tbuckley/cabot-search huggingface dataset:
Abstract 18626: Quadratic Regression Reveals an Accelerated Age-related Decline of Maximal Heart Rate in those with Low and Moderate Cardiorespiratory Fitness
Authors: MaryTuttle, CemalOzemek, MitchellWhaley, HolmesFinch, LeonardKaminsky
Journal: Circulation (2014)

Background: Maximal heart rate (HRmax) obtained from an exercise test provides important prognostic information (chronotropic incompetence). Interpretation of HRmax has typically been derived from age-predicted linear regression equations, such as 220-age with large standard error of estimates of ~ ± 10-12 bpm. Recent investigations, with quadratic regression analyses, suggest a more rapid decline in HRmax may occur in older adults. However, a limitation in those studies was a lack of an objective indicator of maximal exercise test effort and consideration of cardiorespiratory fitness (CRF) as a potential influence of this age-related change. Methods: Cardiopulmonary treadmill exercise tests (respiratory exchange ratio ≥1.0 and measured VO2max) from participants (1161 men, 1070 women; not using HR altering medications) of a university based health-assessment/fitness program were studied. Individuals were categorized into CRF categories (high [A], moderate [B], and low [C]) relative to age and gender norma...
Defective Regulation of Interdomain Interactions Within the Ryanodine Receptor Plays a Key Role in the Pathogenesis of Heart Failure
Authors: TetsuroOda, MasafumiYano, TakeshiYamamoto, TakahiroTokuhisa, ShinichiOkuda, MasahiroDoi, TomokoOhkusa, YasuhiroIkeda, ShigekiKobayashi, NoriakiIkemoto, MasunoriMatsuzaki
Journal: Circulation (2005)

Background— According to our hypothesis, 2 domains within the ryanodine receptor (RyR) of sarcoplasmic reticulum (SR) (N-terminal [0 to 600] and central [2000 to 2500] domains), where many mutations have been found in patients with polymorphic ventricular tachycardia, interact with each other as a regulatory switch for channel gating. Here, we investigated whether the defective FKBP12.6-mediated stabilization of RyR in heart failure is produced by an abnormal interdomain interaction. Methods and Results— SR vesicles were isolated from dog left ventricular muscles, and then the RyR moiety of the SR was fluorescently labeled with methylcoumarin acetate (MCA) using DPc10, a synthetic peptide corresponding to Gly2460-Pro2495 of RyR (one of the mutable domains in polymorphic ventricular tachycardia), as a site-directing carrier; the carrier was removed from the RyR after MCA labeling. Addition of DPc10 induced an unzipped state of the interacting N-terminal and central domains, as evidenced by an increase in t...
Insulin Prevents Cardiomyocytes From Oxidative Stress–Induced Apoptosis Through Activation of PI3 Kinase/Akt
Authors: RyuichiAikawa, MasaoNawano, YapingGu, HidekiKatagiri, TomoichiroAsano, WeidongZhu, RyozoNagai, IsseiKomuro
Journal: Circulation (2000)

Background—Loss of cardiomyocytes by apoptosis is proposed to cause heart failure. Reactive oxygen species induce apoptosis in many types of cells including cardiomyocytes. Because insulin has been reported to have protective effects, we examined whether insulin prevents cardiomyocytes from oxidative stress–induced apoptotic death. Methods and Results—Cultured cardiomyocytes of neonatal rats were stimulated by hydrogen peroxide (H2O2). Apoptosis was evaluated by means of the TUNEL method and DNA laddering. Incubation with 100 μmol/L H2O2 for 24 hours increased the number of TUNEL-positive cardiac myocytes (control, ≈4% versus H2O2, ≈23%). Pretreatment with 10−6 mol/L insulin significantly decreased the number of H2O2-induced TUNEL-positive cardiac myocytes (≈12%) and DNA fragmentation induced by H2O2. Pretreatment with a specific phosphatidylinositol 3 kinase (PI3K) inhibitor, wortmannin, and overexpression of dominant negative mutant of PI3K abolished the cytoprotective effect of insulin. Insulin strongl...
Abstract 2839: Notch3-dependent beta-catenin signaling mediates EGFR TKI drug persistence in EGFR mutant NSCLC
Authors: Rajeswara Rao Arasada, Konstantin Shilo, Jianying Zhang, Rashelle Ghanem, Tadaaki Yamada, Seiji Yano, David Carbone
Journal: Cancer Research (2018)

Abstract EGFR tyrosine kinase inhibitors (EGFR-TKIs) usually cause dramatic responses in EGFR-mutant lung cancer, but different patients with identical drivers have widely different progression-free intervals, and resistance universally develops. In those cases without pre-existing resistant clones, even though every cell expresses the driver, some tumor clonogens survive in order to acquire target reactivation or bypass resistance mechanisms. The involvement of β-catenin in EGFR TKI resistance has been previously reported however the precise mechanism by which β-catenin activation contributes to EGFR TKI resistance is not clear. Our transcriptome analysis identified that EGFR inhibition results in the activation of β-catenin signaling in a Notch3-dependent manner, which facilitates the survival of a subset of cells that we call “adaptive persisters”. We have previously reported that EGFR-TKI treatment rapidly activates Notch3, and here our co-immunoprecipitation studies identified a physical association of Notch3 with β-catenin, which in turn leads to increased stability and activation of β-catenin. In vitro pulmosphere formation assays and in vivo limiting dilution assays reveled that adaptive persisters display characteristics of stem-like cells. Furthermore, tumor xenograft studies using HCC827 and HCC4006 demonstrate that the combination of EGFR-TKI and the β-catenin inhibitor, ICG-001 inhibits the development of these adaptive persisters, decreases tumor burden, improves recurrence free survival, and overall survival. Overall, Notch3 plays a pivotal role in the maintenance of lung cancer stem cells (CSCs) and the induction of EGFR TKI mediated drug persisters with cancer stem cell like characteristics, but is difficult to selectively target. Our study finds that this effect is driven by the Notch3-dependent activation of β-catenin signaling in a non-canonical fashion. A combination of EGFR TKI and β-catenin inhibitors decreases tumor take, delays tumor recurrence and increases overall survival in EGFR mutant models. Thus, our findings provide novel insights on role of drug persistence early after EGFR TKI therapy and presents a rationale for clinical testing of EGFR TKIs with β-catenin inhibitors for the treatment of EGFR mutant NSCLC. Citation Format: Rajeswara Rao Arasada, Konstantin Shilo, Jianying Zhang, Rashelle Ghanem, Tadaaki Yamada, Seiji Yano, David Carbone. Notch3-dependent beta-catenin signaling mediates EGFR TKI drug persistence in EGFR mutant NSCLC [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 2839.
Abstract 2045: Mechanistic insights into the role of cAMP-regulated EPAC1 in tumor-induced angiogenesis and metastatic potential in triple-negative breast cancer
Authors: Muthu Dhandapani, Aaron Goldman, Naveen Kumar, Peeyush Prasad, Eshna Jash, Itender Singh, Kodaganur S. Gopinath, Krishnamurthy S, Prabhusankar P, Seema Sehrawat
Journal: Cancer Research (2018)

Abstract Background: Breast cancer is the leading cause of cancer-related mortality in women. Triple negative breast cancer (TNBC) is one of most aggressive subtypes, which is often accompanied by metastasis, a feature that requires development of new blood vessels (neovasculature) to disseminate tumor cells throughout the body. We recently reported that down-regulation of exchange factor directly activated by Cyclic AMP (cAMP), also known as EPAC1, leads to a reduction in proliferation and inhibition of cell migration. Methods: Here, using gene knockdown by siRNA and a 3-dimensional in-vitro TNBC co-culture model with Human Vascular Endothelial Cells (HUVECs), we studied microvascular density and the role of EPAC1. Angiogenesis proteome profiling was employed to examine protein networks that were regulated by EPAC1 in the TNBC cell line, MDA-MB-231. Immunofluorescence along with Electric cell-substrate impedance sensing (ECIS) was used to study vascular permeability. To confirm these findings in a translational context, we employed a human tumor explant assay that predicts clinical response to therapy (CANscriptTM) and studied CD34+ nodes to determine how neovasculature associates to drug response. Results: We determined that downregulation of EPAC1 in the TNBC cell line, MDA-MB-231, leads to reduction of proteins involved in cell migration, metastasis, angiogenesis and adhesion. Interestingly, we determined that loss of EPAC1 leads to increased expression of negative regulators in these same pathways. Immunofluorescence imaging showed that EPAC1 downregulation in MDA-MB-231 cells leads to diminished expression of proteins such as Paxillin, MENA, MMP-9 and tubulin. indicated that EPAC1 role in vascular permeability. Finally, CANscriptTM demonstrated a link between response to therapy and microvascular density, which was reduced under drug pressure in patients that were predicted to respond to treatment. Conclusion: Our results suggest that EPAC1 is a driver of microvascular density in the tumor microenvironment, a feature that may play a key role in distant metastasis and therapy failure. Ex-vivo modeling of neovasculature may be a novel strategy to predict clinical response and distant metastasis. Citation Format: Muthu Dhandapani, Aaron Goldman, Naveen Kumar, Peeyush Prasad, Eshna Jash, Itender Singh, Kodaganur S. Gopinath, Krishnamurthy S, Prabhusankar P, Seema Sehrawat. Mechanistic insights into the role of cAMP-regulated EPAC1 in tumor-induced angiogenesis and metastatic potential in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2045.
Association Between Local Pulse Pressure, Mean Blood Pressure, and Large-Artery Remodeling
Authors: PierreBoutouyrie, CarolineBussy, PatrickLacolley, XavierGirerd, BrigitteLaloux, StéphaneLaurent
Journal: Circulation (1999)

Background—The aim of the present study was to determine the respective influences of local pulse pressure and mean blood pressure on arterial remodeling in humans at 2 arterial sites: a central, predominantly elastic artery (the common carotid artery) and a peripheral muscular artery (the radial artery). Methods and Results—Forty-three healthy subjects and 124 never-treated hypertensive patients were included in the study. Intima-media thickness and internal diameter of the carotid and radial arteries were noninvasively determined with high-definition echo-tracking devices. Pulse pressure was measured locally with applanation tonometry. Multivariate regression models including mean blood pressure and local pulse pressure were established in the whole population. Carotid internal diameter and intima-media thickness were strongly influenced (P<0.0001) by carotid pulse pressure but not by mean blood pressure or brachial pulse pressure, independently of age and sex. Radial artery internal diameter was correl...
Abstract 3992: Varlitinib demonstrates tumor regression and vessel normalization in ErbB-dependent and mutated beta-catenin hepatocellular carcinoma patient-derived xenograft model
Authors: Wai Ho Shuen, Richard Ong, Chloe Yeo, Rebecca Banu, Lip Seng Koh, Chit Lai Chee, Qihui Seet, Lisa Ooi, Mark McHale, Bertil Lindmark, Han Chong Toh, Huynh Hung
Journal: Cancer Research (2018)

Abstract Hepatocellular carcinoma (HCC) is the most common form of liver cancer and current therapies such as sorafenib, regorafenib and lenvatinib, prolong median overall survival by less than a year. Hence, there is an urgent need for additional HCC therapies. Varlitinib is a potent, reversible, small molecule pan – HER inhibitor that selectively binds to EGFR, HER2 and HER4. Varlitinib is currently being clinically tested across multiple indications including biliary tract cancer and gastric cancer. In HCC patient – derived xenograft (PDX) models, varlitinib has been shown to mediate potent anti – tumour activities (ASCO 2016). To understand the molecular profiles of HCC PDX sensitive to varlitinib, we studied the ErbB family signalling in 56 HCC PDX models and varlitinib was found to be efficacious in HCC PDX with activated ErbB2 / 3 as well as mutated beta – catenin. In HCC PDX models with activated ErbB2 / 3 , treatment with varlitinib inhibited multiple proliferation and anti – apoptosis pathways including AKT, PI3K and Survivin pathways. In addition, normalisation of blood vessels by varlitinib in the PDX models, as assessed by staining with biotinylated lectin and anti – CD31, also reduced hypoxia in the tumour microenvironment as well as enhanced the infiltration of immune cells. Activating mutations in the Wnt / beta – catenin pathway lead to tumour development in HCC and occur in a subset of HCC tumours. HCC PDX models with beta – catenin mutation were found to be sensitive to varlitinib. Varlitinib led to down – regulation of mutated beta – catenin signalling, and enhanced staining of beta – catenin at the membrane instead of in the nucleus. Since activating mutations in the Wnt / beta – catenin pathway are detected in 26 – 40 % of HCC samples, our data shows that varlitinib may represent an alternative treatment for a significant subset of HCC which are ErbB / beta – catenin – dependent. Citation Format: Wai Ho Shuen, Richard Ong, Chloe Yeo, Rebecca Banu, Lip Seng Koh, Chit Lai Chee, Qihui Seet, Lisa Ooi, Mark McHale, Bertil Lindmark, Han Chong Toh, Huynh Hung. Varlitinib demonstrates tumor regression and vessel normalization in ErbB-dependent and mutated beta-catenin hepatocellular carcinoma patient-derived xenograft model [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 3992.
Control of inducible gene expression links cohesin to hematopoietic progenitor self-renewal and differentiation
Authors: Sergi Cuartero, Felix D. Weiss, Gopuraja Dharmalingam, Ya Guo, Elizabeth Ing-Simmons, Silvia Masella, Irene Robles-Rebollo, Xiaolin Xiao, Yi-Fang Wang, Iros Barozzi, Dounia Djeghloul, Mariane T. Amano, Henri Niskanen, Enrico Petretto, Robin D. Dowell, Kikuë Tachibana, Minna U. Kaikkonen, Kim A. Nasmyth, Boris Lenhard, Gioacchino Natoli, Amanda G. Fisher, Matthias Merkenschlager
Journal: Nature Immunology (2018)
Abstract 3625: MET signaling upregulates PD-L1 expression in human lung and gastric cancer
Authors: Hyunkyung Ahn, Sehui Kim, Ji Young Jang, Dohee Kwon, Jaemoon Koh, Young A Kim, Doo Hyung Chung, Yoon Kyung Jeon
Journal: Cancer Research (2018)

Abstract Background: Tyrosine kinase receptor, MET, plays an important role for the progression of tumor through diverse mechanisms. Cancer immunotherapy targeting PD-1/PD-L1 pathway shows clinical benefit in patient with PD-L1 expressing solid tumor. In our previous study on non-small cell lung cancer (NSCLC) using immunohistochemistry, MET overexpression was significantly associated with programmed cell death-ligand 1 (PD-L1) overexpression. Thus, we investigated if MET signaling pathway is involved in PD-L1 expression in tumor cells. Method and Result: Lung adenocarcinoma cell lines including H596 (harboring MET exon 14 skipping mutation), H1993 (harboring MET gene amplification), H23 and H522 (MET wild-type), and a gastric carcinoma cell line, Hs746T (harboring MET exon 14 skipping mutation and gene amplification) were used. Hs746T cells were treated with MET inhibitor or transfected with MET siRNA and subject to microarray analysis. MET inhibition or knockdown led to changes in expression level of variable immune-related molecules, of which PD-L1 was one of the most down-regulated molecules. Stimulation of H596, H23 and H522 cells with HGF, a MET ligand, increased PD-L1 expression at the mRNA and protein level. Treatment of H1993 and Hs746T cells with MET inhibitor or MET knockdown using siRNA resulted in down-regulation of PD-L1 at the mRNA, total protein, and surface expression levels. PI3K/Akt and MAPK/Erk signaling pathways were involved in MET-mediated PD-L1 up-regulation in H1993 and Hs746T cells. Finally, the Cancer Genome Atlas (TCGA) analysis showed that MET and PD-L1 expression are significantly positively correlates with each other in patients with lung cancer (in NSCLC, rho=0.219 [p&amp;lt;0.001]; in adenocarcinoma, r=0.401 [p&amp;lt;0.001]; in squamous cell carcinoma, r=0.144 [p=0.001]) and in patients with gastric cancer (r=0.137 [p=0.005]). Conclusion: This study demonstrates that MET signaling increases PD-L1 transcription and protein overexpression in lung and gastric cancer cells, which might contribute to immune escape of tumor via PD-1/PD-L1 pathway. MET-targeted therapy may be considered as combination therapy with PD-1/PD-L1 blockades. Citation Format: Hyunkyung Ahn, Sehui Kim, Ji Young Jang, Dohee Kwon, Jaemoon Koh, Young A Kim, Doo Hyung Chung, Yoon Kyung Jeon. MET signaling upregulates PD-L1 expression in human lung and gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3625.
Statin-Associated Myopathy—An Elusive Clinical Problem
Authors: Gregory Curfman
Journal: JAMA Internal Medicine (2018)

Muscle disorders resulting from statin therapy, the most common manifestation of statin intolerance, are vexing to both patients and physicians. Statin-associated myopathy may appear as a spectrum of manifestations that include myalgias, myopathy, myositis, myonecrosis, and rhabdomyolysis.1
Abstract 748: Non-internalizing site-specific antibody-drug conjugates based on maytansinoids display curative properties
Authors: Gianluca Sala, Emily Capone, Enza Piccolo, Sara Ponziani, Roberta Gentile, Rodolfo Ippoliti, Francesco Giansanti, Stefano Iacobelli
Journal: Cancer Research (2018)

Abstract Antibody-Drug Conjugates (ADCs) are highly potent biopharmaceuticals that use the targeting ability of monoclonal antibodies to selectively bind to tumor cells where the conjugated cancer drug is released. Traditionally, the anticancer efficacy of ADCs relies on their selective internalization by cancer cells. However, it has recently been shown that non-internalizing, linkerless ADCs targeting the tumor extracellular environment can display a potent therapeutic activity. LGALS3BP (aka Mac-2 BP or 90K) represents an appealing target for non-internalizing ADC development, as the protein is largely secreted by the majority of human tumors, while being virtually undetectable in normal adult tissues except for the prostate and the colorectum. Additionally, once secreted the protein stops from spreading and clusters on the plasma membrane where it binds to some endogenous ligands. Here, we show that an engineered variant of the humanized 1959 antibody to human LGALS3BP selectively localizes around the tumor cells and once site-specifically coupled to the maytansinoid drugs DM3 or DM4 by means of disulfide linker can display a potent therapeutic activity. Both the 1959sss-DM3 and -DM4 conjugates mediated potent antitumor activity in mice bearing human tumor xenografts. Quantitative biodistribution studies confirmed a preferential accumulation of 1959sss-DM3 and -DM4 conjugates around the tumor cells. Notably, we found that both conjugates were well tolerated and cured 100% of tumor-bearing mice. Our findings offer a preclinical proof-of-concept for curative non-internalizing ADC endowed with an innovative mechanism of action. Citation Format: Gianluca Sala, Emily Capone, Enza Piccolo, Sara Ponziani, Roberta Gentile, Rodolfo Ippoliti, Francesco Giansanti, Stefano Iacobelli. Non-internalizing site-specific antibody-drug conjugates based on maytansinoids display curative properties [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 748.
Abstract 19303: Balloon Pulmonary Angioplasty Improves Right Ventricular Energetic Efficiency via the Improvement of Right Ventricular-Pulmonary Artery Coupling in Patients With Chronic Thromboembolic Pulmonary Hypertension
Authors: Takafumi Sakamoto, Kohtaro Abe, Koshin Horimoto, Kazuya Hosokawa, Keiji Oi, Yasushi Mukai, Yuzo Yamasaki, Michunobu Nagao, Kenji Sunagawa, Hiroyuki Tsutsui
Journal: Circulation (2016)

Introduction: Balloon pulmonary angioplasty (BPA) improves hemodynamics and functional capacity in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). However the impact...
Abstract 4759: Designing clinical trials in tumor indications with a positive signal in phase 1
Authors: Cong Chen, Keaven Anderson, Devan V. Mehrotra, Eric H. Rubin, Archie Tse
Journal: Cancer Research (2018)

Abstract Increasingly, the conventional proof-of-concept randomized Phase 2 study is skipped in favor of directly going to Phase 3 after an experimental oncology drug has demonstrated promising anti-tumor activity in Phase 1 with a small sample size. This shift in the balance between certainty and speed is especially evident in the immune-oncology space where the tremendous success of immune checkpoint inhibitors has brought unprecedented competition in the field. The aggressive approach can be very risky no matter how promising an experimental drug appears in Phase 1. In this presentation, we introduce a novel adaptive design that mitigates the risk of late-stage programs. The proposed approach starts with a Phase 2 trial and adds an option in the design that allows the expansion of the Phase 2 trial into Phase 3 if the interim result based on the Phase 2 endpoint is promising. If the decision is to not expand, the study is kept as a Phase 2 trial and the primary analysis is conducted at the end of Phase 2. Otherwise, the study is expanded into a Phase 3 trial and the primary analysis of the study is conducted at the end of Phase 3, utilizing data from all enrolled patients including those already used for the decision making in the ongoing trial. The proposed approach is more efficient than the conventional approach that conducts and analyzes Phase 2 and Phase 3 trials sequentially, and is less risky than the contemporary approach of skipping Phase 2. Importantly, we will show that this design controls overall Type I error regardless of the expansion criterion. As a result, the study can still be considered positive even without expansion to Phase 3. Citation Format: Cong Chen, Keaven Anderson, Devan V. Mehrotra, Eric H. Rubin, Archie Tse. Designing clinical trials in tumor indications with a positive signal in phase 1 [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 4759.