tbuckley/cabot-search huggingface dataset:
Abstract 2686: Polyphenolic triptorelin and leuprorelin derivatives as anticancer prodrugs
Authors: Yousef Beni, Samiyah Alhamed, Jawzah Alnakhli, Kaleh Karim, William Boadi
Journal: Cancer Research (2018)

Abstract Triptorelin (TRP) and Leuprorelin (LEP) are two synthetic analogue of gonadotropin-releasing hormone (GnRH), first was approved by the FDA for treatment of advanced prostate cancer and endometriosis in mid 80s. The surge of testosterone, known as a flare effect, is the major side-effect of cancer chemotherapy using TRP and LEP in a combination regiment. Therefore, improving of the biological activity of TRP and LEP by increasing the cellular uptake and retention is a remedy to this end.In this research, polyphenolic derivatives were linked to TRP and LEP through hydrophobic linkers to enhance and optimize the hydrophobicity of these drugs with the expectation to improve the cellular uptake. In this regard, several TRP and LEP conjugates of tris(4-methoxyphenyl)methanol (TPM) derivatives with optimized hydrophobicity were synthesized by the reaction of methoxy benzenes (e.g. methyl 2-methoxybenzoate, 1,2-dimethoxybenzene, methoxy-2-methylbenzene, methoxy-2-nitrobenzene, chloro-2-methxyenzene, anisole, 2-fluoroanisole or 2-methylanisole and 1,3,5-trioxane, followed by the conjugation with TRP or LEP and decanedioic acid or dodecanedioic acid in the presence of HBTU/DIPEA/DIC in moderate yields.Comparative antiproliferative assays between TPM-TRP conjugates and the corresponding non-covalent physical mixtures of the TPM derivatives and TRP were performed against human acute lymphoblastic leukemia (CCRF-CEM), human ovarian adenocarcinoma (SK-OV-3), and mouse pre adipocytes (3T3-L1) cells. TPM-TRP conjugates inhibited the cell proliferation of CCRF-CEM, SK-OV-3 and 3T3-L1 cells by 55-92%, 24-73%, 37-56%, respectively, at a concentration of 10-50 µM after 24-72 h of incubation. Similar antiproliferative assays between TPM-LEP conjugates and the corresponding non-covalent physical mixtures of the TPM derivatives and LEP were performed against human Caucasian prostate adenocarcinoma (PC3), human breast cancer cell line (BT549) and mouse pre-adipocytes (3T3-L1) cells and indicated moderare to high inhibition of the cell proliferation at a concentration of 5-100 µM after 24-72 h of incubation. These data suggest that TPM-TRP and TPM-LEP derivatives with optimized hydrophobicity can be used to improve the biological activity of TRP or LEP. Citation Format: Yousef Beni, Samiyah Alhamed, Jawzah Alnakhli, Kaleh Karim, William Boadi. Polyphenolic triptorelin and leuprorelin derivatives as anticancer prodrugs [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 2686.
Abstract 19890: Pre-operative Cerebral Hemodynamics From Birth Until Surgery in Neonates With Critical Congenital Heart Disease
Authors: Jennifer M Lynch, John J Newland, Madeline Winters, David R Busch, Ann L McCarthy, Rui Xiao, Susan C Nicolson, Lisa M Montenegro, Stephanie Fuller, J. W Gaynor, Thomas L Spray, Arjun G Yodh, Daniel J LIcht, Maryam Y Naim
Journal: Circulation (2015)

Introduction: Neonates with critical congenital heart disease (CHD) exhibit a high prevalence of white matter injury (WMI). Recent work in neonates with hypoplastic left heart syndrome has shown that a longer wait from birth to surgery was associated with lower cerebral tissue oxygen saturations (StO2) on the morning of surgery and an increased risk for postoperative white matter injury (WMI). Understanding the daily preoperative changes in cerebral physiology during this vulnerable period may lead to new therapeutic algorithms aimed at prevention of WMI. Methods: Term neonates with critical CHD were recruited for this study. Frequency domain diffuse optical spectroscopy was employed to noninvasively quantify StO2. Daily StO2 measurements were made from day of recruitment until the day of surgery. Results: We studied 37 neonates with critical CHD. Operations were performed at 1-8 days of life. Non-elective reasons for timing of surgery resulted only in earlier surgery in this cohort. The subjects were placed in 2 groups depending on if they had a normal arch (N=20) or obstructed arch (N=17). In a linear mixed-effects model, StO2 decreased as a function of time from birth but was not specific to diagnostic group. Conclusions: Observed longitudinal daily decline in StO2 from birth until surgery supports our earlier findings and extends them to other groups of CHD. These results suggest that reported increases in risk for WMI with time-to-surgery could be due to mismatched oxygen delivery to metabolic demand. Therapeutic interventions such as increasing cerebral blood flow or decreasing cerebral oxygen demand may be considered when earlier surgery is not possible.
Abstract 4400: MicroRNA loaded circular dumbbell RNAs, a novel antiangiogenic approach
Authors: Manu Gnanamony, Sajani S. lakka, Jaime Libes, Julian Lin, Pushpa A. Joseph, Christopher S. Gondi
Journal: Cancer Research (2018)

Abstract Angiogenesis is a tightly regulated biological process where new blood vessels are formed from pre-existing blood vessels. This process is also critical in diseases such as cancer; therefore, angiogenesis has been actively explored as a drug target for cancer therapy. Many patients treated with endogenous angiogenesis inhibitors show increased survival; however, eventual resistance to therapies is associated with disease progression and death. The future of effective anti-angiogenic therapy lies in the intelligent combination of multiple targeting agents with novel modes of delivery to maximize therapeutic effects. We therefore propose a novel and ‘out of the box' approach that utilizes dumbbell-RNA (dbRNA) to target pathological angiogenesis by simultaneously targeting multiple molecules and processes that contribute to angiogenesis. Dumbbell RNAs are a stable and safe alternative to viral, non-viral, and naked plasmid-based gene-transfer systems. They integrate the advantages of durable expression that is achievable with integrating viral vectors and short-term effects triggered by naked RNA. In this study, we have successfully constructed a plasmid expressing miR-34a dbRNA using the permuted intron-exon (PIE) method. We have also modified and optimized a cost effective protocol to purifiy dbRNA from bacterial culture with high purity. To test the efficacy of miR-34a dbRNA, we used the pancreatic cancer cell line MIA-PaCa2. When transfected into MIA-PaCa2 cell line we observed increased expression of miR-34a. Further, miR-34a overexpression caused a 3- fold and 2.5-fold decrease in VEGFA and VEGFB RNA expression respectively. Functional validation on the effect of miR-34a on angiogenesis was performed on Human umbilical vein endothelial cells (HUVEC) using the tube formation assay, where miR-34a dbRNA showed significant decrease in tube formation when compared to cells treated with scrambled dbRNA. We will further validate these results in vivo using Zebrafish angiogenesis model. In conclusion, our study demonstrate for the first time a novel approach to block angiogenesis using miR-34a loaded dbRNA. Our data also show that this approach may be used in targeting multiple molecules/pathways, and when used in combination with existing therapies can improve the efficacy of current treatment modalities. Citation Format: Manu Gnanamony, Sajani S. lakka, Jaime Libes, Julian Lin, Pushpa A. Joseph, Christopher S. Gondi. MicroRNA loaded circular dumbbell RNAs, a novel antiangiogenic approach [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 4400.
Pro-inflammatory effects of e-cigarette vapour condensate on human alveolar macrophages
Authors: Aaron Scott, Sebastian T Lugg, Kerrie Aldridge, Keir E Lewis, Allen Bowden, Rahul Y Mahida, Frances Susanna Grudzinska, Davinder Dosanjh, Dhruv Parekh, Robert Foronjy, Elizabeth Sapey, Babu Naidu, David R Thickett
Journal: Thorax (2018)

Objective Vaping may increase the cytotoxic effects of e-cigarette liquid (ECL). We compared the effect of unvaped ECL to e-cigarette vapour condensate (ECVC) on alveolar macrophage (AM) function. Methods AMs were treated with ECVC and nicotine-free ECVC (nfECVC). AM viability, apoptosis, necrosis, cytokine, chemokine and protease release, reactive oxygen species (ROS) release and bacterial phagocytosis were assessed. Results Macrophage culture with ECL or ECVC resulted in a dose-dependent reduction in cell viability. ECVC was cytotoxic at lower concentrations than ECL and resulted in increased apoptosis and necrosis. nfECVC resulted in less cytotoxicity and apoptosis. Exposure of AMs to a sub-lethal 0.5% ECVC/nfECVC increased ROS production approximately 50-fold and significantly inhibited phagocytosis. Pan and class one isoform phosphoinositide 3 kinase inhibitors partially inhibited the effects of ECVC/nfECVC on macrophage viability and apoptosis. Secretion of interleukin 6, tumour necrosis factor α, CXCL-8, monocyte chemoattractant protein 1 and matrix metalloproteinase 9 was significantly increased following ECVC challenge. Treatment with the anti-oxidant N-acetyl-cysteine (NAC) ameliorated the cytotoxic effects of ECVC/nfECVC to levels not significantly different from baseline and restored phagocytic function. Conclusions ECVC is significantly more toxic to AMs than non-vaped ECL. Excessive production of ROS, inflammatory cytokines and chemokines induced by e-cigarette vapour may induce an inflammatory state in AMs within the lung that is partly dependent on nicotine. Inhibition of phagocytosis also suggests users may suffer from impaired bacterial clearance. While further research is needed to fully understand the effects of e-cigarette exposure in humans in vivo, we caution against the widely held opinion that e-cigarettes are safe.
Identification of Novel Signaling Complexes by Functional Proteomics
Authors: PeipeiPing
Journal: Circulation Research (2003)

The rapid development of proteomic technologies, combined with the completion of the Human Genome Map, has enabled the compiling of an unprecedented inventory of cellular proteins. Functional proteomics is an emerging field that aims to utilize the enormous amount of information provided by these proteomic technologies to understand the functions of cellular proteins. The utility of functional proteomics has been recently exploited to elucidate cellular mechanisms in numerous fields, of particular salience in the area of signal transduction. This review presents a functional proteomic approach for the study of cardiac cell signaling. It illustrates the strategies by which the subproteome of a targeted signaling system is characterized in an unbiased fashion, the manner in which the biochemical functions of this subproteome are assessed using established molecular and protein chemistry methods, and the challenges associated with these studies.
Abstract 4968: Tumor innate immunity primed by specific interferon stimulated endogenous retroviruses
Authors: David A. Barbie
Journal: Cancer Research (2018)

Abstract Introduction: Tumor cell heterogeneity is a key determinant of cancer progression and drug resistance, which is often mediated by mesenchymal cell subpopulations. While these subclones can secrete growth factors, chemokines and cytokines, the immune signaling networks that fuel this pro-tumorigenic state remain incompletely defined. Elucidating what underlies this state would provide insights into tumor biology and inform clinical strategies to improve anti-cancer therapies. Methods: Because of their well-defined nature, we used the phenotypically distinct H69M and H69AR Small Cell Lung Cancer (SCLC) mesenchymal subclones to uncover a novel mechanism of dysregulated innate immune signaling as compared with parental neuroendocrine H69 cells. Analysis of gene signatures across TCGA and CCLE databases, functional studies in additional cell lines, and ex vivo testing of patient-derived organotypic tumor spheroids (PDOTS) were conducted to determine the broader relevance across human cancers. Results: We discovered a novel epigenetically regulated subclass of endogenous retroviruses (ERVs) that engages innate immune signaling in mesenchymal cancer subpopulations. Stimulated 3 Prime Antisense Retroviral Coding Sequences (SPARCS) are oriented inversely in 3'UTRs of certain interferon-inducible genes and silenced by EZH2. De-repression of these loci resulted in dsRNA generation following IFNγ exposure due to bi-directional transcription from the STAT1-activated gene promoter and the 5' LTR of the antisense ERV. We found that dsRNA sensing preferentially by MAVS fuels activation of TBK1, IRF3, and STAT1 signaling, sustaining a positive feedback loop. SPARCS induction across specific human tumors and cell lines is tightly associated with downregulation of chromatin modifying enzymes, including EZH2, a mesenchymal AXL positive cell state, and B2M and MHC class 1 antigen expression. SPARCS high tumors were marked by immune infiltration, but also exhibited multiple features of tumor immune suppression. IFNγ treatment of PDOTS with de-repressed SPARCS markedly enhanced CXCL10 production and sensitized them to PD-1 blockade. Conclusions: Together, these data unveil a novel subclass of ERVs whose de-repression triggers pathologic innate immune signaling in cancer, with potentially important implications for cancer immunotherapy. Citation Format: David A. Barbie. Tumor innate immunity primed by specific interferon stimulated endogenous retroviruses [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 4968.
Abstract 1320: An integrative and interactive colorectal cancer biomarker database
Authors: Xueli Zhang, Xiao-Feng Sun, Yang Cao, Benchen Ye, Qiliang Peng, Xingyun Liu, Bairong Shen, Hong Zhang
Journal: Cancer Research (2018)

Abstract We created a colorectal cancer (CRC) biomarker database (CBD) with credible content as a powerful and time-saving tool to provide better and accurate information concerning CRC biomarkers. CRC biomarker database (http://sysbio.suda.edu.cn/CBD/) was established based on 870 identified CRC biomarkers and their relevant information from 1115 original articles in PubMed published from 1986 to 2017. In this version of the CBD, CRC biomarker data was collected, sorted, displayed, and analysed. The CBD with the credible contents as a powerful and time-saving tool can provide more comprehensive and accurate information for further CRC biomarker researches. The CBD was constructed under MySQL server. HEML, PHP and JavaScript languages have been used to implement the web interface. The Apache was selected as HTTP server. All of these web operations were implemented under the Windows system. The CBD was concluded the multiple individual biomarker information and categorised into the biological category, source and application of biomarkers; the experiment methods, results, authors and publication resources; the research region, the patient's age, gender, race, the number of tumours, tumour location, and stage. The key words for searching in PubMed are: (((biomarker[Title/Abstract] OR marker[Title/Abstract]) OR indicator[Title/Abstract]) OR predictor[Title/Abstract]) AND ((colorectal cancer[Title/Abstract] OR rectal cancer[Title/Abstract]) OR bowel cancer[Title/Abstract]). The CBD can provide a professional platform to researchers who are interested in CRC research to communicate, exchange their research ideas and further design high quality research in CRC. They can submit their new findings to our database via th submission page, and communicate with us in the CBD. Citation Format: Xueli Zhang, Xiao-Feng Sun, Yang Cao, Benchen Ye, Qiliang Peng, Xingyun Liu, Bairong Shen, Hong Zhang. An integrative and interactive colorectal cancer biomarker database [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 1320.
Results of a Multicenter Randomized Clinical Trial of Exercise and Long-Term Survival in Myocardial Infarction Patients
Authors: JoanDorn, JohnNaughton, DaiImamura, MaurizioTrevisan
Journal: Circulation (1999)

Background—This study examined whether a supervised exercise program improved 19-year survival in 30- to 64-year-old male myocardial infarction patients. Methods and Results—The men (n=651) were participants in the National Exercise and Heart Disease Project, a 3-year multicenter randomized clinical trial conducted in the United States (1976–1979). The treatment group (n=315) exercised for 8 weeks in a laboratory. Thereafter, they jogged, cycled, or swam in a gymnasium/pool setting guided by an individualized target heart rate. Participants in the control group (n=319) were to maintain normal routines but not participate in any regular exercise program. Participants were followed up until their death or December 31, 1995. Cox proportional hazards analysis revealed the all-cause mortality risk estimates (95% CIs) in the exercise group compared with controls to be 0.69 (0.39 to 1.25) after an average follow-up of 3 years, 0.84 (0.55 to 1.28) after 5 years, 0.95 (0.71 to 1.29) after 10 years, 1.02 (0.79 to 1...
Abstract 1442: Novel linkage of thymidine catabolism and the glycolytic pathway in human cancer cells
Authors: Sho Tabata, Masatatsu Yamamoto, Hisatsugu Goto, Yasuhiko Nishioka, Masaru Tomita, Tomoyoshi Soga, Tatsuhiko Furukawa, Shin-ichi Akiyama
Journal: Cancer Research (2018)

Abstract Thymidine phosphorylase (TP), a rate-limiting enzyme in the thymidine catabolic pathway, catalyzes the reversible conversion of thymidine to thymine and 2-deoxy-D-ribose 1-phosphate (DR1P). We previously demonstrated that TP is identical to an anigogenic factor, platelet-derived endothelial cell growth factor (PD-ECGF). Although many reports indicate that TP has angiogenic activity and plays a pivotal role in tumor progression, the mechanism of the TP functions is not fully understood. Here, we find that TP-mediated thymidine catabolism can supply the carbon source in the glycolytic pathway and thus contribute to cell survival under conditions of nutrient deprivation. In certain procaryotes, phosphopentosemutase converts thymidine-derived DR1P to 2-deoxy-D-ribose 5-phosphate (DR5P), which is then converted to glyceraldehyde 3-phosphate (GAP) and acetaldehyde by deoxyriboaldorase (DERA). Given that GAP is an intermediate in the glycolytic pathway and the pentose phosphate pathway (PPP), we hypothesized that the activation of thymidine catabolism by TP could supply the carbon source for those pathways. However, the thymidine catabolic pathway in mammalian cells remains unclarified. We used 13C-labeled thymidine (13C5-thymidine) as a tracer and examined whether 13C5-thymidine-derived metabolites enter the glycolytic pathway and the PPP in TP-expressing cancer cells using capillary electrophoresis time-of-flight mass spectrometry. Thymidine was converted to metabolites, including glucose 6-phosphate, lactate, 5-phospho-α-ribose 1-diphosphate, and serine, via the glycolytic pathway both in vitro and in vivo. These thymidine-derived metabolites were required for the survival of cells under low-glucose conditions. Furthermore, enhanced thymidine catabolism was observed in human gastric cancer. These findings suggest that the thymidine catabolism plays an important role in the survival and growth of cancer cells in a microenvironment where glucose is insufficient. Citation Format: Sho Tabata, Masatatsu Yamamoto, Hisatsugu Goto, Yasuhiko Nishioka, Masaru Tomita, Tomoyoshi Soga, Tatsuhiko Furukawa, Shin-ichi Akiyama. Novel linkage of thymidine catabolism and the glycolytic pathway in human cancer 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 1442.
Contribution and Risks of Left Ventricular Endomyocardial Biopsy in Patients With Cardiomyopathies
Authors: CristinaChimenti, AndreaFrustaci
Journal: Circulation (2013)

Background—Use of left ventricular (LV) endomyocardial biopsy (EMB) to investigate cardiomyopathies is currently discouraged because it is considered riskier than and as contributive as right ventricular (RV) biopsy. The aim of our study is to report our experience with this option and to discuss its advantages and disadvantages. Methods and Results—In our center from 1983 to 2010, 4221 patients underwent diagnostic EMB. In particular, 2396 (56.8%) underwent biventricular EMB, 1153 (27.3%) underwent selective LVEMB, and 672 (15.9%) underwent selective RVEMB. The rate of complications and histological findings were retrospectively analyzed. The periprocedural major complication rate (perforation with or without cardiac tamponade, embolization) was 0.33% for LVEMB and 0.45% for RVEMB, with a significant decrease in the rate of major complications with time (from 1.6% and 1.9% in 1983–1988 to 0% and 0.3% in 2007–2013, respectively; P<0.001 for both), denoting a steep learning curve. No patients died. When th...
Development of a Comorbidity Index to Identify Patients With Small Bowel Bleeding at Risk for Rebleeding and Small Bowel Vascular Diseases
Authors: Naoki Ohmiya, Masanao Nakamura, Hayato Osaki, Hyuga Yamada, Tomomitsu Tahara, Mitsuo Nagasaka, Yoshihito Nakagawa, Tomoyuki Shibata, Tetsuya Tsukamoto, Makoto Kuroda
Journal: Clinical Gastroenterology and Hepatology (2018)
Abstract 60: Higher Fitness is Associated with Lower Health Care Costs: The Veterans Exercise Testing Study
Authors: JonathanMyers, RobertKing, HollyFonda, JoshuaAbella, VictorFroelicher, PeterKokkinos
Journal: Circulation (2014)

Introduction: The association between poor physical fitness and adverse health outcomes is well-established, but few data are available regarding the association between fitness and health care costs. Hypothesis: Higher fitness is associated with lower overall health care costs. Methods: We studied 1,294 patients (mean 64±12 years) who underwent maximal exercise testing for clinical reasons as part of the Veterans Exercise Testing Study (VETS). Fitness was expressed as the percentage of age-predicted peak METs achieved, and categorized in quartiles. Total and annualized health care costs, derived from the VA Allocated Resource Center, were assessed between 2005 and 2010. Health care costs between quartiles of fitness were compared using ANOVA; multiple regression was used to determine clinical and exercise test predictors of health care costs. Follow-up for all-cause mortality (mean 8.5±5 years) was performed through March 2013. Results: A gradient for reduced health care costs was observed with increased...