tbuckley/cabot-search huggingface dataset:
Abstract 5350: Single cell RNA-seq reveals transcriptionally distinct subpopulations within patient-derived pancreatic cancer organoids
Authors: Mohana Ray, Rajib K. Nandi, Isabel Romero Calvo, Kori Kirby, Christopher Weber, Hedy L. Kindler, Mary Buschmann, Kevin Roggin, Kevin P. White
Journal: Cancer Research (2018)

Abstract Advances in 3D cell culture over the last decade have enabled the establishment of organoid models from a multitude of organs in varying stages of development and disease. Organoids recapitulate the tissue-specific cell types and exhibit similar morphology and spatial organization as the organ it is derived from. However, to the best of our knowledge, tumor organoids have never been profiled at a single cell level. In this study, we applied Drop-seq, a high throughput single cell RNA-seq platform, to characterize the different cell types present in pancreatic cancer organoids. We sequenced the transcriptomes of 5494 single cells from organoids derived from a patient undergoing a Whipple procedure for pancreatic ductal adenocarcinoma (PDAC). We then developed a novel clustering approach based on a class of probabilistic generative models called topic models, leading to the identification of two subpopulations of cells. One subgroup expressed marker genes known to play important roles in PDAC biology, such as MUC1, CLDN4 and GAS5. Interestingly, this subgroup also bore markers for cancer stem cells (HES1 and SQSTM1) that have been found by multiple studies to mediate chemoresistance in PDAC. The other subpopulation differentially expressed AGR2 and TMBIM6, which are associated with endoplasmic reticulum (ER) stress and correlates with invasiveness of PDAC cell lines. Functional studies are underway to determine the exact role of these subgroups, but our preliminary findings are suggestive of a subpopulation of cells that maybe involved in resistance to chemotherapy. This is consistent with the clinical progression of this patient's cancer, suggesting that rapid, inexpensive single cell transcriptomics might provide more precise molecular information to personalized medicine programs than traditional RNA-seq alone. Citation Format: Mohana Ray, Rajib K. Nandi, Isabel Romero Calvo, Kori Kirby, Christopher Weber, Hedy L. Kindler, Mary Buschmann, Kevin Roggin, Kevin P. White. Single cell RNA-seq reveals transcriptionally distinct subpopulations within patient-derived pancreatic cancer organoids [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 5350.
Abstract 3707: PD-L1 antibody drug conjugate for cancer immune-chemo combination therapy
Authors: Samaresh Sau, Alex Petrovici, Hashem Alsaab, Arun K. Iyer
Journal: Cancer Research (2018)

Abstract Antibody drug conjugates (ADCs) are a new form of targeted therapy to cancer, consisting of an antibody, a conditionally stable linker, and a cytotoxic drug. Immune checkpoint molecule, such as programmed death ligand-1 (PD-L1) overexpressed in various solid tumors including triple negative breast cancer (TNBC) and non-small cell lung cancer (NSCLC) and it has a crucial role in tumor immune evasion. Blocking the interaction between PD-L1 and PD-1 (programmed death-1 receptor) resurrects tumor immune surveillance, resulting CD8+ cytotoxic T cells activation to attack the tumor cells. This is an emerging anticancer mechanism and more than four antibody inhibitors have been recently FDA approved against PD-1 or PD-L1 biomarker. Targeting PD-L1 in TNBC and NSCLC is an excellent approach for tumor immunotherapy. However, the major challenges of anti-PD-L1 therapy (Atezolizumab) are (i) the transient expression of PD-L1 in tumor microenvironment, (ii) development of anti-PD-L1 resistance, (iii) difficulty of tumor stroma penetration that retard its clinical outcome. To overcome these challenges, we chemically conjugated Atezolizumab (ATZ) with potent chemotherapeutic payload, such as Doxorubicin (Dox) through polyethylene glycol (PEG) linkers. The role of Dox is to break the tumor stroma so that PD-L1 antibody can penetrate to the core of the tumor. Introduction of PEG-linker with high molecular weight ATZ (155 kD) has drastically improved the solubility of ADC and successful chemical conjugation of between ATZ and PEG-Dox was evaluated by MALDI-TOF analysis. Our data has revealed significantly tumor cell killing effect and induction of apoptosis in PD-L1-Dox treated MDA-MB-231 cells. The near infrared imaging of PD-L1 dye conjugate in TNBC and NSCLC patient derived xenograft (PDx) supports the selective tumor targetability. Based on the synergistic anticancer effect and selective tumor targetability demonstrated in this study build a strong rational of using PD-L1 ADC approach for cancer immune-chemo therapy and diagnosis. Citation Format: Samaresh Sau, Alex Petrovici, Hashem Alsaab, Arun K. Iyer. PD-L1 antibody drug conjugate for cancer immune-chemo combination therapy [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 3707.
Loss of Preconditioning by Attenuated Activation of Myocardial ATP-Sensitive Potassium Channels in Elderly Patients Undergoing Coronary Angioplasty
Authors: Tsung-MingLee, Sheng-FangSu, Tsai-FwuChou, Yuan-TehLee, Chang-HerTsai
Journal: Circulation (2002)

Background— The ischemic preconditioning response among elderly patients is known to be lower than in adult patients. Since mitochondrial ATP-sensitive potassium (KATP) channels exert preconditioning effects, we undertook this study to determine whether this attenuated activation of KATP channels influences the reduced responsiveness of elderly patients to ischemic preconditioning. Methods and Results— Fifty-six patients undergoing angioplasty for a major epicardial coronary artery were randomly allocated to either an ischemic preconditioning group, a nicorandil (an agonist of KATP channels) group, or a glibenclamide (an antagonist of KATP channels), group based on their age: adult groups (n=26; age, ≤55 years; mean age, 45±5 years) and elderly groups (n=30; age, ≥65 years; mean age, 71±3 years). Ischemic preconditioning with a 120-second coronary occlusion significantly lowered the ischemic burden assessed by ST-segment shift, chest pain score, and myocardial lactate extraction ratios in the adult group....
Functional and Biochemical Analysis of Angiotensin II–Forming Pathways in the Human Heart
Authors: ArleneWolny, Jean-PaulClozel, JosianeRein, PaulMory, PaulVogt, MarkoTurino, WolfgangKiowski, WalterFischli
Journal: Circulation Research (1997)

Blockade of the renin-angiotensin system by inhibition of angiotensin-converting enzyme (ACE) is beneficial for the treatment of hypertension and congestive heart failure. However, it is unclear how complete the blockade by ACE inhibitors is and if there is continuing angiotensin II (Ang II) formation during chronic treatment with ACE inhibitors. Indeed chymase, a serine protease, which is able to form angiotensin II from angiotensin I (Ang I) and cannot be blocked by ACE inhibitors, has been shown to be present in human heart. The goal of the present study was to evaluate the extent of renin-angiotensin system blockade and the Ang II–forming pathways in cardiac tissue of patients chronically treated with ACE inhibitors or in patients without ACE inhibition therapy. Our studies indicate an incomplete ACE inhibition in human heart tissue after chronic ACE inhibitor therapy. Moreover, ACE contributes only a small portion to the total Ang I conversion, as shown in biochemical studies in ventricular and coron...
Abstract 4388: Anti-cancer effects of oleuropein olive leaf extract in K562 leukemia cells
Authors: Sophia Fagan, Natalie Fulco, Justin Gilbertson, Aaron R. Van Dyke, Shelley A. Phelan
Journal: Cancer Research (2018)

Abstract Olive leaves come from a Mediterranean plant that many believe to have positive effects on human health, including anti-cancer properties. Oleuropein is one of the two main phenolic compounds derived from olive leaves, and it has been shown to increase apoptosis in many types of cancer cells. Numerous studies have found that the polyphenols contained in olive leaves possess strong antioxidant properties, suggesting that the compound could be effective in anti-cancer treatments. The purpose of this study was to examine the effects of oleuropein extract on cell growth and viability in K562 human leukemia cells, and begin to investigate possible molecular mechanisms of action. We purified our own extract from olive leaves for these studies. Oleuropein was microwave extracted from olive leaf powder using methanol and water as solvent. The oleuropein was successfully identified using HPLC to characterize elution time in comparison to an authentic standard. HPLC was then used in purification and fractions were lyophilized. Isolated oleuropein was greater than 94% in comparison to the authentic standard. We next demonstrated that K562 cells treated with 50-150 ug/ml of oleuropein exhibited significant reduction in cell growth and cell viability after four days when compared to 70% ethanol-treated controls. This effect was markedly greater after 6 days . Current studies are being conducted to determine the most effective concentration and duration of treatment for oleuropein-induced cell death. We are also examining cellular cyytotoxicity and cell cycle progression in these experiments using LDH assay and cell cycle staging, and further studies are being conducted to examine inflammatory and antioxidant pathways for their involvement in the anti-cancer effect of the compound in these cells. Given the observation that many of the cytotoxic effects of oleuropein are cancer-cell specific, this research provides a promising new avenue for the use of natural products as anti-cancer agents. Citation Format: Sophia Fagan, Natalie Fulco, Justin Gilbertson, Aaron R. Van Dyke, Shelley A. Phelan. Anti-cancer effects of oleuropein olive leaf extract in K562 leukemia cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4388.
Oral Sildenafil Is an Effective and Specific Pulmonary Vasodilator in Patients With Pulmonary Arterial Hypertension
Authors: EvangelosMichelakis, WayneTymchak, DaleLien, LindaWebster, KyokoHashimoto, StephenArcher
Journal: Circulation (2002)

Background— The prognosis of patients with severe pulmonary hypertension (PHT) is poor. To determine prognosis and guide therapy, an acute hemodynamic trial of selective pulmonary vasodilators, usually inhaled nitric oxide (iNO), was performed. We hypothesized that oral sildenafil, a phosphodiesterase-5 inhibitor, is a safe and effective alternative to iNO. Methods and Results— We studied 13 consecutive patients (mean±SEM, 44±2 years of age; 9 women) referred for consideration of heart-lung transplantation or as a guide to medical therapy. All but one were functional class III or IV. Patients had primary PHT (n=9), pulmonary arterial hypertension (n=2), or secondary PHT (n=2). Hemodynamics and serum cyclic guanosine-monophosphate levels (cGMP) were measured at baseline and at peak effects of iNO (80 ppm), sildenafil (75 mg), and their combination. The decrease in pulmonary vascular resistance was similar with iNO (−19±5%) and sildenafil (−27±3%), whereas sildenafil+iNO was more effective than iNO alone (−...
Propranolol Prevents the Development of Heart Failure by Restoring FKBP12.6-Mediated Stabilization of Ryanodine Receptor
Authors: MasahiroDoi, MasafumiYano, ShigekiKobayashi, MasateruKohno, TakahiroTokuhisa, ShinichiOkuda, MasaeSuetsugu, YuhjiHisamatsu, TomokoOhkusa, MichihiroKohno, MasunoriMatsuzaki
Journal: Circulation (2002)

Background— In heart failure, protein kinase A-mediated hyperphosphorylation of ryanodine receptors (RyRs) in sarcoplasmic reticulum (SR) causes dissociation of FKBP12.6 from RyRs. This results in an abnormal Ca2+ leak through RyRs, possibly leading to cardiac dysfunction. In the present study, we assess whether β-blockers can correct this defect in RyR in tachycardia-induced heart failure and thereby improve cardiac function. Methods and Results— SRs were isolated from dog left ventricular muscles (normal group, 4 weeks of rapid right ventricular pacing with or without propranolol [P(+) or P(−)]). End-diastolic and end-systolic diameters both increased less in P(+) than P(−), associated with a smaller decrease in fractional shortening in P(+). In SR from P(−), a prominent Ca2+ leak was observed, and FK506 (which dissociates FKBP12.6 from RyR) did not induce an additional Ca2+ leak. However, there was no appreciable Ca2+ leak in SR from P(+), although FK506 induced a Ca2+ leak as in normal SRs. In SR from...
Abstract 231: Identification of susceptible loci and enriched pathways for post-radiotherapy pain in breast cancer patients
Authors: Eunkyung Lee, Christina Takita, Jean L. Wright, Eden Martin, Susan Slifer, Jennifer Hu
Journal: Cancer Research (2018)

Abstract Pain is one of the most prevalent symptoms among breast cancer survivors, which negatively impact on their quality of life (QOL). Adjuvant radiotherapy (RT) can increase the risk of development or persistence of pain; however, little is known about the mechanisms of RT-related pain or genetic susceptibility. The current study aimed to identify susceptible loci and enriched pathways for clinically relevant pain, which is defined as pain score ≥ 4, at the completion of RT (post-RT pain). We conducted a genome-wide association study (GWAS) of 1,112 breast cancer patients with 1,344,832 tagging SNPs, gene-based analysis using PLINK set-based tests for 19,621 genes, and functional enrichment analysis of a gene list (875 genes having p &amp;lt; 0.05) using NIH DAVID functional annotation module with KEGG pathways and GO terms (n=380). About 29% of patients reported post-RT pain, and 4 SNPs showed suggestive associations; rs16970540 in RFFL or near to LIG3 gene (p=1.7x10-6), rs4584690 and rs7335912 in ABCC4/MPR4 gene (p=5.5x10-6 and p=7.8x10-6, respectively), and rs73633565 in EGFL6 gene (p=8.1x10-6). Gene-based analysis suggested the importance (involvement) of neurotransmitter, olfactory receptor, and cytochrome P450 in post-RT pain, and functional analysis suggested glucuronidation and olfactory receptor activity as the most enriched biological processes/features. With a limited size of sample, this is the first GWA study showing (confirming) that post-RT pain is a complex polygenic trait influenced by many biological processes and functions. If validated in a larger population, the results can provide biological targets for pain management to improve cancer survivor's QOL. Additionally, these findings may be used as predictive biomarkers of personalized pain management. Citation Format: Eunkyung Lee, Christina Takita, Jean L. Wright, Eden Martin, Susan Slifer, Jennifer Hu. Identification of susceptible loci and enriched pathways for post-radiotherapy pain in breast cancer patients [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 231.
Change in Aortic End-Systolic Pressure by Alterations in Loading Sequence and Its Relation to Left Ventricular Isovolumic Relaxation
Authors: FujimasaKohno, ToshiakiKumada, MasashiKambayashi, WataruHayashida, NoboruIshikawa, ShigetakeSasayama
Journal: Circulation (1996)

Background A brief, sustained constriction of the descending and the ascending aortas produces systolic loads at different times during ejection, and descending intervention prolongs left ventricular (LV) relaxation more than ascending intervention. Although alterations in the sequence of loading the ventricle have been suggested as a cause of such load-induced relaxation abnormalities, the relation of the loading system to relaxation has been unclear. Methods and Results LV peak systolic pressure was elevated by approximately 40 mm Hg by constricting the descending and ascending aortas in seven anesthetized dogs. The descending intervention increased aortic end-systolic pressure (AoESP, 110.4±9.3 to 150.8±11.5 mm Hg; P<.05), reduced aortic flow (P<.05), and prolonged LV relaxation (time constant [T], 31.9±4.4 to 69.8±12.8 ms; P<.05). LV ejection time was reduced, but the systolic time interval was unchanged. In contrast, ascending intervention decreased AoESP (111.9±11.4 to 101.5±10.3 mm Hg; P<.05), redu...
Abstract 2028: ZEB2 promotes cancer cell survival and angiogenesis by cooperating with transcription factor Sp1
Authors: Dongjoon Ko
Journal: Cancer Research (2018)

Abstract The metastatic cascade essential for tumor progression consists of local invasion, intravasation, extravasation, micrometastasis, cancer cell survival in the circulation, and metastatic colonization. In particular, epithelial-mesenchymal transition (EMT) has been demonstrated a critical process whereby epithelial cells undergo molecular changes to acquire mesenchymal phenotypes through upregulation of EMT-inducing transcription factors. We previously showed that ZEB2, through cooperation with the transcription factor Sp1, plays an important role in the transcriptional upregulation of mesenchymal genes such as integrin α5 and vimentin during cancer cell invasion. Here, we show that ZEB2 cooperates with Sp1 for promoting not only EMT and invasion but also diverse cellular functions during metastasis. ZEB2 induces expression of Sp1-regulated genes such as VEGF, survivin, bcl-2 and cyclin D1 in an Sp1-dependent manner. Collaboration between ZEB2 and Sp1 induces cancer cell survival and proliferation, endothelial cell activation, and tumor angiogenesis. Furthermore, Sp1 stabilizes ZEB2 protein, supporting the presence of a positive feedback loop between ZEB2 and Sp1. Clinical data show that ZEB2 expression was correlated to Sp1 expression, and that those factors were a crucial for predicting survival in cancer patients. Our findings demonstrate cooperative roles of ZEB2 and Sp1 in regulating cancer cell survival and angiogenesis beyond invasion during cancer progression. Citation Format: Dongjoon Ko. ZEB2 promotes cancer cell survival and angiogenesis by cooperating with transcription factor Sp1 [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 2028.
Abstract 15697: Fingertip-Based Monitoring of Vascular Reactivity and Endothelial Function: A Three-Way Comparison of Testing Modalities
Authors: Morteza Naghavi, Alex Wei Haw Lin, Stanley Kleis, Albert Yen
Journal: Circulation (2015)

Introduction: In recent years fingertip-based measurement of vascular reactivity and endothelial function using a 5-min arm-cuff reactive hyperemia protocol has become a clinical tool for clinicians to evaluate patients in the exam room. Our group previously introduced Digital Thermal Monitoring (DTM) as a simple, easy and operator-independent test that measures vascular reactivity and endothelial function by monitoring fingertip temperature. Recently we developed fingertip photoplethysmography (PPG). In this study, we performed a simultaneous comparison of the three methods to evaluate their similarities and dissimilarities. Hypothesis: We hypothesized that PPG correlates strongly with PAT and could be used as a replace. Methods: Cuff-induced reactive hyperemia protocol (5 min. baseline, 5 min. ischemia, 5 min. post deflation) tests were performed with simultaneous recording of signals from PAT Pressure sensors (on index finger), DTM temperature sensors (3rd finger), and PPG photoelectric sensors (4th finger). A total of 39 tests were performed on 17 individual subjects. Signal data were analyzed, cross correlated, and graphed using Excel software and MATLAB functions. Results: As shown in Figure below, all three modalities showed similar patterns. Analyses of data during reactive hyperemia phase showed the strongest correlation between PPG and PAT (mean crosscorr = 0.79), compared to PAT and DTM (mean crosscorr = 0.64) and PPG and DTM (mean crosscorr = 0.49). Conclusions: DTM, PPG, and PAT signals are well correlated. The strong correlation between PPG and PAT suggests they can be used interchangeably.
Abstract 3982: Dual inhibition of HDAC and PI3 kinase signaling pathways with CUDC-907 in treatment of p53-driven medulloblastoma
Authors: Jennifer S. Ronecker, Julia Pazniokas, Anubhav G. Amin, Raphael Salles Scortegagna de Medeiros, Sidnei Epelman, Chirag Ghandi, Nelci Zanon, Meic H. Schmidt, Meena Jhanwar-Uniyal
Journal: Cancer Research (2018)

Abstract Comprehensive studies of the medulloblastoma (MB) genome, epigenome and transcriptome have placed MB in four molecular subgroups: WNT, SHH, and two non-WNT/non-SHH: Group 3 and Group 4. Furthermore, studies suggest that p53-mutated SHH MBs frequently harbor genetic anomalies involving MYCN and GLI2 amplifications, which confer poor prognosis and resistance to treatments. The phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) intracellular signaling pathway that regulates cell growth, survival and invasion, is commonly deregulated in MB. Therefore, the PI3K/Akt/mTOR pathway may be a suitable target for therapeutic intervention. Moreover, Histone deacetylases (HDAC) regulate cancer initiation and progression, and studies have shown that small molecule inhibitors of HDAC can effectively limit MB proliferation. We aim to determine the status of tumor suppressor gene p53 in defining metastatic potential in SHH-MB and to establish the therapeutic efficacy of targeting these pathways in p53-driven MB cells with a dual agent or individual agents. Immunohistochemistry and FISH were used to determine the status of mutant p53 and MYC amplification or iso-p53, respectively, in MB tumors (n=41). p53-mutant MB cell line was used to investigate the signaling pathway that regulates proliferation, migration, and drug resistance using inhibitors of HDAC (LBH-589) and PI3K/mTOR (BKM-120/rapamycin) or CUDC-907 (dual inhibitor of HDACs and the PI3K/AKT). Results demonstrated that: 1) GAB-1 was highly expressed in the Shh group (82%) and KV1 expression was evenly distributed in all subtypes; 2) loss of p53 and overexpression of MYC varied in each subtype, but did not correlate with metastasis; 3) combined treatment with LBH-589 and BKM-120 or single treatment with CUDC-907 reduced cell proliferation, migration and S-phase entry; 4) MB cells were resistant to BKM -120, while LBH-589 or CUDC-907 caused apoptosis; 5) tumor formation was suppressed by BKM-120 given with mTOR inhibitors; 6) AKT and 4E-BP1 dephosphorylated following treatments with BKM-120 or CUDC-907. In conclusion, despite current clinical limitations, dual HDAC and PI3K inhibitors may benefit the understanding of aberrant signaling pathways in genetically driven MB, and may provide basis for future targeted therapies. Citation Format: Jennifer S. Ronecker, Julia Pazniokas, Anubhav G. Amin, Raphael Salles Scortegagna de Medeiros, Sidnei Epelman, Chirag Ghandi, Nelci Zanon, Meic H. Schmidt, Meena Jhanwar-Uniyal. Dual inhibition of HDAC and PI3 kinase signaling pathways with CUDC-907 in treatment of p53-driven medulloblastoma [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 3982.