seen between these two agents suggest an overlapping mechanism of action. Ongoing studies are evaluating the mechanism for this synergy. Citation Format: Sara E. F. Kost, Ali Saleh, Edgard M. Mejia, Marina Mostafizar, Eric D. J. Bouchard, Versha Banerji, Aaron J. Marshall, Spencer B. Gibson, Sachin Katyal, James B. Johnston. Cross-resistance and synergy between idelalisib and bendamustine in chronic lymphocytic leukemia [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 1891.
Abstract MP045: The Ratio of Visceral and Subcutaneous Adipose Tissue Area was Positively Associated with Subclinical Atherosclerosis for Smoking Men
Authors: Jung H Lee, Hyeon C Kim, Jee-Seon Shim, Myung H Lee, Bo M Song, Il Suh
Journal: Circulation (2017)

Introduction: Several studies have examined the association between adipose tissue distribution and atherosclerosis. However, the effect of smoking on this association has not been evaluated yet. Hypothesis: We assessed the hypothesis that there is positive association between the ratio of visceral and subcutaneous adipose tissue areas and carotid intima media thickness (CIMT), and the association can be modified according to gender and smoking status in South Korea. Methods: A total of 1,606 middle-aged participants without cardiovascular disease were enrolled in this cross-sectional study from 2013 to 2015 in South Korea (568 men; 1,038 women). The CIMT of study participants was measured using B-mode ultrasonography at distal right common carotid artery, based on a predetermined protocol. We measured the abdominal adipose tissue distribution of study participants using computerized tomography. The area of adipose tissue at L4 vertebrae level was calculated, and the area of visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were separated by abdominal wall. Then, we calculated the ratio of VAT and SAT (VAT/SAT) area. Other major cardiovascular risk factors were measured by standardized questionnaire, physical exam and fasting blood analysis. Smoking status of study participants was classified into three groups: current, former and never smokers. For evaluating the association between adipose tissue area and CIMT, we used multiple linear regressions. Separated analyses based on gender and smoking status were also performed. Results: Mean CIMT of study participants was 0.62 mm (SD, 0.12 mm), and mean VAF/SAF ratio of study participants was 0.62 (SD, 0.29). The prevalence of current smoker was 36.8% (209 of 568) for men, and 4.1% (42 of 1038) for women. In our multiple linear regression models, the VAT/SAT ratio showed statistically significant positive β-coefficient for total participants (β =8.62, p=0.008): showing significant for men (β =15.95, p=0.001) and not for women (β =3.15, p=0.377). When considering men only with respect to smoking status, the association between VAT/SAT ratio and CIMT was significant for current smokers (β=30.37, p&lt;0.001), while it was not for never smokers (β=0.62, p=0.958) and former smokers (β=12.84, p=0.119). There was no significant interaction for gender and also for smoking status for men (p for interaction&gt;0.05). Conclusions: In conclusion, the VAT/SAT ratio was positively associated with CIMT, and more preeminent positive association was observed for current men smokers than for never and former men smokers. The results of this study supported the need of smoking cessation to prevent atherosclerosis by adipose tissue distribution, especially for men.
Prediction of Transition to Chronic Atrial Fibrillation in Patients With Paroxysmal Atrial Fibrillation by Signal- Averaged Electrocardiography
Authors: YasushiAbe, MasatakeFukunami, TakahisaYamada, MasaharuOhmori, TsuyoshiShimonagata, KazuakiKumagai, JiyoongKim, ShojiSanada, MasatsuguHori, NoritakeHoki
Journal: Circulation (1997)

Background It is well known that paroxysmal atrial fibrillation (PAF) often precedes the establishment of chronic atrial fibrillation (CAF). However, there have been no definite methods to predict the transition from PAF to CAF. The purpose of this report was to determine prospectively whether P-wave–triggered signal-averaged ECG (P-SAE) is useful for the prediction of the transition to CAF in patients with PAF. Methods and Results One hundred twenty-two consecutive patients with PAF were prospectively followed after P-SAE, echocardiography, and 24-hour Holter monitoring at study entry. The duration (Ad) and root-mean-square voltage for the last 30 ms (LP30) of the filtered P wave were measured in P-SAE. The abnormality of P-SAE for the prediction of transition to CAF was defined as Ad ≥145 ms and LP30 <3.0 μV. Twenty-three (19%; group 1) of the patients had the abnormality of P-SAE, whereas the others (group 2) did not. During the follow-up period (mean, 26±12 months), 10 patients (43%) in group 1 acquir...
Abstract 2322: Ferroptosis induced by erastin in RAS mutant ovarian cancer cells
Authors: Motoki Takenaka, Noriko Suzuki, Minako Mori, Hitomi Aoki, Tasuku Hirayama, Hideko Nagasawa, Ken-ichirou Morishige
Journal: Cancer Research (2018)

Abstract Although apoptosis has been thought as the principal mechanism of programed cell death in chemotherapy, other forms of non-apoptotic death also has been noted. The oncogenic RAS-selective lethal small molecule erastin triggers a unique iron-dependent form of cell death termed ferroptosis. This mechanism is expected to induce eradication of chemotherapeutic (e.g. platinum) resistant cancer cells. In this study we demonstrate this new form of cell death in ovarian cancer cells. The clear cell epithelial ovarian cancer cell lines, TOV-21G (KRAS_G13C) and KOC-7C (RAS wild type) were used in this study. Erastin dose-dependently inhibited growth in TOV-21G cells, but not KOC-7C cells. Treatment of TOV-21G cells with erastin resulted in increase of ROS. Iron chelator deferoxamine (DFO) rescued growth inhibition induced by erastin in TOV-21G cells. Although cisplatin inhibited growth in TOV-21G cells, this inhibition was not rescued by DFO. The GSH level was reduced by erastin, but this reduction was not rescued by DFO. In addition, the basal GSH level was higher and the basal ROS level was lower in KOC-7C cells than those in TOV-21G cells. Erastin induced ferroptosis by reducing the GSH level in RAS mutant ovarian cancer cells. Although DFO rescued growth inhibition induced by erastin, the pathway was not on System Xc-. The sensitivity to erastin might depends on the basal level of GSH in cells. Ferroptosis had great potential to become a new approach in anti-tumor therapies in ovarian cancer. Citation Format: Motoki Takenaka, Noriko Suzuki, Minako Mori, Hitomi Aoki, Tasuku Hirayama, Hideko Nagasawa, Ken-ichirou Morishige. Ferroptosis induced by erastin in RAS mutant 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 2322.
Abstract 2345: The genomic landscape of small cell carcinoma of the oesophagus
Authors: Feng Wang, Dongbing Liu, Qi Zhao, Gang Chen, Xinming Liu, Yingnan Wang, Hong Su, Yanru Qin, Yifu He, Qingfeng Zou, Yanhui Liu, Youen Lin, Hui Sheng, Jiajia Hu, Zexian Liu, Zhixiang Zuo, Jinxin Bei, Ruihua Xu
Journal: Cancer Research (2018)

Abstract Background &amp; Aims—Small cell carcinoma of the oesophagus (SCCE) is a deadly malignancy but its genetic characteristics remain unknown and treatment is commonly adopted from therapies for its histologically identical counterpart, small cell lung cancer (SCLC). We conducted a large-scale genomic analysis of SCCE to determine the mutational landscape of this deadly disease. Methods—We performed whole-exome sequence of tumour and para normal esophageal tissues from 55 patients with SCCE who underwent surgery at seven institutions in China. Comprehensive analyses were carried out to identify key genetic events in SCCE, including significant mutations, copy number variation, pathway disruption. We also performed ultra-deep targeted sequencing on 20 specimens and microarray assays on 24 specimens to validate somatic mutations and copy number variations respectively. Using an unsupervised hierarchical clustering approach, the genomic characteristics of SCCE were compared with other types of malignancies including oesophageal squamous cell carcinoma, oesophageal adenocarcinoma and et al. In vitro proliferation and migration assays were conducted to assess the function of PDE3A. Results—The mutational spectrum of SCCE was dominated by C&amp;gt;T/G&amp;gt;A transitions and the mutational signatures classified the patients into 3 groups. We identified three novel significantly mutated genes (PDE3A, PTPRM and CBLN2) and mutations in five other well-known tumour-associated genes (TP53, RB1, NOTCH1, FAT1 and FBXW7). Non-silent alterations of chromatin remodeling genes were detected in 96.4%. Moreover, pathway enrichment analysis revealed that genes involved in the cell cycle, p53, Notch and Wnt signaling were frequently altered in SCCE. Mutations in NOTCH family correlated with shorter overall survival. Furthermore, comparison analysis of mutation signatures revealed that SCCE tumours were more closely related to oesophageal squamous cell carcinoma, rather than oesophageal adenocarcinoma and SCLC, suggesting that current therapies for SCCE may be inadequate. Functional characterizations suggested that PDE3A acts as a novel oncogene. Conclusions—Our findings reveal key somatic alterations in SCCE, and provide insights to better understand the pathogenesis of SCCE and to develop better treatment strategies for patients with the condition. Citation Format: Feng Wang, Dongbing Liu, Qi Zhao, Gang Chen, Xinming Liu, Yingnan Wang, Hong Su, Yanru Qin, Yifu He, Qingfeng Zou, Yanhui Liu, Youen Lin, Hui Sheng, Jiajia Hu, Zexian Liu, Zhixiang Zuo, Jinxin Bei, Ruihua Xu. The genomic landscape of small cell carcinoma of the oesophagus [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 2345.
Abstract 5866: Discovery and profiling of a highly potent and selective ERK5 inhibitor: BAY-885
Authors: Clara Lemos, Duy Nguyen, Lars Wortmann, Ulf Bömer, Simon Holton, Christian Lechner, Stefan Prechtl, Detlev Sülzle, Franziska Siegel, Dominik Mumberg, Marcus Bauser, Andrea Hägebarth
Journal: Cancer Research (2018)

Abstract ERK5 (Extracellular signal regulated kinase 5, also known as MAPK7, Gene ID: 5598) is a key integrator of cellular signal transduction and it has been shown to play a role in various cellular processes such as proliferation, differentiation, apoptosis and cell survival. Several studies have demonstrated that inhibition of ERK5 with siRNA or shRNA decreases proliferation and increases cell death in different tumor models, thereby highlighting the potential of ERK5 as a therapeutic target in cancer. By HTS and subsequent lead identification, we discovered a highly potent and selective ERK5 inhibitor, BAY-885, which was used to investigate the therapeutic potential of ERK5 in tumor cells displaying ERK5 genomic amplifications or with constitutive activation of the ERK5 pathway. BAY-885 inhibited ERK5 enzymatic activity with IC50 = 40 nM and was highly selective vs. 357 kinases (Eurofins panel). Inhibition by BAY-855 was confirmed in a cellular setting using a MEF2 reporter cell line (SN12C-MEF2-luc). The EGF-stimulated MEF2 transcriptional activity was strongly inhibited by BAY-885 (IC50 = 115 nM; IC90 = 691 nM). In contrast, the compound had no effect on a reporter cell line with constitutive luciferase expression (SN12C-CMV-luc, IC50 &amp;gt; 50 µM), thereby ruling out potential effects as a general inhibitor of transcription or translation. Importantly, despite its high potency, BAY-885 failed to inhibit the proliferation of cells with ERK5 genomic amplification (SN12C, SNU-449, MFM-223) or with constitutively active ERK5 signaling (BT-474, SK-BR-3). Altogether, our results demonstrate that inhibition of ERK5 kinase and transcriptional activity with a small molecule did not translate into antiproliferative activity in different relevant cell models, thus raising doubts as to the viability of ERK5 as a therapeutic target for anticancer drug development. The availability of potent and selective chemical probes, as the one described here, will contribute to further understanding the biology of ERK5 signaling in cancer. Citation Format: Clara Lemos, Duy Nguyen, Lars Wortmann, Ulf Bömer, Simon Holton, Christian Lechner, Stefan Prechtl, Detlev Sülzle, Franziska Siegel, Dominik Mumberg, Marcus Bauser, Andrea Hägebarth. Discovery and profiling of a highly potent and selective ERK5 inhibitor: BAY-885 [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 5866.
Ventricular Fibrillation Studied by the Microelectrode Method
Authors: Toyomisano, Hiromichitsuchihashi, Takioshimamoto
Journal: Circulation Research (1958)

Capillary ultramicroelectrodes were inserted into ventricular muscle fibers of dogs in ventricular fibrillation and action potentials obtained were compared with deflections of unipolar direct lead, adjoining bipolar direct lead or other electrocardiograms taken simultaneously. In most stages of ventricular fibrillation neither synehronism nor any other regular time relationship could he found between them. Microelectrodes inserted at two points variously distant on various regions of the ventricular surface also failed to show any regular time relationship. Total incoordination of ventricular muscle fibers was thus supported.