tbuckley/cabot-search huggingface dataset:
Abstract LB-295: Discovery of potent selective oral ACSS2 inhibitors for the treatment of acetate avid tumors
Authors: Andreas Goutopoulos, Omri Erez, Philippe Nakache, Iris Alchanati, Avital Hay-Koren, Dikla Paz, Dimitri Kovalerchik, Hannah Oppenheimer, Eyal Gottlieb, Simone Botti, Inbal Mor, Nina Pastukh
Journal: Cancer Research (2020)

Abstract Under the low oxygen and lipid-depleted conditions, often encountered in the tumor microenvironment, acetate is used as nutrient by cancer cells for the biosynthesis of fatty acids. ACSS2, the enzyme responsible for acetate capture within the cell and its conversion into Acetyl-CoA, is upregulated under metabolically stressed conditions and its silencing is shown to inhibit tumor growth in xenografts. Two independent HTS campaigns identified the same small molecule ACSS2 inhibitor series that exhibited uncompetitive binding behavior in respect to ATP. A co-crystal structure of human ACSS2 in complex with a congener of the series revealed that it binds in the acetate pocket and forms favorable interactions with ATP, which is bound adjacently. These compounds were over 1000-fold times selective for ACSS2 over the mitochondrial ACSS1 and other Acyl-CoA synthetases. Medicinal chemistry optimization of this series resulted in advanced compounds with sub-nanomolar biochemical potency and single digit nanomolar cellular EC50s in inhibiting de novo fatty acid synthesis from labeled acetate and excellent pharmacokinetic properties. In vivo, in mice, these compounds inhibited labeling of fatty acids in various tissues after administration of labelled acetate or ethanol. They exhibited in vivo anti-tumor efficacy after oral administration in xenograft models that are acetate avid, whereas had no effect in tumors that show low acetate uptake. MTB-9655, one of the compounds from this series with optimally balanced properties, is currently entering IND-enabling studies to allow its testing in cancer patients. Citation Format: Andreas Goutopoulos, Omri Erez, Philippe Nakache, Iris Alchanati, Avital Hay-Koren, Dikla Paz, Dimitri Kovalerchik, Hannah Oppenheimer, Eyal Gottlieb, Simone Botti, Inbal Mor, Nina Pastukh. Discovery of potent selective oral ACSS2 inhibitors for the treatment of acetate avid tumors [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr LB-295.
Abstract 1534: Vimentin prevents a miR-dependent negative regulation of tissue factor mRNA during epithelial-mesenchymal transitions and facilitates early metastasis
Authors: Aline Vanwynsberghe, Marie-Emilie Francart, Christine Gilles
Journal: Cancer Research (2020)

Abstract Epithelial-Mesenchymal Transitions (EMTs) are high-profile in the field of circulating tumor cells (CTCs). EMT-shifted CTCs are considered to encompass pre-metastatic subpopulations though underlying molecular mechanisms remain elusive. Our previous work identified Tissue Factor (TF) as an EMT-induced gene providing tumor cells with coagulant properties and supporting metastatic colonization by CTCs. We here report that vimentin, the type III intermediate filament considered a canonical EMT marker, contributes to TF regulation and positively supports coagulant properties and early metastasis. Different evidence further pointed to a new post-transcriptional regulatory mechanism of TF mRNA by vimentin: (i) vimentin silencing accelerated TF mRNA decay after actinomycin-D treatment, reflecting TF mRNA stabilization, (ii) RNA immunoprecipitation revealed enriched levels of TF mRNA in vimentin immunoprecipitate, (iii) TF 3'-UTR-luciferase reporter vector assays implicated the 3'-UTR of TF mRNA in vimentin-dependent TF regulation, and (iv) using different TF 3'UTR luciferase reporter vectors mutated for potential miR binding sites and specific Target Site Blockers identified a key miR binding site in vimentin-dependent TF mRNA regulation. All together, these data support a novel mechanism by which vimentin interferes with a miR-dependent negative regulation of TF mRNA, thereby promoting coagulant activity and early metastasis of vimentin-expressing CTCs. Citation Format: Aline Vanwynsberghe, Marie-Emilie Francart, Christine Gilles. Vimentin prevents a miR-dependent negative regulation of tissue factor mRNA during epithelial-mesenchymal transitions and facilitates early metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1534.
Sinking In: The Peripheral Baldwinisation of Human Cognition
Authors: Cecilia Heyes, Nick Chater, Dominic Michael Dwyer
Journal: Trends in Cognitive Sciences (2020)

The Baldwin effect is a hypothetical process in which a learned response to environmental change evolves a genetic basis. Modelling has shown that the Baldwin effect offers a plausible and elegant explanation for the emergence of complex behavioural traits, but there is little direct empirical evidence for its occurrence. We highlight experimental evidence of the Baldwin effect and argue that it acts preferentially on peripheral rather than on central cognitive processes. Careful scrutiny of research on taste-aversion and fear learning, language, and imitation indicates that their efficiency depends on adaptively specialised input and output processes: analogues of scanner and printer interfaces that feed information to core inference processes and structure their behavioural expression.
Abstract 4017: Biochemical and biophysical characterization of a covalent inhibitor of Src kinase
Authors: Deepak Gurbani, Kenneth Westover, Asim Bera
Journal: Cancer Research (2020)

Abstract Background: c-Src was among the first oncogenes discovered. It encodes a non-receptor tyrosine kinase that regulates many cancer-related cellular processes including mitogenesis, angiogenesis, adhesion, invasion, migration, and survival. Src activity drives malignant phenotypes in hematologic and solid cancers including breast, prostate, lung, colorectal, and pancreatic cancer. However, no specific Src-directed targeted therapies are in clinical use. Various Src inhibitors such as dasatinib, bosutinib and others have been tested in human trials, but with variable outcomes including dose-limiting toxicity, which is due to the multi-targeted nature of these compounds, which also hit Src, SFKs, BCR-ABL, c-KIT, PDGFR, c-FMS, EPHA2 and others. Improved selective Src inhibitors may overcome these challenges to enable Src-directed therapies. Engineering selectivity into Src inhibitors is challenging because of the high degree of sequence homology between Src family members and other receptor tyrosine kinases. The selective, covalent Src inhibitor DGY-06-116, which targets a relatively unusual targetable cysteine near the active site in the p loop, was recently reported. Here, we further characterize DGY-06-116. Methods: We characterized the inhibitory activity DGY-06-116 using an enzymatic assay and surface plasmon resonance (SPR). We also determined the co-crystal structure of DGY-06-116 bound to Src. Results: DGY-06-116 showed a substantial improvement over both SM171 and bosutinib for inhibition of Src kinase activity: SM1-71 (IC50, 26.6 nM); bosutinib (IC50, 9.5 nM); DGY-06-116 (IC50, 2.59 nM). Determination of kinact using SPR showed a value of 5.7 x 10-7 (s-1) for DGY-06-116, slower than FDA-approved neratinib (2 x 10-3 s-1) and afatinib (1 x 10-3 s-1). A 2.15 Å resolution co-crystal structure of DGY-06-116 bound to Src (PDB ID: 6E6E) showed a covalent bond with Cys-280 and bending of the p-loop relative to other Src-inhibitor structures. Conclusions: DGY-06-116 demonstrates a slow inactivation rate that likely reflects the need for repositioning of the p-loop for a covalent bond to occur. Src inhibitors based on DGY-06-116 may benefit from optimization of p-loop, inhibitor interactions. Citation Format: Deepak Gurbani, Kenneth Westover, Asim Bera. Biochemical and biophysical characterization of a covalent inhibitor of Src kinase [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4017.
Abstract PR03: Single-cell proteomic analysis of the tumoral heterogeneity in response to PARP inhibitor
Authors: Nicholas D. Kendsersky, Hongli Ma, Yong Fang, Lydia G. Campbell, Jenny Eng, Sanghoon Lee, Koei Chin, Shannon N. Westin, Gordon B. Mills, Marilyne Labrie
Journal: Clinical Cancer Research (2020)

Abstract Although poly (ADP-ribose) polymerase (PARP) inhibitors have shown efficacy in the treatment and maintenance of ovarian cancer patients, development of PARP inhibitor resistance is frequent. Our group and others have demonstrated that the cancer cells’ adaptive responses to PARP inhibitor can be detected at the protein level and targeting these adaptive responses increases the depth and duration of treatment and might prevent the development of drug resistance. However, it is still unclear if these adaptive responses are conserved across cancer cells from the same tumor and across cells from different lesions. Having a better understanding of the heterogeneity of adaptive responses might help develop better approaches of PARP-based combination therapies. The objective of this study was to develop a single-cell proteomic approach to investigate the heterogeneity of adaptive responses in ovarian cancer tumors. We developed a cyclic-immunofluorescence antibody panel and measured the expression of more than 40 proteins at the single-cell level in several ovarian cancer tumors that have been treated with PARP inhibitors. We also performed reverse-phased protein array (RPPA) analysis on protein extracted from the tumors and measured the activity of several pathways know to be altered in response to PARP inhibitors. Overall, our results demonstrated that adaptive responses can be detected at the single-cell level through cyclic immunofluorescence. Furthermore, although RPPA assays capture the main pathway alterations in response to PARP inhibitors, cyclic immunofluorescence adds complementary information by allowing a spatial-oriented analysis of the different cell populations as well as their frequency. Overall, this approach might lead to a better understanding of how cancer cells try to survive therapeutic stress and improve the decision-making process in the treatment of ovarian cancer patients. This abstract is also being presented as Poster A19. Citation Format: Nicholas D. Kendsersky, Hongli Ma, Yong Fang, Lydia G. Campbell, Jenny Eng, Sanghoon Lee, Koei Chin, Shannon N. Westin, Gordon B. Mills, Marilyne Labrie. Single-cell proteomic analysis of the tumoral heterogeneity in response to PARP inhibitor [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr PR03.
Assessment of a Deep Learning Model to Predict Hepatocellular Carcinoma in Patients With Hepatitis C Cirrhosis
Authors: George N. Ioannou, Weijing Tang, Lauren A. Beste, Monica A. Tincopa, Grace L. Su, Tony Van, Elliot B. Tapper, Amit G. Singal, Ji Zhu, Akbar K. Waljee
Journal: JAMA Network Open (2020)

Deep learning, a family of machine learning models that use artificial neural networks, has achieved great success at predicting outcomes in nonmedical domains.To examine whether deep learning recurrent neural network (RNN) models that use raw longitudinal data extracted directly from electronic health records outperform conventional regression models in predicting the risk of developing hepatocellular carcinoma (HCC).This prognostic study included 48 151 patients with hepatitis C virus (HCV)-related cirrhosis in the national Veterans Health Administration who had at least 3 years of follow-up after the diagnosis of cirrhosis. Patients were identified by having at least 1 positive HCV RNA test between January 1, 2000, to January 1, 2016, and were followed up from the diagnosis of cirrhosis to January 1, 2019, for the development of incident HCC. A total of 3 models predicting HCC during a 3-year period were developed and compared, as follows: (1) logistic regression (LR) with cross-sectional inputs (cross-sectional LR); (2) LR with longitudinal inputs (longitudinal LR); and (3) RNN with longitudinal inputs. Data analysis was conducted from April 2018 to August 2020.Development of HCC.Area under the receiver operating characteristic curve, area under the precision-recall curve, and Brier score.During a mean (SD) follow-up of 11.6 (5.0) years, 10 741 of 48 151 patients (22.3%) developed HCC (annual incidence, 3.1%), and a total of 52 983 samples (51 948 [98.0%] from men) were collected. Patients who developed HCC within 3 years were older than patients who did not (mean [SD] age, 58.2 [6.6] years vs 56.9 [6.9] years). RNN models had superior mean (SD) area under the receiver operating characteristic curve (0.759 [0.009]) and mean (SD) Brier score (0.136 [0.003]) than cross-sectional LR (0.689 [0.009] and 0.149 [0.003], respectively) and longitudinal LR (0.682 [0.007] and 0.150 [0.003], respectively) models. Using the RNN model, the samples with the mean (SD) highest 51% (1.5%) of HCC risk, in which 80% of all HCCs occurred, or the mean (SD) highest 66% (1.2%) of HCC risk, in which 90% of all HCCs occurred, could potentially be targeted. Among samples from patients who achieved sustained virologic response, the performance of the RNN models was even better (mean [SD] area under receiver operating characteristic curve, 0.806 [0.025]; mean [SD] Brier score, 0.117 [0.007]).In this study, deep learning RNN models outperformed conventional LR models, suggesting that RNN models could be used to identify patients with HCV-related cirrhosis with a high risk of developing HCC for risk-based HCC outreach and surveillance strategies.
Abstract 1539: NDRG1 promotes epithelial-mesenchymal transition in lung cancer cells by upregulation of SLUG expression
Authors: En-Chu Liu, Hui-Chia Liu, Jeremy J. M. Chen, Meng-Feng Tsai
Journal: Cancer Research (2020)

Abstract N-myc down-regulated gene 1 (NDRG1) is a member of the NDRG family which belongs to α/β hydrolase superfamily, but without presenting a hydrolytic catalytic site. NDRG1 gene has been proposed that involved in cellular stress response pathways, including the heavy metal response, hypoxia response, DNA damage response, cellular differentiation, and proliferation. An oncogenic and tumor-promoting role of NDRG1 has been suggested in lung cancer and various malignant cancers. However, the biological functions and downstream molecular mechanisms of NDRG1 gene in lung cancer are still unclear. In this study, we detected the expression of NDRG1 in various lung adenocarcinoma cell lines using quantitative RT-PCR and Western blotting methods. The constitutive NDRG1-expression, and NDRG1-knockdown stable transfectants were established. Over-expression of NDRG1 in lung cancer cells exhibited markedly promoting in the proliferation and anchorage independent growth, whereas reduced of NDRG1 was found to suppress lung cancer cell progression. We also indicated that NDRG1 play an important role in the epithelial-mesenchymal transition (EMT) features, including a morphological change, increased migratory and invasive ability, reduction the epithelial marker expression and up-regulated EMT regulators. In addition, microarray assays were performed to further explore the potential molecular mechanisms of NDRG1 in lung cancer. The candidate NDRG1-regulated genes, including IL11, SOX7, TCF4, IGF2, SLUG and SLIT2, were verified by quantitative RT- PCR. Finally, we demonstrated that NDRG1 induces EMT and invasion process in lung cancer cell through up-regulation SLUG expression. These results will provide information and help us to understand the roles of NDRG1 in lung cancer cells. Citation Format: En-Chu Liu, Hui-Chia Liu, Jeremy J. M. Chen, Meng-Feng Tsai. NDRG1 promotes epithelial-mesenchymal transition in lung cancer cells by upregulation of SLUG expression [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1539.
Abstract 12145: Effect of Metformin on Microvascular Endothelial Function in Polycystic Ovary Syndrome
Authors: Behnam Heidari, Alice Y Change, Lilach O Lerman, Amir Lerman
Journal: Circulation (2018)

Background: Polycystic Ovary Syndrome (PCOS) is associated with increased prevalence of cardiovascular risk factors. Endothelial Function (EF) is an important index of subclinical atherosclerosis, ...
Abstract 10319: Randomized, Controlled Trial of Transcatheter versus Surgical Closure of Perimembranous Ventricular Septal Defects in Children
Authors: Jian Yang, Lifang Yang, Shiqiang Yu
Journal: Circulation (2013)

Background: Perimembranous ventricular septal defect (pmVSD) is the most common form of congenital heart disease in childhood. The optimal treatment for this defect must be evaluated. Methods and R...
Establishment and effectiveness evaluation of a scoring system for exertional heat stroke by retrospective analysis
Authors: Meng-Meng Yang, Lu Wang, Yu Zhang, Rui Yuan, Yan Zhao, Jie Hu, Fei-Hu Zhou, Hong-Jun Kang
Journal: Military Medical Research (2020)

Abstract Background Heat stroke (HS) is a serious, life-threatening disease. However, there is no scoring system for HS so far. This research is to establish a scoring system that can quantitatively assess the severity of exertional heat stroke (EHS). Methods Data were collected from a total of 170 exertional heat stroke (EHS) patients between 2005 and 2016 from 52 hospitals in China. Univariate statistical methods and comparison of the area under the receiver operating characteristic (ROC) curve (AUC) were used to screen exertional heat stroke score (EHSS) parameters, including but not limited body temperature (T), Glasgow Coma Scale (GCS) and others. By comparing the sizes of the AUCs of the APACHE II, SOFA and EHSS assessments, the effectiveness of EHSS in evaluating the prognosis of EHS patients was verified. Results Through screening with a series of methods, as described above, the present study determined 12 parameters – body temperature (T), GCS, pH, lactate (Lac), platelet count (PLT), prothrombin time (PT), fibrinogen (Fib), troponin I (TnI), aspartate aminotransferase (AST), total bilirubin (TBIL), creatinine (Cr) and acute gastrointestinal injury (AGI) classification – as EHSS parameters. It is a 0–47 point system designed to reflect increasing severity of heat stroke. Low (EHSS&lt; 20) and high scores (EHSS&gt; 35) showed 100% survival and 100% mortality, respectively. We found that AUCEHSS &gt; AUCSOFA &gt; AUCAPACHE II. Conclusion A total of 12 parameters – T, GCS, pH, Lac, PLT, PT, Fib, TnI, AST, TBIL, Cr and gastrointestinal AGI classification – are the EHSS parameters with the best effectiveness in evaluating the prognosis of EHS patients. As EHSS score increases, the mortality rate of EHS patients gradually increases.
Stimulus‐Responsive Nanoparticle Magnetic Resonance Imaging Contrast Agents: Design Considerations and Applications
Authors: Shengxiang Fu, Zhongyuan Cai, Hua Ai
Journal: Advanced Healthcare Materials (2020)

Abstract Magnetic resonance imaging (MRI) has been widely used for disease diagnosis because it can noninvasively obtain anatomical details of various diseases through accurate contrast between soft tissues. Over one‐third of MRI examinations are performed with the assistance of contrast agents. Traditional contrast agents typically display an unchanging signal, thus exhibiting relatively low sensitivity and poor specificity. Currently, advances in stimulus‐responsive contrast agents which can alter the relaxation signal in response to a specific change in their surrounding environment provide new opportunities to overcome such limitation. The signal changes based on stimulus also reflects the physiological and pathological conditions of the site of interests. In this review, how to design stimulus‐responsive nanoparticle MRI contrast agents from the perspective of theory and surface design is comprehensively discussed. Key structural features including size, clusters, shell features, and surface properties are used for tuning the T 1 and T 2 relaxation properties. The reversible or non‐reversible signal changes highlight the contrast agents have undergone structural changes based on certain stimulus, as an indication for disease diagnosis or therapeutic efficacy.
Abstract 15001: Tsg101 Protects the Heart Against Ischemia/Reperfusion Injury Through Aggregation of P62 and Activation of NRF2 Signaling
Authors: Shan Deng, Xiao Hong Wang, Kobina Essandoh, Yutian Li, Jiang tong Peng, Xingjiang Mu, Kai Huang, Guochang Fan
Journal: Circulation (2018)

Introduction: Cellular oxidative stress, an important contributor to ischemia/reperfusion (I/R)-induced cardiac dysfunction, is regulated by p62-induced aggregation of Keap1 and subsequent activati...
White Rice Intake and Incident Diabetes: A Study of 132,373 Participants in 21 Countries
Authors: Balaji Bhavadharini, Viswanathan Mohan, Mahshid Dehghan, Sumathy Rangarajan, Sumathi Swaminathan, Annika Rosengren, Andreas Wielgosz, Alvaro Avezum, Patricio Lopez-Jaramillo, Fernando Lanas, Antonio L. Dans, Karen Yeates, Paul Poirier, Jephat Chifamba, Khalid F. Alhabib, Noushin Mohammadifard, Katarzyna Zatońska, Rasha Khatib, Mirac Vural Keskinler, Li Wei, Chuangshi Wang, Xiaoyun Liu, Romaina Iqbal, Rita Yusuf, Edelweiss Wentzel-Viljoen, Afzalhussein Yusufali, Rafael Diaz, Ng Kien Keat, P.V.M. Lakshmi, Noorhassim Ismail, Rajeev Gupta, Lia M. Palileo-Villanueva, Patrick Sheridan, Andrew Mente, Salim Yusuf
Journal: Diabetes Care (2020)

Previous prospective studies on the association of white rice intake with incident diabetes have shown contradictory results but were conducted in single countries and predominantly in Asia. We report on the association of white rice with risk of diabetes in the multinational Prospective Urban Rural Epidemiology (PURE) study.Data on 132,373 individuals aged 35-70 years from 21 countries were analyzed. White rice consumption (cooked) was categorized as <150, ≥150 to <300, ≥300 to <450, and ≥450 g/day, based on one cup of cooked rice = 150 g. The primary outcome was incident diabetes. Hazard ratios (HRs) were calculated using a multivariable Cox frailty model.During a mean follow-up period of 9.5 years, 6,129 individuals without baseline diabetes developed incident diabetes. In the overall cohort, higher intake of white rice (≥450 g/day compared with <150 g/day) was associated with increased risk of diabetes (HR 1.20; 95% CI 1.02-1.40; P for trend = 0.003). However, the highest risk was seen in South Asia (HR 1.61; 95% CI 1.13-2.30; P for trend = 0.02), followed by other regions of the world (which included South East Asia, Middle East, South America, North America, Europe, and Africa) (HR 1.41; 95% CI 1.08-1.86; P for trend = 0.01), while in China there was no significant association (HR 1.04; 95% CI 0.77-1.40; P for trend = 0.38).Higher consumption of white rice is associated with an increased risk of incident diabetes with the strongest association being observed in South Asia, while in other regions, a modest, nonsignificant association was seen.