tbuckley/cabot-search huggingface dataset:
Abstract 2665: Bioassay approach isolation and crystal structure elucidation of isoglabratephrin: A prenylated flavonoid from <i>Tephrosia apollinea</i> and its anticancer property
Authors: Loiy E. Ahmed Hassan, Muhammad Adnan Iqbal, Aman Shah Abdul Majid, Amin M. Abdul Majid, Zarina Thasneem Zainudeen
Journal: Cancer Research (2018)

Abstract Cancer is characterized by uncontrolled cell division caused by dysregulation of cell proliferation. Therefore, agents that impair cancer cell proliferation could have potential therapeutic value. Higher plants are considered to be a good source of anticancer agents, and several clinically tested chemotherapeutic agents have been isolated from plants or derived from constituents of plant origin. In the present study, a prenylated flavone (isoglabratephrin) was isolated from aerial parts of Tephrosia apollinea using a bioassay-guided technique. Chemical structure of the isolated compound was elucidated using spectroscopic techniques (NMR, IR, and LC-MC) and confirmed using single crystal X-ray analysis. The antiproliferative effect of isoglabratephrin was tested using three human cancer cell lines (prostate (PC3), pancreatic (PANC-1), and colon (HCT-116) and one normal cell line (human fibroblast). Isoglabratephrin displayed selective inhibitory activity against proliferation of PC3 and PANC-1 cells with median inhibitory concentration values of 20.4 and 26.6μg/ml, respectively. Isoglabratephrin demonstrated pro-apoptotic features, as it induced chromatin dissolution, nuclear condensation, and fragmentation. It also disrupted the mitochondrial membrane potential in the treated cancer cells. Thus, isoglabratephrin could be a new lead for development of cancer chemotherapies to treat human prostate and pancreatic malignancies. Citation Format: Loiy E. Ahmed Hassan, Muhammad Adnan Iqbal, Aman Shah Abdul Majid, Amin M. Abdul Majid, Zarina Thasneem Zainudeen. Bioassay approach isolation and crystal structure elucidation of isoglabratephrin: A prenylated flavonoid from Tephrosia apollinea and its anticancer property [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 2665.
Abstract 2809: Novel 2,5,8-trihydro-6,7-disubstituted-4-(3'-alkylsulfonamidoanilino) quinazoline derivatives as RAF inhibitor
Authors: Shih Chieh Yen, Shao-Zheng Peng, Hung-Jyun Huang, Ju-Ying Yang, Yen-Hsi Liu, Sian-Yi Ciou, Mann-Yan Kuo, Chu-Bin Liao
Journal: Cancer Research (2018)

Abstract The oncogenic mutations of BRAF which occur most frequently in V600E, leading to constitutive activation of the MAPK signaling pathway, are common in a variety of human cancers. Recently, drugs targeting RAF kinase have been approved as an effective treatment for human malignancies that rely on this target for their growth. Thus, suppressing RAF kinase activity is a clinically meaningful approach to treat cancer patients harboring RAF driven oncogene. In this study, a series of 2,5,8-trihydro-6,7-disubstituted-4-(3'-alkylsulfonamidoanilino)quinazoline was synthesized and evaluated for their RAF kinases inhibition activity. Several potent compounds displayed double-digit nanomolar IC50 values for RAF kinases including CRAF, BRAF, and BRAFV600E. Preliminary profiling of one of the most active compounds in a panel of protein kinases revealed its selectivity for RAF kinases. In cells, this compound exhibited selective cytotoxicity against cancer cells harboring BRAF V600E mutation and dose-dependent inhibition of phosphorylation of RAF downstream effectors MEK and ERK. Moreover, the compound was oral active in mice bearing A375 BRAFV600E-mutant melanoma xenograft. Therefore, the novel quinazoline derivative proved to be active as RAF inhibitor. Citation Format: Shih Chieh Yen, Shao-Zheng Peng, Hung-Jyun Huang, Ju-Ying Yang, Yen-Hsi Liu, Sian-Yi Ciou, Mann-Yan Kuo, Chu-Bin Liao. Novel 2,5,8-trihydro-6,7-disubstituted-4-(3'-alkylsulfonamidoanilino) quinazoline derivatives as RAF inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2809.
Abstract 19419: A Phase IIa Randomized Double-Blind, Placebo Controlled Study to Evaluate Plasmid Stromal Cell-Derived Factor-1 for Treatment of Critical Limb Ischemia - The STOP-CLI Trial
Authors: Melina R Kibbe, Ajay Yadav, Rajiv Parakh, Farrell O Mendelsohn, Jason Q Alexander, Joseph R McShannic, Joseph M Pastore, Michael L Fitzgerald, Rahul Aras, Marc S Penn
Journal: Circulation (2014)

Background: Stromal cell-derived factor-1 (SDF-1) promotes tissue repair by increasing cell survival, endogenous stem cell recruitment and vasculogenesis. Preclinical studies demonstrated that non-viral DNA plasmid encoding human SDF-1 (pSDF-1) is safe and increased vessel density in animal models of hindlimb ischemia versus placebo. Additionally, clinical studies have demonstrated safety of pSDF-1 and evidence of neovascularization at the microvascular level. A Phase IIa multi-center double blind randomized placebo-controlled dose escalation study (STOP-CLI) was initiated to evaluate the safety and efficacy of pSDF-1 administered via direct intramuscular injection in patients with critical limb ischemia (CLI). Methods: Forty eight CLI (Rutherford 4 or 5) patients who were poor candidates for surgical revascularization on stable medical therapy with ankle systolic pressure ≤70 mmHg or toe systolic pressure ≤50 mmHg were enrolled into 4 cohorts (n=12 each). Within each cohort, subjects were randomized 3:1 to receive a single set of direct intramuscular injections (8 or 16) to the ischemic limb of escalating doses of 1 mg/ml pSDF-1 (4, 8, 8 or 16mg) or placebo and were followed for 12 months post-dosing. Efficacy endpoints include: quality of life via SF-36, visual analog scale (VAS), Rutherford class, time to first/number of amputations, wound healing, and survival. Results: Enrollment was completed in July 2013. At baseline, patients were, 58.6±13.7 years, 88% male, and had an equal number of Rutherford 4 and 5 (n=24 each). To date, 482 follow up months have been completed with 36 Serious Adverse Events reported, none drug-related. Interim 12 month efficacy results show patients who received 8 injections (8 x 1 mg) totaling 8 mg pSDF-1 improved in rest pain (VAS -3.3±2.5 cm vs. -0.8±2.4 cm; 8 x 1 mg injections vs. placebo, p=0.12) and demonstrate improvements in SF-36 Overall Physical (22.4 ± 27 vs. -2.6 ± 29.7, p=0.22) and Mental (21.0 ± 12.7 vs. 0.26 ± 28.2, p=0.16) Health. Final 12 month data will be available in September 2014. Conclusions: STOP-CLI tests the hypothesis that delivery of pSDF-1 is safe and will improve the clinical status of patients with CLI. The interim results of STOP-CLI demonstrate safety and bioactivity of pSDF-1 for treatment of CLI.
Abstract 1332: Autophagic clearance of protein aggregates is impaired in cancer cells with dysfunctional mitochondria
Authors: Thomas Biel, Ashutosh Rao
Journal: Cancer Research (2018)

Abstract Mitophagy and aggrephagy are selective types of autophagy that degrade damaged mitochondria and protein aggregates, respectively. Dysfunctional mitochondria are known to undergo mitophagy and cause protein aggregation. How a cell can simultaneously coordinate the removal of dysfunctional mitochondria and protein aggregates via autophagy is unknown. Here, two agents, Mitoquinone (MitoQ) and MitoApocynin (MitoApo), known to induce mitochondrial dysfunction and mitophagy in MDA-MB-231 cells were used to investigate the accumulation of protein aggregates and the mechanisms that contribute to selective autophagy. Using a protein aggregate dye and a poly-ubiquitinated antibody, carbonyl cyanide m-chlorophenyl hydrazine (CCCP), MitoQ, and MitoApo were identified as agents that caused an accumulation of poly-ubiquitinated protein aggregates in cancer cells by FACS analysis and confocal imaging. Microflow imaging of the cellular lysates confirmed a relative accumulation of large protein (&amp;gt;460 kDa) complexes. To establish the presence of aggrephagy, the aggregates were colocalized with LC3. Wild type and ATG7 knockout MEF cells were used to test whether protein aggregates accumulated in an autophagy-dependent manner. Our data currently demonstrates the kinetics of autophagic clearance of drug-induced protein aggregation and dysfunctional mitochondria. Citation Format: Thomas Biel, Ashutosh Rao. Autophagic clearance of protein aggregates is impaired in cancer cells with dysfunctional mitochondria [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 1332.
Abstract 4183: Gold nanorods-assisted photothermal therapy inhibits metastasis by decreasing the mammary tumors bleeding in canine and felines
Authors: Moustafa Ragab Khalil Ali
Journal: Cancer Research (2018)

Abstract Metastasis enables cancer cells to migration, which is responsible for most cancer-related deaths. It usually begins with local invasion to the surrounding tissues, followed by intravasation into the lymph and blood microvasculature before the cancer cells finally colonize within the microenvironment of other locations in the patient's body. Recently, we discovered that gold nanorods assisted photothermal therapy (AuNRs-PPTT) inhibits cancer cell migration and prevent metastasis. AuNRs-PPTT is a therapy in which AuNRs are injected to a tumor before near-infrared light is transiently applied to the tumor producing localized heat. However, AuNRs-PPTT has great potential in replacing the current ineffective anti-metastasis treatments but most of the studies has been performed in vitro. The objectives of this study to understand the AuNRs-PPTT impacting blood and blood vessels in naturally occurring mammary glands tumor in cats and dogs. Our histopathology results showed AuNRs-PPTT caused infiltration of neoplastic cells into lymphatic vessels. Furthermore, we observed that AuNRs-PPTT significantly cause blood coagulation around the tumor, which could be incorporated in the surgery to decrease the bleeding and potentially avoiding the risk of metastasis caused by the surgery. This observation might explain why AuNRs-PPTT inhibited metastasis for mammary gland metastasis upon AuNRs-PPTT. After 24 months, the optimized doses of 2.5 nm of AuNRs irradiated by near-Infrared laser with 0.5 w/cm2 intensity for 2 minutes, have shown no any toxicity signs in liver and kidney functions. Citation Format: Moustafa Ragab Khalil Ali. Gold nanorods-assisted photothermal therapy inhibits metastasis by decreasing the mammary tumors bleeding in canine and felines [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 4183.
Mechanical Stretch Activates the JAK/STAT Pathway in Rat Cardiomyocytes
Authors: JingPan, KeiichiFukuda, MikiyoshiSaito, JunichiMatsuzaki, HiroakiKodama, MotoakiSano, ToshiyukiTakahashi, TakahiroKato, SatoshiOgawa
Journal: Circulation Research (1999)

Abstract—This study was designed to determine whether mechanical stretch activates the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway in cardiomyocytes and, if so, by what mechanism. Neonatal rat/murine cardiomyocytes were cultured on malleable silicone dishes and were stretched by 20%. Mechanical stretch induced rapid phosphorylation of JAK1, JAK2, Tyk2, STAT1, STAT3, and glycoprotein 130 as early as 2 minutes and peaked at 5 to 15 minutes. It also caused gel mobility shift of sis-inducing element, which was supershifted by preincubation with anti-STAT3 antibody. Preincubation with CV11974 (AT1 blocker) partially inhibited the phosphorylation of STAT1, but not that of STAT3. Preincubation with TAK044 (endothelin-1-type A/B-receptor blocker) did not attenuate this pathway. RX435 (anti–glycoprotein 130 blocking antibody) inhibited the phosphorylation of STAT3 and partially inhibited that of STAT1. Phosphorylation of STAT1 and STAT3 was strongly inhibited by HOE642 (Na+...
Mildly Oxidized LDL Induces Activation of Platelet-Derived Growth Factor β-Receptor Pathway
Authors: IsabelleEscargueil-Blanc, RobertSalvayre, NathalieVacaresse, GüntherJürgens, BenoitDarblade, Jean-FrançoisArnal, SampathParthasarathy, AnneNègre-Salvayre
Journal: Circulation (2001)

Background Mildly oxidized LDL (moxLDL) is thought to play a role in atherogenesis. MoxLDL induces derivatization of cell proteins and triggers a variety of intracellular signaling. We aimed to investigate whether moxLDL-induced protein derivatization may influence the activity of platelet-derived growth factor receptor β (PDGFRβ), a tyrosine kinase receptor of major importance in vascular biology and atherogenesis. Methods and Results In cultured rabbit arterial smooth muscle cells, moxLDL induces activation of the PDGFRβ signaling pathway, as shown by PDGFRβ tyrosine phosphorylation on Western blot and coimmunoprecipitation of SH2-containing proteins. The cellular events involved in the moxLDL-induced PDGFRβ activation can be summarized as follows. Oxidized lipids from moxLDL trigger two phases of PDGFRβ activation involving two separate mechanisms, as shown by experiments on cultured cells (in situ) and on immunopurified PDGFRβ (in vitro): (1) the first phase may be mediated by 4-hydroxynonenal, which ...
Abstract 1181: Structure and evolution of double minutes in a pediatric high-grade glioma
Authors: Ke C. Xu, Liang Ding, Ti-Cheng Chang, Shuoguo Wang, Yong-Dong Wang, Heather Mulder, Ying Shao, John Easton, Jinghui Zhang, Suzanne J. Baker, Gang Wu
Journal: Cancer Research (2018)

Abstract Double minutes (DMs) are circular extrachromosomal DNA frequently found in brain tumors, often associated with overexpression of oncogenes. To understand the evolution of DMs, we developed a graph-based method to identify simple cycles in a directed graph consisting of highly amplified copy number alteration (CNA) segments and structural variants (SVs) found at the boundaries of each segment. With this method, we presented a case of DM evolution in a pair of diagnosis and relapse whole genome sequencing (WGS) samples from a pediatric high-grade glioma patient, followed by validation with Chromium linked-read sequencing. Using an empirical value of CNA threshold, we extracted 44 and 29 highly amplified CNA segments from the diagnosis and relapse samples respectively. We then identified 29 and 19 unique SVs associated with these CNA segments from the two samples. We constructed five major DMs in the diagnosis sample and five major DMs in the relapse sample, covering all the CNA segments and the SVs. One DM harboring EGFR is identified in both samples. Two of the five relapse DMs are also found in the diagnosis sample but in a trace amount, suggesting a shifting from minor clones in the diagnosis to dominant clones in the relapse. Two major DMs, one carrying MYC and the other carrying CDK6, were only identified in the relapse sample. Analysis of mutations on the DMs revealed that new somatic mutations were acquired on sub-populations of the DMs. Importantly, for the EGFR-carrying DM shared in both samples, we identified an 8-bp deletion at a splicing site of EGFR that has 2% allele frequency in the diagnosis but reached 96% in the relapse. This deletion leads to a mRNA transcription skipping of exon 16 with an 87 fold up-regulation of EGFR compared with other high-grade gliomas, suggesting a possible drug resistance mechanism and positive selection of tumor cells resulting from the mutated DM. We propose an evolutionary model that simultaneously involves a branching model for DM formation and a selection model for mutations on DM. We applied the same methods to the WGS data from two adult glioblastoma patients in TCGA, and found that our proposed model could also explain the DM evolution in these patients. Therefore, our study reveals that DMs follow an evolutionary trajectory independent of linear chromosomes and contribute to tumor heterogeneity. Citation Format: Ke C. Xu, Liang Ding, Ti-Cheng Chang, Shuoguo Wang, Yong-Dong Wang, Heather Mulder, Ying Shao, John Easton, Jinghui Zhang, Suzanne J. Baker, Gang Wu. Structure and evolution of double minutes in a pediatric high-grade glioma [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 1181.
Hypertensive Pulmonary Vascular Disease
Authors: Donaldheath, Williamwhitaker
Journal: Circulation (1956)

Patients with pulmonary artery blood pressures that are chronically elevated to levels of the order of the systemic blood pressures, form a distinct clinicopathologic entity. This condition may complicate a ventricular septal defect, Eisenmenger's complex, patent ductus arteriosus, atrial septal defect, and mitral stenosis, and it may occur as idiopathic pulmonary hypertension. The clinical picture is dominated by symptoms and signs characteristic of pulmonary hypertension, which often mask underlying cardiac anomalies, and definitive pathologic changes occur in the pulmonary vasculature. The term hypertensive pulmonary vascular disease is therefore suggested for this distinct group of patients.
Abstract 5562: A 3D image-based quantification of T cell-mediated killing of CRC organoids in the presence of immuno-modulators
Authors: Gera Goverse, Lidia Daszkiewicz, Kuan Yan, Mohamed Tleis, Mariusz Madej, Lucia Salinaro, Leo Price
Journal: Cancer Research (2018)

Abstract BACKGROUND Cancer immunotherapy has already yielded promising clinical results but most patients still do not respond. The mechanisms of action of these treatment modalities are also not fully understood and the progress in this direction is hampered by a lack of appropriate pre-clinical testing models. To investigate the role of novel therapeutics targeting the immune cell compartment to kill tumor cells, we developed an in vitro assay based on 3D cultures and image based analysis in a 384-wells plate format. Immune cells are added to recapitulate the tumor micro-environment and its complex interactions between different cellular players. Specifically, infiltration of immune cells into the tumoroids and their killing are visualized and measured, enabling a better understanding of the immune-modulatory profile of different treatments. METHODS Autologous patient derived colon organoids from normal and tumor tissue from several patients were cultured in a 3D environment. HLA-matched PBMCs with and without activation were added and immune-cell infiltration and killing of the CRC organoids was visualized in 3D using automated microscopy. Quantification of immune cell effects was achieved with morphometric analysis with OMinerTM software. RESULTS 3D image data analysis enabled the discrimination of immune-tumor cell interactions and revealed a higher immune cell infiltration and tumoroid killing upon activation. In addition, we were able to compare both normal and tumor colon tissue from the same patient and compare between patients, demonstrating patient related differences and elucidating the effect of immune cell targeting on normal colon tissue. CONCLUSIONS The 3D assay presented here allows the analysis of different cell types that engage in a more realistic setting than when culturing them in traditional 2D cultures. Using image-based analysis, immune-tumor interactions can be visualized and quantified. The 3D environment, both for the cell culture and image analysis, allows for measurement of spatially resolved information, not accessible by monolayer cultures or biochemical assays. This new and innovative platform can empower immunotherapy drug developers to select the most promising candidates and better understand their mechanism of action. Citation Format: Gera Goverse, Lidia Daszkiewicz, Kuan Yan, Mohamed Tleis, Mariusz Madej, Lucia Salinaro, Leo Price. A 3D image-based quantification of T cell-mediated killing of CRC organoids in the presence of immuno-modulators [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 5562.
Abstract 38: Tandem Effects of Specific Foods on Cardiometabolic Risk within the Context of Overall Dietary Patterns: A Meta-analysis of Randomized Controlled Feeding Trials
Authors: Gitanjali M Singh, Marcia Otto, Dariush Mozaffarian
Journal: Circulation (2016)

Background: Cardiometabolic (CMB) risk factors are major mediators of the effects of diet on health. Multiple foods are often consumed in tandem, yet CMB effects of individual dietary factors are often studied in isolation, leading to estimates that may not represent true effects as part of diet patterns. Objective: To quantify the effects of major foods (fruits, vegetables, nuts/seeds, whole grains, fish) and dietary fiber, when consumed within the context of overall diet patterns, on systolic BP, serum lipids, and glucose-insulin homeostasis. Methods: PubMed was searched through Oct 2015 to identify randomized controlled feeding studies evaluating effects of major dietary patterns on CMB factors. We included trials evaluating major dietary patterns including fruits, vegetables, nuts/seeds, whole grains, fish, and dietary fiber as major components and evaluating effects on systolic BP, serum lipids (total cholesterol, LDL-C, HDL-C, or triglycerides), or markers of glucose-insulin homeostasis (fasting plasma glucose, HbA1c, postprandial glucose, or fasting insulin). Multivariate metaregression was used to estimate food-specific effects on CMB factors. Results: Among 15 included trials, diet-pattern related decreases in SBP ranged from -2.2 to -9.5 mmHg; and in LDL-C, from -5.0 to -14.7 mg/dL. Each specific food had different, independent, and additive effects on these risk factors ( Figure ). Results for measures of glucose-insulin homeostasis are in progress. Conclusions: Each of these foods independently influences major CMB risk factors, even when consumed in tandem as part of overall diet patterns . Such quantification more accurately reflects the complementary effects of diverse dietary components and highlights the importance of integrated approaches to investigating dietary factors and implementing relevant dietary policies.
Stable Microreentrant Sources as a Mechanism of Atrial Fibrillation in the Isolated Sheep Heart
Authors: RaviMandapati, AllanSkanes, JayChen, OmerBerenfeld, JoséJalife
Journal: Circulation (2000)

Background—Atrial fibrillation (AF) has traditionally been described as aperiodic or random. Yet, ongoing sources of high-frequency periodic activity have recently been suggested to underlie AF in the sheep heart. Our objective was to use a combination of optical and bipolar electrode recordings to identify sites of periodic activity during AF and elucidate their mechanism. Methods and Results—AF was induced by rapid pacing in the presence of 0.1 to 0.5 μmol/L acetylcholine in 7 Langendorff-perfused sheep hearts. We used simultaneous optical mapping of the right and left atria (RA and LA) and frequency sampling of optical and bipolar electrode recordings (including a roving electrode) to identify sites having the highest dominant frequency (DF). Rotors were identified from optical recordings, and their rotation period, core area, and perimeter were measured. In all, 35 AF episodes were analyzed. Mean LA and RA DFs were 14.7±3.8 and 10.3±2.1 Hz, respectively. Spatiotemporal periodicity was seen in the LA d...