tbuckley/cabot-search huggingface dataset:
Abstract 12244: The Impact of Anti-angiogenic Isoform of Vascular Endothelial Growth Factor A in Patients With Pulmonary Hypertension
Authors: Satoshi Suzuki, Kazuhiko Nakakzato, Koichi Sugimoto, Akiomi Yoshihisa, Takayoshi Yamaki, Hiroyuki Kunii, Hitoshi Suzuki, Shu-ichi Saitoh, Yasuchika Takeishi
Journal: Circulation (2015)

Background: The primary form of pulmonary hypertension (PH) is classified as idiopathic pulmonary artery hypertension (IPAH), while the secondary disease state, including collagen disease, thromboembolism and congenital heart disease with systemic-to-pulmonary shunts. Vascular endothelial growth factor (VEGF) is a key contributor for angiogenesis and vasculogenesis, and production of VEGF is urged in PH patients due to hypoxia. Alternative splicing and proteolytic processing of VEGF-A, which is the most important member of VEGF family, produces various isoforms, including VEGF165b, which has anti-angiogenic effect. The purpose of this study was to examine the clinical significance of circulating levels of VEGF165b in patients with PH. Methods and Results: Plasma levels of VEGF165b were measured in 39 patients with PH (9 in IPAH, 7 in PH related to collagen disease, 13 in chronic thromboembolic PH (CTEPH), 10 in others including congenital heart disease) and 27 normal subjects as control. In baseline clinical characteristics, female was more frequent and body mass index was smaller in PH patients than in control. Plasma VEGF165b level in PH patients was higher than in control subjects (97.1±56.2 vs. 53.3±13.4 pg/ml, P&lt;0.001). Especially, plasma VEGF165b level was higher in IPAH (137.1±108.1 pg/ml, P&lt;0.001), but not in PH related to collagen disease (80.1±16.1 pg/ml), CTEPH (86.4±16.7 pg/ml), and others (88.4±9.7 pg/ml). Tricuspid regurgitation pressure gradient (TR-PG) was higher in PH patients than in control (71.9 ± 25.8 vs. 11.2 ± 11.6 mmHg, P&lt;0.001), and TR-PG had significant positive correlation with plasma VEGF165b level (R=0.281, P=0.373). Right ventricular dimension, right ventricular fractional area change and SpO2 level were not correlated with plasma VEGF165b level. Conclusions: VAGF165b, anti-angiogenic isoform, might contribute to the pathophysiology in PH, especially in idiopathic pulmonary artery hypertension.
Abstract 1347: Autophagy inhibitor, chloroquine synergize oxaliplatin by modulating activity of cytosolic HMGB1 in pancreatic cancer
Authors: Seonmin Lee, Kyu-Pyo Kim, Changhoon Yoo, Danbi Kim, Chorong Kim, Heejung Chae, Jihoon Kang, Baek-Yeol Ryoo
Journal: Cancer Research (2018)

Abstract Autophagy is a regulated, destructive catabolic mechanism to degrade cellular organelles and macromolecules. In cancer, the role of autophagy in tumor cell survival or death is still controversial because of each tumor type has a heterogeneity on metabolic status and microenvironment. In this study, we showed that autophagy inhibitor, chloroquine (CQ), increased sensitivity to oxaliplatin in pancreatic cancer cell lines. The autophagy inhibitor, chloroquine effectively inhibited autophagic flux which is important for maintenance of pancreatic cancer cell metabolism and drug resistance. Treatment of oxaliplatin after blockade of autophagy increased chromatin instability and facilitated loss of nuclear HMGB1. In consequence the cells turned into apoptotic cell death. The drug combination effect of chloroquine and oxaliplatin shows that inhibition of autophagy by chloroquine carry on dual role in pancreatic cancer cell death. First, chloroquine occurs cytosolic redox imbalance based on increase mitochondrial ROS (mtROS) following rupture of autolysosome. Second, the cytosolic redox imbalance occurred by chloroquine induces failure of autophagy by incapacitation of cytosolic HMGB1. Here we suggest that autophagy inhibition by chloroquine synergize oxaliplatin by modulating activity of cytosolic HMGB1. Also we suggest HMGB1 as a new target for therapeutic agents against pancreatic cancer. Citation Format: Seonmin Lee, Kyu-Pyo Kim, Changhoon Yoo, Danbi Kim, Chorong Kim, Heejung Chae, Jihoon Kang, Baek-Yeol Ryoo. Autophagy inhibitor, chloroquine synergize oxaliplatin by modulating activity of cytosolic HMGB1 in pancreatic 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 1347.
Abstract 4178: AKT-ERK axis in circulating tumor cells is a target for metastatic suppression
Authors: Hung-Chi Cheng, Ying-Jan Wang, Li-Hsin Cheng
Journal: Cancer Research (2018)

Abstract Cytotoxic cancer therapies often result in unwanted side effects, drug resistance, and cancer metastasis. To avoid this, an anti-metastatic therapeutic strategy independent of apoptosis is alternatively desired. Malignant circulating tumor cells (CTCs) may escape from anoikis by sustaining AKT survival signals. Moreover, cancerous fibronectin polymers (polyFN) are known to mediate the adhesion of CTCs to endothelia and lung metastasis. Depletion of polyFN from CTCs without lowering AKT signaling may thus be an ideal anti-metastatic approach. Screening several phytochemical compounds, we found that Pterostilbene (PS), a resveratrol derivative, potently reduced polyFN on suspended tumor cells, whereas it significantly elevated AKT phosphorylation (pAKT), apparently in contrast to its well-known anti-apoptotic effect on adherent tumor cells. Inactivation of ERK signaling in suspended tumor cells was responsible for the enhanced pAKT by PS, leading to suppressions of polyFN assembly and tumor metastasis. Pretreatment with a PI3K inhibitor, LY294002, effectively reduced PS-activated AKT, rescued PS-inactivated ERK, and consequently reversed the PS-suppressed polyFN assembly which was then overturned by the ERK inhibitor U0126. Indeed, PS-suppressed lung metastasis was counteracted by LY294002, which was reversed with U0126. Dietary PS may serve as a novel complementary medicine, for it could be orally administered and efficiently blockaded tumor metastasis by targeting AKT-ERK signaling axis in CTCs. Citation Format: Hung-Chi Cheng, Ying-Jan Wang, Li-Hsin Cheng. AKT-ERK axis in circulating tumor cells is a target for metastatic suppression [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 4178.
Abstract 18119: Structural and Functional Right Ventricular Remodelling is Related to Training Intensity in an Experimental Model of Endurance Training
Authors: Maria Sanz, Cira Rubies, Marta Sitges, Montserrat Battle, Bart Bijnens, Lluis Mont, Josep Brugada, Eduard Guasch
Journal: Circulation (2015)

Background: a deleterious, potentially arrhythmogenic right ventricle (RV) remodelling has been documented in response to regular training in athletes. However, it is unclear how exercise intensity contributes to RV adverse remodelling. Aim: Our aim was to evaluate the relationship between RV functional and structural remodelling,and the intensity of exercise in an animal model. Methods: Thirty-six Wistar rats were conditioned to run daily in a treadmill at a moderate (MOD, 45 min at 30cm/s; estimated 60% VO2max) or vigorous (VIG, 60 min at 60cm/s; estimated 85-90% VO2max) intensity for 16 weeks; Sedentary rats (SED) served as controls. An standard echocardiographic assessment of both ventricles and Tissue Doppler Imaging (TDI) of the RV were performed. Hemodynamics of both ventricles were evaluated with a sensor tip pressure catheter. Results: After MOD training, both ventricles similarly dilated (roughly 15%). RV function improved as shown by increased RV apical function assessed by TDI (Figure).With VIG training, though, RV disproportionately dilated (in comparison to MOD: 10±13% RV dilation vs 1±12% LV dilation, p&lt;0.05), RV systolic function declined, and RV diastolic function worsened (Figure).The hemodynamic experiments confirmed a decreased RV contractility and impaired relaxation with VIG training (Figure) in comparison to MOD. The LV systolic and diastolic function were unchanged in all groups. Conclusion: In this animal model we show that exercise intensity critically determines a dual response of the RV. A favourable adaptation of the RV after MOD training turned into disproportionate RV dilatation, decreased contractility and worse diastolic function in the VIG group. Our findings suggest the existence of an intensity threshold beyond which remodelling of the RV becomes maladaptive. Our work provides valuable data to identify athletes at risk of exercise related complications
Abstract 931: Discovery of ABBV-744, a first-in-class highly BDII-selective BET bromodomain inhibitor
Authors: George S. Sheppard, Le Wang, Steven D. Fidanze, Lisa A. Hasvold, Dachun Liu, John K. Pratt, Chang H. Park, Mai-Ha Bui, Emily J. Faivre, Xiaoli Huang, Xiaoyu Lin, Denise M. Wilcox, Yu Shen, Daniel H. Albert, Terrance J. Magoc, Ganesh Rajaraman, Warren M. Kati, Keith F. McDaniel
Journal: Cancer Research (2018)

Abstract The BET family of proteins consists of BRD2, BRD3, BRD4 and BRDT, with each of these proteins containing two distinct bromodomains (BDI and BDII). ABBV-075, like other first generation BET family bromodomain inhibitors currently under clinical development, binds to each of the 8 bromodomains with similar affinity and inhibits the proliferation of cancer cells that represent a wide range of tumor types. We hypothesized that selectively targeting specific subsets of the BET bromodomain might abolish this broad spectrum profile such that only the tumor types that are highly addicted to the subtype specific BET bromodomain-mediated transcription would remain sensitive to these selective agents. Both BDI and BDII are highly conserved across BET family members (&amp;gt; 70% identity), suggesting that the generation of compounds that are selective for the BDI bromodomains or the BDII bromodomains might be achievable. Structure-based design targeting the Asp144/His 437 and Ile146/Val439 sequence differences (BRD4 BDI/BDII numbering) led to the identification of structural analogs of ABBV-075 demonstrating greater than 100X selectivity for BRD4 BDII over BRD4 BDI. Further elaboration led to compounds with improved BDII-selectivity and oral bioavailability and the identification of the clinical asset ABBV-744. Disclosures: All authors are employees or former employees of AbbVie. The design, study conduct, and financial support for this research were provided by AbbVie. AbbVie participated in the interpretation of data, review, and approval of the publication. Citation Format: George S. Sheppard, Le Wang, Steven D. Fidanze, Lisa A. Hasvold, Dachun Liu, John K. Pratt, Chang H. Park, Mai-Ha Bui, Emily J. Faivre, Xiaoli Huang, Xiaoyu Lin, Denise M. Wilcox, Yu Shen, Daniel H. Albert, Terrance J. Magoc, Ganesh Rajaraman, Warren M. Kati, Keith F. McDaniel. Discovery of ABBV-744, a first-in-class highly BDII-selective BET bromodomain inhibitor [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 931.
Abstract 281: Identifying genetic variation and cellular heterogeneity with a comprehensive cancer analysis toolkit
Authors: Sarah Garcia, Rajiv Bharadwaj, Stéphane Boutet, Claudia Catalanotti, Valeria Giangerra, Josephine Lee, Jessica Terry, Stephen Williams, Grace X. Zheng, Tarjei Mikkelsen, Michael Schnall-Levin, Ben Hindson, Deanna M. Church
Journal: Cancer Research (2018)

Abstract Understanding disease development, progression and response to treatment remains elusive for most types of cancer. This is due both to the genetic complexity seen in tumors as well as differences in how the surrounding cells and immune system respond to the developing tumor. To fully understand all aspects of disease progression and response to treatment, a systems level approach is needed. We have developed a platform that allows for high resolution multi-omics analysis of the tumor and its microenvironment. This platform is built upon a microfluidic system that enables the production of hundreds of thousands to millions of partitioned barcoded reactions. On this platform we generate Linked-Reads that allow for the detailed resolution of complex structural variant events. To obtain more detailed information about tumor heterogeneity and clonal structure, we also perform single cell DNA analysis that allows for the detection of sub-megabase copy number variants at the single cell level.The platform also provides detailed resolution of the cells occupying the microenvironment surrounding the tumor. Using a combination of single cell gene expression and enriched V(D)J B and T cell repertoire analysis, we identify cells constituting a tumor, as well as the immune and nonimmune cells surrounding the tumor. We also provide single cell profiling of the paired antigen receptor chains for both B and T cells. As a demonstration, we have performed this analysis on three types of tumor samples: metastatic melanoma (MM), primary colorectal cancer (CRC) and primary clear cell renal carcinoma (CCRC). We are able to identify a clonal expansion in the CCRC sample and determine there is no expansion in the CRC sample. The combination of these approaches allows for unparalleled characterization of disease development, progression and response. Citation Format: Sarah Garcia, Rajiv Bharadwaj, Stéphane Boutet, Claudia Catalanotti, Valeria Giangerra, Josephine Lee, Jessica Terry, Stephen Williams, Grace X. Zheng, Tarjei Mikkelsen, Michael Schnall-Levin, Ben Hindson, Deanna M. Church. Identifying genetic variation and cellular heterogeneity with a comprehensive cancer analysis toolkit [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 281.
Targeting EGFR<sup>L858R/T790M</sup> and EGFR<sup>L858R/T790M/C797S</sup> resistance mutations in NSCLC: Current developments in medicinal chemistry
Authors: Xiaoyun Lu, Lei Yu, Zhang Zhang, Xiaomei Ren, Jeff B. Smaill, Ke Ding
Journal: Medicinal Research Reviews (2018)

Both the first-generation reversible epidermal growth factor receptor (EGFR) inhibitors gefitinib and erlotinib and the second-generation covalent epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) afatinib have significantly improved the survival of non-small-cell lung cancer (NSCLC) patients with activating EGFR mutations. However, a secondary EGFRT790M mutation leads to the clinically acquired resistance to the first- and second-generation EGFR-TKIs drugs. A number of the third-generation wild-type sparing EGFR inhibitors, for example, WZ4002, CO1686, AZD9291, HM61713, EGF816, ASP8173, and PF0674775, have been developed, among which AZD9291 has been approved by US FDA for the treatment of NSCLC patients with EGFRT790M . More recently, a tertiary EGFRC797S mutation was reported as the dominant resistance mechanism to the third-generation irreversible inhibitors. It is highly desirable to develop the fourth-generation EGFR inhibitors. This review summarizes the mechanisms of acquired resistance and the latest medicinal chemistry advances on the third- and fourth-generation EGFR inhibitors, with special attention being paid to the allosteric and reversible inhibitors combating the tertiary EGFRC797S mutation.
Antiglioma via regulating oxidative stress and remodeling tumor-associated macrophage using lactoferrin-mediated biomimetic codelivery of simvastatin/fenretinide
Authors: Xiaopeng Mo, Zening Zheng, Yang He, Huihai Zhong, Xuejia Kang, Mingjie Shi, Tuanbing Liu, Zheng Jiao, Yongzhuo Huang
Journal: Journal of Controlled Release (2018)
Abstract 11095: Prevalence of Metabolic Syndrome in Healthy Middle-Aged Adults: Insights from the Primary Care Audit of Global Risk Management (PARADIGM) Study
Authors: Mahesh Kajil, Michelle Tsigoulis, Subodh Verma, Milan Gupta
Journal: Circulation (2012)

BACKGROUND: The metabolic syndrome (MS) is associated with increased risk for cardiovascular disease and all-cause mortality. We assessed the prevalence of MS and associated clinical characteristic...
Abstract 4883: Suppression of breast cancer by reprogramming glucose metabolism and energy production with HJC0152
Authors: Hyejin Kim, Jiabin Dong, Jimin Xu, Dengfeng Li, Zhi Zheng, Na Ye, Ziwei Zhang, Haiying Chen, Jia Zhou, Qiang Shen
Journal: Cancer Research (2018)

Abstract Most mammalian cells use glucose as the primary fuel source. Glucose is metabolized via glycolysis to pyruvate, which is further transferred into mitochondria for generation of ATP through the Krebs cycle in normal condition. However, metabolism is characteristically reprogrammed and cancer cells or highly proliferative cells preferably generate ATP through lactate production by lactate dehydrogenase (LDH/LDHA), referred to as the Warburg effect or metabolic reprogramming toward anaerobic glycolysis. Efficient control of energy metabolism is the key to maintaining metabolic homeostasis, and disturbance in energy balance provokes diseases such as obesity, diabetes and cancer. However, the mechanisms underlying efficient energy metabolic homeostasis and breast cancer development are poorly understood. HJC0152, a novel small-molecule glucose metabolism modulator, was developed using structure-/fragment-based drug design strategies and molecular modeling techniques. Aggressively growing and metastatic breast cancer cells of triple-negative subtype (MDA-MB-231) treated with HJC0152 showed inhibited cell growth. Intriguingly, HJC0152 decreased activity and protein level of LDHA, which resulted in a decrease of lactate production in breast cancer cells. In addition, these cells also exhibited a decrease of glucose uptake by reducing Glut1 and HK2 protein level and modulation of the expression of glycolytic enzymes. Furthermore, HJC0152 treatment causes decreased mitochondrial membrane energy potential, resulting in significantly reduced level of intracellular ATP in MDA-MB-231 cells. Our findings suggest that HJC0152 is capable of reprogramming caner metabolism by modulating glucose metabolism and ATP production. These results may provide a rationale to develop HJC0152 as an effective therapeutics for cancer and other metabolic diseases with aberrant glucose metabolism. In addition, HJC0152 can serve as a molecular probing tool for elucidating the key factors responsible for developing breast cancer and other metabolic diseases. Citation Format: Hyejin Kim, Jiabin Dong, Jimin Xu, Dengfeng Li, Zhi Zheng, Na Ye, Ziwei Zhang, Haiying Chen, Jia Zhou, Qiang Shen. Suppression of breast cancer by reprogramming glucose metabolism and energy production with HJC0152 [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 4883.
Abstract 678: Raf-1 cysteine-rich domain (CRD) supports active orientations of KRas4B/Raf-1 at the membrane
Authors: Hyunbum Jang, Ruth Nussinov
Journal: Cancer Research (2018)

Abstract Ras is a small GTPase, controlling signal transduction pathways and promoting cell proliferation and survival. In cancer, there are two independent pathways in tumor proliferation: one includes Raf/MEK/ERK (MAPK) and PI3K/Akt/mTOR. KRas4B is the most abundant oncogenic isoform. In the MAPK pathway, KRas4B preferentially recruits Raf-1 and activates it. The high-affinity interaction of Ras binding domain (RBD) of Raf with Ras was solved, but the relative position of Raf's cysteine-rich domain (CRD) in the Ras/Raf complex at the membrane and the key question of exactly how it affects Raf signaling are daunting. Here, we employ all-atom MD simulations to investigate membrane-anchored Raf-1 CRD and suggest a model of KRas4B/Raf-1 complex at the anionic lipid bilayer composed of 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) and 1,2-dioleoyl-sn-glycero-3-phosphoserine (DOPS) in mole ratio 4:1. Active Ras modulates Raf activation, with KRas4B preferentially activating Raf-1. We show that the Raf-1 CRD stably binds anionic lipid bilayers inserting a positively-charged loop into the amphipathic interface. The loop contains key basic residues, responsible for the membrane association. Importantly, when in complex with Ras/RBD, covalently-connected CRD presents the same membrane interaction mechanism, with CRD locating at the space between the RBD and membrane, suggesting that CRD is an intrinsic membrane binding domain of Raf kinase. To date, CRD's role was viewed in terms of stabilizing Raf-membrane interaction. Our observations argue for a key role of CRD that Raf-1 CRD not only offers an additional anchor for the KRas4B/Raf-1 complex, but by reducing the fluctuations of Ras/RBD it also increases the population of Ras/RBD at the membrane and enhances the already high affinity between Ras and RBD. In the KRas4B/RBD-CRD complex, Raf-1 CRD supports the active-state Ras orientation at the membrane, releasing the catalytic domain from the transiently confined orientation. This promotes MAPK signaling, the key Ras proliferative pathway, above other pathways. Even though in the absence of CRD the Ras/Raf-1 RBD interaction can elicit MAPK signaling, the enhanced stability of the complex at the membrane rendered by CRD can considerably intensify it, by helping in Raf's dimerization. Our data reveal these significant roles of CRD at the membrane in the Raf activation. Funded by Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. Citation Format: Hyunbum Jang, Ruth Nussinov. Raf-1 cysteine-rich domain (CRD) supports active orientations of KRas4B/Raf-1 at the membrane [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 678.
Abstract 1351: Inhibition of autophagy enhances dihydroartemisinin (DHA)-induced cytotoxicity through DR5 upregulation
Authors: Chen Mei-Chuan
Journal: Cancer Research (2018)

Abstract Artemisinin (Qinghaosu) comes originally from Qinghao has been used against Plasmodium falciparum malaria for a long time. Dihydroartemisinin, an analogue of artemisinin, is also be listed by WHO to exhibit antimalarial and anticancer properties. In our study, DHA exhibits antiproliferative activity in several solid tumors, especially against colorectal cancer (CRC) HCT116 cells. Our current results show DHA suppresses cell proliferation and induces caspase-dependent apoptosis without inducing necrosis-like cell death in HCT116 cells. In addition, DHA interferes autophagy pathway by upregulating of LC3 II formation in HCT116 cells. Inhibition of autophagy with either autophagy inhibitor 3-methyladenine (3MA) or KD of ATG5 potentiated DHA-induced cell death. We found DHA increased expression level of DR5 while had no effect on DR4 expression level on surface of tumor cells. Further, cell-surface DR5 expression was significantly elevated in DHA-treated ATG5-KD cells. These findings suggest that inhibition of the autophagy enhances DHA-induced cytotoxicity through DR5 upregulation. Key words: Apooptsis, DR5 (Death Receptor 5), autophagy, colorectal cancer Citation Format: Chen Mei-Chuan. Inhibition of autophagy enhances dihydroartemisinin (DHA)-induced cytotoxicity through DR5 upregulation [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 1351.