tbuckley/cabot-search huggingface dataset:
Abstract 278: Artificial intelligence accelerate drug discovery
Authors: Weidong Xie, Xing Cheng, Zhengfang Ding, Riqiang Deng, Dawei Gu
Journal: Cancer Research (2021)

Abstract Drug discovery is resource intensive, and involves typical timelines of 10-20 years and costs that range from US$0.5 billion to US$2.6 billion. Artificial intelligence (AI) has recently started to gear-up its application in various sectors of the society and the pharmaceutical industry as a frontrunner beneficiary.Artificial intelligence can accelerate drug discovery and reduce costs by facilitating the rapid screening and identification of compounds. We have developed DM-AI drug discovery platform, including convolutional neural networks, decision treealgorithm, reinforcement learning, generative adversarial networks, big data, and knowledge graphs, along with structure and ligand-based high-throughput virtual screening , for new drug discovery and development. DM-AI optimizes biological activity,toxicity,physicochemical property. We used DM-AI to discover potent inhibitors of SHP2, PIM1, DNA-PK, kinases target implicated in solid tumor and other diseases.We started to train a biological activity prediction model on a database of the given target kinase inhibitors (positive set) and non-kinase targets molecules (negative set), and then predicted the activity of existing million data sets, obtained an initial output of thousands structures. We then evaluated these structures using a pharmacophore reward model on the basis of virtual chemical spaces of kinase inhibitors in complex with target protein. To narrow our focus to a smaller set of molecules for analysis, compounds with higher score were filtered to remove patents and applications molecules, also remove molecules bearing structural alerts and reactive groups.By day 7 after target selection, We had selected dozens structures with structural diversity for experimental validation. and by day 28, they were tested for in vitro inhibitory activity in an enzymatic kinase assay, active compounds accounted for up to 65% in some target models. This illustrates the utility of our DM-AI drug discovery platform for the successful, rapid discovery of drug candidates. Citation Format: Weidong Xie, Xing Cheng, Zhengfang Ding, Riqiang Deng, Dawei Gu. Artificial intelligence accelerate drug discovery [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 278.
Risk and impact of chronic cough in obese individuals from the general population
Authors: Eskild Morten Landt, Yunus Çolak, Børge G Nordestgaard, Peter Lange, Morten Dahl
Journal: Thorax (2021)

Obese individuals may be at higher risk of chronic cough. We investigated the risk and impact of chronic cough in obese individuals from the general population.We recorded chronic cough, body mass index (BMI) and other related clinical conditions in 44 554 adults from the Copenhagen General Population Study. Individuals with asthma and/or chronic obstructive pulmonary disease were excluded (n=10 977). BMI was divided into: underweight (BMI <18.5 kg/m2), normal weight (18.5-24.9 kg/m2), overweight (25.0-29.9 kg/m2), obese (30.0-34.9 kg/m2) and severely obese (≥35.0 kg/m2).Among 33 577 adults from the general population, 27 829 (83%) were non-obese and 5748 (17%) were obese. Compared with individuals with normal weight, multivariable adjusted ORs for chronic cough risk were 1.4 (95% CI 1.2 to 1.6) in overweight, 1.9 (95% CI 1.7 to 2.2) in obese and 2.6 (95% CI 2.1 to 3.2) in severely obese individuals. Mediation analyses showed that chronic cough due to obesity was up to 23% mediated by gastro-oesophageal reflux disease (GERD). Other mediators included low vegetable intake with 10% and occupational exposure with 8%. Among obese individuals, those with versus without chronic cough had worse accompanying respiratory symptoms, more often comorbidities including GERD and diabetes, greater healthcare utilisations, lower lung function and higher blood inflammation (all p<0.05).There is dose-response relationship between BMI and chronic cough, and chronic cough risk is twofold to threefold higher in obese individuals from the general population. This increased risk was partly mediated by GERD, low vegetable intake and occupational exposure, supporting that there may be benefit to gain by ameliorating some of these factors in obese individuals with chronic cough.
Abstract 713: Inhibition of pseudo SARS-CoV-2 binding activity of a anti-cancer polypharmacological agent analogs
Authors: Rao V. Papineni, Amitava Adhikary, Ritesh Tandon, Dipanwita Mitra
Journal: Cancer Research (2021)

Abstract Severe acute respiratory syndrome coronavirus (SARS-CoV-2), a single-stranded RNA virus with largest genomes (∼ 29,800 bases) of all viruses, causes the infectious disease, COVID-19. SARS-CoV-2 is a zoonotic betacoronavirus transmitted through airborne and fecal-oral routes infecting nasal, lung, and intestinal tissues causing over 26 million confirmed coronavirus disease 2019 (COVID-19) cases and nearly 900,000 associated deaths worldwide as of September 2020. The surface of SARS-CoV-2 is covered with copies of spike glycoprotein (SGP) that plays a pivotal role in virus entry in host cells utilizing angiotensin-converting enzyme 2 (ACE2) as an attachment and entry receptor. We have successfully made a high titer replication-incompetent third-generation lentiviral vector pseudotyped with SARS-2-CoV SGP (pLV-S). Upon successful attachment and entry, the lentiviral vector causes enhanced green fluorescent protein (eGFP) to be expressed in the infected cell. Here, we show how the polypharmacological agent, 2-Deoxy-D-glucose (2-DG), a glucose mimic, and well characterized anti-cancer drug, and its analogs inhibit spike protein binding to the ACE2 receptors. This is as suggested from the 2DG and two analogs inhibition, with a low micromolar affinity, the pLV-S attachment and entry resulting in reduced cell fluorescence of infected HEK293 cells. In addition, we describe 2DG and analogs has the potential to deliver polypharmacological effects on the COVID-through inhibition of glycolysis (at energy status), modulation of inflammatory responses (cytokine storm) and alterations in glycosylation of viral proteins. A unique class of adjuvants and mitigants in the anti-SARS-CoV-2 activity is presented here. Citation Format: Rao V. Papineni, Amitava Adhikary, Ritesh Tandon, Dipanwita Mitra. Inhibition of pseudo SARS-CoV-2 binding activity of a anti-cancer polypharmacological agent analogs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 713.
Abstract 234: Risk of sepsis among patients with prostate cancer: A network-based modeling approach
Authors: Ali Jazayeri, Niusha Jafari, Christopher C. Yang, Nikita Nikita, Grace Lu Yao
Journal: Cancer Research (2021)

Abstract Background: Prostate cancer (PCa) is the most common cancer among men, and sepsis is a leading cause of death in PCa, yet their association has not been quantified. This study aims to quantify the association between sepsis severity (identified as sepsis, severe sepsis, and septic shock) and prostate complications among PCa subgroups. Methods: We used the SEER-Medicare data to identify patients diagnosed with PCa in 2010 -2015. PCa patients were classified as: localized or regional (L/R) stage and distant (D) stage and further stratified as survivors and non-survivors. Patients with no history of PCa composed the control group. Our network-based modeling approach used sepsis and prostate complications (identified using ICD codes) as network nodes. The association between complication pairs, represented as edges, were weighted by the probability of complication pairs occurring concurrently. The network densities for each subgroup were computed at different thresholds based on the weights of the edges. Results: We identified 27,166 patients with PCa and 22,223 as controls. Increase in threshold was associated with highest decline in network density among controls followed by L/R survivors (Table). Additionally, prostate and sepsis complications co-occur more frequently among stage D than stage L/R patients. Also, stage D patients experience prostate complications with more severe sepsis conditions (severe sepsis and septic shock) than other subpopulations. The variances and medians of edges' weights among all subgroups were statistically different (p&amp;lt;0.001). Conclusions: This is the first population-based study using network-based modeling to quantify the association between varying degrees of sepsis severity and prostate complications among PCa subgroups. The differentiating complication pairs identified among subgroups can be used as features in machine-learning algorithms to predict the severity of patient outcomes and to improve patient prognosis. Table: Network densities of sepsis and PCa complication pairs at different weight thresholds for each PCa subgroupsNetwork densities at various threshold weightsQuantiles of Weights in Network (Median (Q1,Q3))Threshold Levels0.0000.0100.0200.0300.040Control0.1930.0050.0030.0010.0010.005 (0.002, 0.016)Stage L\R survivors0.2410.0290.0110.0070.0050.007 (0.003, 0.021)Stage L\R non-survivors0.1580.0380.0140.0070.0040.012 (0.005, 0.029)Stage D survivors0.0840.0270.0060.0020.0010.013 (0.006, 0.032)Stage D non-survivors0.1300.0360.0170.0090.0040.012 (0.005, 0.029) Citation Format: Ali Jazayeri, Niusha Jafari, Christopher C. Yang, Nikita Nikita, Grace Lu Yao. Risk of sepsis among patients with prostate cancer: A network-based modeling approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 234.
Abstract LB246: E-cadherin loss drives Id2-dependent dampening of cell cycle progression and predicts increased susceptibility to CDK4/6 inhibition in lobular breast cancer
Authors: Max Antonius Klaus Rätze, Thijs Koorman, Thijmen Sijnesael, Blessing Bassey-Archibong, Robert van de Ven, Lotte Enserink, Daan Visser, Sridevi Jaksani, Elvira Bakker, François Richard, Andrew Tutt, Rebecca Steele, Stephen Pettitt, Christopher J. Lord, Amanda Fitzpatrick, Clare Isacke, Paul J. van Diest, Christine Desmedt, Juliet M. Daniel, Patrick W.B. Derksen
Journal: Cancer Research (2021)

Abstract Invasive lobular breast carcinoma (ILC) is a low grade and mostly chemo-refractory luminal-type breast cancer that has been linked to sustained proliferative quiescence and long-term latency relapses (15-20 years). Loss of E-cadherin causes metastatic lobular breast cancer, partly through acquisition of anchorage independence. It is however still unknown how ILC cells control the balance between proliferative indolence and cell cycle re-entry at the metastatic site. We show here that E-cadherin loss leads to upregulation of Id2 through p120-catenin/Kaiso-dependent transcriptional derepression. Anchorage independent conditions further exacerbate p120-driven Id2 expression, leading to a sustained G0/G1 cell cycle arrest through binding of cytosolic Id2 to hypo-phosphorylated Rb. Intriguingly, we find that E-cadherin inactivation causes increased sensitivity to CDK4/6 inhibition in mouse and human breast cancer cell lines and primary tumor organoids. Finally, we find that Id2 expression is elevated in human ILC when compared to ductal breast cancers. Based on these data, we propose that combined E-cadherin loss and cytosolic Id2 expression can be used for the differential diagnosis of ILC and represent a candidate predictive biomarker pair for cell cycle targeting drug efficacy. Citation Format: Max Antonius Klaus Rätze, Thijs Koorman, Thijmen Sijnesael, Blessing Bassey-Archibong, Robert van de Ven, Lotte Enserink, Daan Visser, Sridevi Jaksani, Elvira Bakker, François Richard, Andrew Tutt, Rebecca Steele, Stephen Pettitt, Christopher J. Lord, Amanda Fitzpatrick, Clare Isacke, Paul J. van Diest, Christine Desmedt, Juliet M. Daniel, Patrick W.B. Derksen. E-cadherin loss drives Id2-dependent dampening of cell cycle progression and predicts increased susceptibility to CDK4/6 inhibition in lobular breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB246.
Abstract LB139: VRN10, Discovery of Potent Irreversible HER2 Kinase Inhibitors with Intracranial Activity
Authors: Hwan Kim, Younho Lee, Jinhee Park, Youngyi Lee, Jieun Choi, Jihye Yoo, Chanmi Park, Somi Lee, Eunhwa Ko, Jung Beom Son, Hwan Geun Choi, Nam Doo Kim, Daekwon Kim, Sunghwan Kim
Journal: Cancer Research (2021)

Abstract Human epidermal growth factor receptor 2 (HER2) amplification is one of oncogenic drivers most found in breast cancer but also occurs in multiple other tumor types. Approximately 10-30% of patients with breast cancer develop brain metastases (BCBM), a devastating cause of morbidity and mortality. To address this unmet medical need, VRN10s, brain penetrant, orally bioavailable, and irreversible small molecule inhibitors were designed to target HER2 while sparing EGFR wild type. In biochemical assays VRN10s had low nanomolar potency to inhibit catalytic activity of HER2. In cell viability assays using HER2+ breast and gastric cancer cell lines, VRN10s inhibited proliferation with single-digit nanomolar potency and exhibited an exceptional selectivity for HER2 over EGFR, with an enhancement of &amp;gt; 30-fold. Neuregulin-1 (NRG-1) has been suggested to decrease the anti-tumor activity of HER2 kinase inhibitors by induction of HER3 in brain microenvironment. Two FDA-approved HER2 kinase inhibitors tucatinib and lapatinib are not only less brain permeable, but they also show significantly decreased activity in the presence of NRG-1. However, the addition of NRG-1 did not rescue the proliferation of HER2+ breast cancer cell lines treated with VRN10s. Western blot confirmed that VRN10s inhibit signal transduction downstream of HER2 and HER3 through the AKT and ERK pathways. Inhibition of HER2 is reported to cause cytotoxicity on cardiomyocytes. In spite of potent inhibition of HER2 catalytic inhibition, VRN10s did not show cardiomyocyte cytotoxicity more than other HER2 kinase inhibitors, including tucatinib and neratinib. We confirm VRN10s to have high brain exposure in several preclinical models. Consistent with our in vitro results, potent activity was observed in the xenograft and intracranial models using once daily oral administration with strong tumor growth inhibition. Based on in vitro assay, brain permeability and in vivo efficacy, VRN10s may be promising therapeutic candidates for patients with HER2+ tumors including BCBM. Citation Format: Hwan Kim, Younho Lee, Jinhee Park, Youngyi Lee, Jieun Choi, Jihye Yoo, Chanmi Park, Somi Lee, Eunhwa Ko, Jung Beom Son, Hwan Geun Choi, Nam Doo Kim, Daekwon Kim, Sunghwan Kim. VRN10, Discovery of Potent Irreversible HER2 Kinase Inhibitors with Intracranial Activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB139.
Profile of Thrombosis Distribution Following Haploidentical and Identical-Sibling Transplantation: A 15-Year Experience at a Single Center in China
Authors: Xiao Liu, Qian-Ming Wang, Yun He, Xiao-Lu Zhu, Jia-Min Zhang, Wei Han, Huan Chen, Yu-Hong Chen, Feng-Rong Wang, Jing-Zhi Wang, Yuan-Yuan Zhang, Xiao-Dong Mo, Yao Chen, Yu Wang, Hai-Xia Fu, Ying-Jun Chang, Lan-Ping Xu, Kai-Yan Liu, Xiao-Jun Huang, Xiaohui Zhang
Journal: Blood (2017)
Abstract 872: Pathogenesis underlying the bidirectional relationship between non-Hodgkin lymphomas and primary Sjögren's Syndrome
Authors: Kevin Sheng-Kai Ma, Cho-Han Chiang, Li-Tzu Wang
Journal: Cancer Research (2021)

Abstract Introduction: Bidirectional relationship between non-Hodgkin lymphomas (NHLs) and Sjögren's syndrome (SS) has been recognized in large scale cohort studies. To investigate the underlying pathogenesis of this association, we identified highly expressed genes and altered pathways with RNA-sequencing (RNA-seq) data from SS and NHLs patients. Methods: Canonical pathway analysis was conducted by comparing RNA-seq data from whole-transcriptome expression profiling to identify underlying pathogenesis among NHL patients with Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), or marginal zone lymphoma (MZL), and SS patients. Collected biopsies included lymphoma biopsies for NHLs, including BL (n = 59), DLBCL (n = 88), FL (n = 65), MCL (n = 43), and MZL (n = 23), sorted B cells from healthy donors (n=10), as well as parotid gland tissues for SS (n=17). Fold changes and z-scores were derived after normalized by the expression levels among controls. RNA-seq data with P values less than 0.05 or -log10(P) values larger than 1.3 were considered significantly expressed. Positive z-scores indicated up-regulation while negative z-scores indicated down-regulation. Results: There were 17 identified significantly expressed genes (P &amp;lt; 0.05 for all NHLs and SS), including well-known cancer-associated genes CXCL13, COL1A1, IGFBP7, COL3A1, CXCL9, CXCL12, CCL19, and CLU. Among them, CXCL13 was the most expressed gene involved in NHLs and SS. The fold changes of CXCL13 were 14.09, 465.57, 319.51, 369.70, 817.63, and 4.03 for BL, DLBCL, FL, MCL, MZL, and SS, respectively. Among all identified pathways underlying SS and NHL development, which were ordered based on the sum of z-scores, the endocannabinoid system-driven cancer inhibition pathways were the most significantly altered in both SS and NHLs, followed by interferon-involved antiviral responses, when compared to matched healthy controls. The z-scores of the cancer inhibition pathways were -0.14 for BL (-log10(P) = 4.54), -1.30 for DLBCL (-log10(P) = 3.00), -0.33 for FL (-log10(P) = 4.67), -0.87 for MCL (-log10(P) =3.77), -2.61 for MZL (-log10(P) = 4.31), and -1 for SS (-log10(P) = 1.44). Conclusion: The underlying pathogenesis for SS-associated NHL development involved 17 highly expressed genes, including CXCL13, and down-regulated cancer inhibition pathways. Citation Format: Kevin Sheng-Kai Ma, Cho-Han Chiang, Li-Tzu Wang. Pathogenesis underlying the bidirectional relationship between non-Hodgkin lymphomas and primary Sjögren's Syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 872.
Integrating High-Sensitivity Troponin T and Sacubitril/Valsartan Treatment in HFpEF
Authors: Mauro Gori, Michele Senni, Brian Claggett, Jiankang Liu, Aldo P. Maggioni, Michael Zile, Margaret F. Prescott, Dirk J. Van Veldhuisen, Faiez Zannad, Burkert Pieske, Carolyn S.P. Lam, Jean Rouleau, Pardeep Jhund, Milton Packer, Marc A. Pfeffer, Martin Lefkowitz, Victor Shi, John J.V. McMurray, Scott D. Solomon
Journal: JACC Heart Failure (2021)
Abstract 2194: Comparison of molecular profiling between Chinese cholangiocarcinoma and gallbladder cancer through next-generation sequencing
Authors: Chao Yu, Hushan Zhang, Jun Luo, Songling Zhao
Journal: Cancer Research (2021)

Abstract Background: Recently, some researchers proposed that molecular targeted therapies is ready for “prime time” in biliary tract cancer. However, few large-scale research data specifically analyze and compare the molecular characteristics of biliary tumors in the Chinese population. Here, we aim to report difference of molecular profiling of biliary tract cancers between Chinese cholangiocarcinoma (CCA) and gallbladder cancer (GCC) through next-generation sequencing, and summarize percentage of main targetable genetic alterations for CCA and GBC. Methods: Totally 1439 tumor sample of Chinese patient with biliary tract cancer were consecutively collected in China from January 2018 to July 2020, 907 patients were CCA, 532 were GCC. Gene mutation, microsatellite instability (MSI) were detected through next generation sequencing (NGS) by 3D Medicines, a laboratory accredited by College of American Pathologists (CAP) and Clinical Laboratory Improvement Amendments (CLIA). Results: The main mutational gene between CCA and GCC were compared, and results showed that the top ten gene mutation in CCA patients were TP53 (57.6%,522/907), KRAS (35.2%, 320/907), XRCC5 (27.7%, 251/907), CYP2D6 (26.8%,243/907), MDM2 (26.0%,236/907), MSH2 (25.7%,233/907), BLM/VEGFA (24.9%,226/907), POLD (24.7%,224/907), PRSS1 (23.6%,214/907), ATM (23.3%, 212/907). While top ten gene mutation in GCC group were TP53 (76.3%,406/532), MSH2 (43.0%,229/532), CYP2D6 (30.4%, 162/532), MDM2 (28.8%,153/532), VEGFA (27.6%,147/532), POLD1 (27.4%, 146/532), BLM (27.4%,146/532), ATM (25.6%,136/532), PRSS1 (25.2%,134/532), PRKDC (24.8%,132/532). In addition, percentage of the main targetable genetic alterations were also compared between CCA and GCC, such as IDH (5.7% vs 0.9%), FGFR (10.2% vs 10.7%), BRAF (5.1% vs 4.3%), PIK3CA (9.9% vs 14.8%), NTRK (7.4% vs 8.3%), ERBB2/3 (11.8% vs 24.8%), CDKN2A/2B(18.5% vs 23.9%), ARID1A(17.3% vs 17.7&amp;), PTEN (10.3% vs 13.9%), MET (6.3% vs 7.3%), SMAD4 (14.6% vs 14.5%). Conclusion: Accurately understand the gene mutation characteristics of biliary tract tumors is required to make “Precision Medicine” a reality for the “majority” of patients diagnosed with biliary tract cancer. Chinese patients with CCA and GCC have different gene mutations, especially the proportion of mutant genes that are currently targetable. Therefore, different strategy should be performed for CCA and GCC patients. Citation Format: Chao Yu, Hushan Zhang, Jun Luo, Songling Zhao. Comparison of molecular profiling between Chinese cholangiocarcinoma and gallbladder cancer through next-generation sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2194.