tbuckley/cabot-search huggingface dataset:
Abstract 2815:Ganoderma lucidumchemosensitizes triple negative breast cancer to carboplatin mediated by DNA damage response
Authors: Ivette J. Suarez-Arroyo, Michelle M. Martinez-Montemayor
Journal: Cancer Research (2018)

Abstract Management of triple negative breast cancer (TNBC) is challenging because of a lack of targeted therapy, its aggressive behavior and poor prognosis. Interest in using platinum agents, such as carboplatin as a line of treatment emerged from data suggesting frequent DNA repair defects in TNBC. Carboplatin resistance may occur due to multiple factors including increased activation of DNA repair mechanisms. Studies show that Ganoderma lucidum extract (GLE) sensitizes cancer cells to different anti-cancer therapies. Thus, we aim to investigate the effects of GLE in combination with carboplatin in the DDR signaling and in tumorigenesis. To study whether GLE sensitizes TNBC cells to carboplatin therapy, we treated SUM-149 and MDA-MB-231 cells with several concentrations of carboplatin, GLE, or both treatments simultaneously for 72h. Our results demonstrate that when carboplatin and GLE are used in combination the IC50s decreased in both breast cancer cell lines in comparison with treatments alone. Immunobloting assays revealed that GLE and/or the combination decrease the expression of 53BP1, p-CHK2, CHK2, p-CHK1, CHK1, p-ATR, p-ATM and p-BRCA1 in SUM-149. Accordingly, immunofluorescence studies to monitor the recruitment of DNA repair proteins 53BP1 and phosphorylated γH2AX at the lesion sites after treatments suggest that the GLE and/or carboplatin combination impair DDR. To determine tumor progression, severe combined immune deficient mice were injected with SUM-149 cells and then treated with carboplatin/GLE or carboplatin for 10 weeks. The combination significantly decrease tumor volume in comparison with the vehicle. Taken together, our results provide evidence of GLE's potential in chemosensitizing TNBC cells to carboplatin therapy affecting the DDR. These results highlight GLE's anti-breast cancer therapeutic potential. Citation Format: Ivette J. Suarez-Arroyo, Michelle M. Martinez-Montemayor. Ganoderma lucidum chemosensitizes triple negative breast cancer to carboplatin mediated by DNA damage response [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 2815.
Abstract 2807: Cytotoxic activity of novel organotin compounds against different cancer cell lines
Authors: Paulina Cherek, Michaela Balogova, Krishna Damodaran, Helga M. Ögmundsdottir
Journal: Cancer Research (2018)

Abstract Cisplatin has been a successful drug in oncology for decades. Its use is however limited by toxicity and development of resistance. Efforts for improvement by screening a large number of different platinum compounds have only yielded to new drugs to the clinic, oxaloplatin and carboplatin. An alternative approach is therefore to explore the potential of other metal-containing compounds. The toxic properties of organic tin compounds have been exploited in industry for a long time. More recently such compounds have been studied for potential therapeutic cytotoxic effects yielding promising results. Here we describe the first screening of two novel organotin compounds, based on the same basic structure, containing bromide (SNO7) or chloride (SNO8). The compounds are being screened against the following cancer cell lines: T47-D (breast), A549 (lung), OVCAR-3 (ovarian), Aspc-1 (pancreatic). IC50 was determined from survival analysis by Crystal violet, and induction of apoptosis by Annexin V staining, monitored by IncuCyte. Cisplatin was used as reference. IC50 values (µg/ml) for T47-D and Aspc-1 were, respectively: 44.5 and 13.8 (SNO7), 13.4 and 26.3 (SNO8) and 34.9 and 34.5 (Cisplatin). SNO7 induced apoptosis starting after 24 hours in OVCAR-3 and A549 at 10 µg/ml and also T47-D at 25 µg/ml; SNO8 in T47-D at 25 µg/ml (OVCAR-3 and A549 not tested) and Cisplatin in OVCAR-3 at 10 µg/ml (A549 not tested). These early results indicate differences in sensitivities between compounds and cell lines implying some specificity in mode of action and suggest that tin-containing compounds could be active against cancer cells that are resistant to cisplatin. Citation Format: Paulina Cherek, Michaela Balogova, Krishna Damodaran, Helga M. Ögmundsdottir. Cytotoxic activity of novel organotin compounds against different cancer cell lines [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 2807.
Multirow Detector Computed Tomography Assessment of Intraseptal Dissection and Ventricular Pseudoaneurysm in Postinfarction Ventricular Septal Defect
Authors: Jean-FrançoisPaul, LoïcMacé, ChristopheCaussin, AbdelhamidFsihi, XavierBerthaux, PhilippeBrenot, ClaudeAngel
Journal: Circulation (2001)
Exogenous Amino Acid‐Loaded Nanovehicles: Stepping across Endogenous Magnetic Resonance Spectroscopy
Authors: Jing Wang, Dalong Ni, Zhiwei Shen, Yan Ren, Yanyan Liu, Wenpei Fan, Yue Wu, Guishan Zhang, Hua Zhang, Renhua Wu, Xiaoyuan Feng, Wenbo Bu, Zhenwei Yao
Journal: Advanced Healthcare Materials (2018)

Abstract Magnetic resonance spectroscopy (MRS) allows the assessment of metabolic contents and biochemical information in vivo. It provides essential compositional information in the diagnosis and monitoring of central nervous system (CNS) diseases, especially brain tumors. Conventional MRS is usually confined to endogenous metabolites that may lack specificity for certain disease such as differentiating glioma from other tumor and non‐tumorous lesions. Therefore, exogenous MRS contrast agents (CAs) that may improve the sensitivity and specificity of MRS are highly desirable for its clinical use. In this work, a novel MRS CA, β‐alanine loaded hollow mesoporous silica nanospheres, with a high biosafety profile and characteristic MRS spectrum was synthesized and investigated. This new CA is further tested to realize the accurate functional MRS diagnosis of brain glioma with high sensitivity. The general approach of synthesizing disease specific CA for MRS may lead to a new era of molecular imaging.
ATP-Binding Cassette G-Subfamily Transporter 2 Regulates Cell Cycle Progression and Asymmetric Division in Mouse Cardiac Side Population Progenitor Cells
Authors: Konstantina-IoannaSereti, AngelosOikonomopoulos, KazumasaUnno, XinCao, YilingQiu, RonglihLiao
Journal: Circulation Research (2013)

Rationale:After cardiac injury, cardiac progenitor cells are acutely reduced and are replenished in part by regulated self-renewal and proliferation, which occurs through symmetric and asymmetric cellular division. Understanding the molecular cues controlling progenitor cell self-renewal and lineage commitment is critical for harnessing these cells for therapeutic regeneration. We previously have found that the cell surface ATP-binding cassette G-subfamily transporter 2 (Abcg2) influences the proliferation of cardiac side population (CSP) progenitor cells, but through unclear mechanisms. Objective:To determine the role of Abcg2 on cell cycle progression and mode of division in mouse CSP cells. Methods and Results:Herein, using CSP cells isolated from wild-type and Abcg2 knockout mice, we found that Abcg2 regulates G1-S cell cycle transition by fluorescence ubiquitination cell cycle indicators, cell cycle–focused gene expression arrays, and confocal live-cell fluorescent microscopy. Moreover, we found that...
Cystic Fibrosis Liver Disease: Outcomes and Risk Factors in a Large Cohort of French Patients
Authors: Pierre‐Yves Boëlle, Dominique Debray, Loic Guillot, Annick Clement, Harriet Corvol
Journal: Hepatology (2018)

Cystic fibrosis (CF)-related liver disease (CFLD) is a common symptom in patients with CF. However, its prevalence, risk factors, and evolution are unclear. We analyzed a large database of patients with CF to investigate the incidence of CFLD, its related risk factors, and the use and effect of ursodeoxycholic acid (UDCA) treatment. We retrospectively analyzed 3,328 CF patients with pancreatic insufficiency born after 1985 and recruited into the French CF Modifier Gene Study since 2004. We determined liver status, age at CFLD and severe CFLD onset, sex, CFTR genotype, history of meconium ileus, treatment with UDCA, and respiratory and nutritional status. The incidence of CFLD increased by approximately 1% every year, reaching 32.2% by age 25. The incidence of severe CFLD increased only after the age of 5, reaching 10% by age 30. Risk factors for CFLD and severe CFLD were male sex, CFTR F508del homozygosity, and history of meconium ileus. Increasingly precocious initiation of UDCA treatment did not change the incidence of severe CFLD. Finally, patients with severe CFLD had worse lung function and nutritional status than other CF patients. Conclusion: CFLD occurs not only during childhood but also later in the lifetime of patients with CF; male sex, CFTR F508del homozygosity, and history of meconium ileus are independent risk factors for CFLD development; earlier use of UDCA over the last 20 years has not changed the incidence of severe CFLD, leading to questions about the use of this treatment in young children given its possible adverse effects.
Thrombin Stimulates Smooth Muscle Cell Differentiation From Peripheral Blood Mononuclear Cells via Protease-Activated Receptor-1, RhoA, and Myocardin
Authors: KennethMartin, SharonWeiss, PatMetharom, JeffreySchmeckpeper, BrianHynes, JohnO'Sullivan, NoelCaplice
Journal: Circulation Research (2009)

Rationale: Smooth muscle precursor cells have previously been reported to reside in bone marrow and in the circulation, but little is currently known regarding the proximate stimuli for smooth muscle cell differentiation of these putative progenitors. Objective: Because local thrombin generation occurs as an initial response to vascular injury, we hypothesized that thrombin may influence the differentiation of circulating smooth muscle progenitor cells. Methods and Results: Peripheral blood mononuclear cells were cultured on type I collagen using a protocol optimized to stimulate smooth muscle cell outgrowth. Thrombin-stimulated upregulation of the transcription factor myocardin and smooth muscle myosin heavy chain, and both were inhibited by hirudin or the RhoA inhibitor Y27632. After 10 days of culture, smooth muscle outgrowth colonies formed, which stained positive for α-smooth muscle actin, smooth muscle myosin heavy chain, and calponin, in addition to having a contractile response to 100 nmol/L angio...
α-Adrenergic Coronary Vasoconstriction and Myocardial Ischemia in Humans
Authors: GerdHeusch, DietrichBaumgart, PaoloCamici, WilliamChilian, LuisaGregorini, OttoHess, CiroIndolfi, OrnellaRimoldi
Journal: Circulation (2000)

Abstract—The use of quantitative coronary angiography, combined with Doppler and PET, has recently been directed at the study of α-adrenergic coronary vasomotion in humans. Confirming prior animal experiments, there is no evidence of α-adrenergic coronary constrictor tone at rest. Again confirming prior experiments, responses to α-adrenoceptor activation are augmented in the presence of coronary endothelial dysfunction and atherosclerosis, involving both α1- and α2-adrenoceptors in epicardial conduit arteries and microvessels. Such augmented α-adrenergic coronary constriction is observed during exercise and coronary interventions, and it is powerful enough to induce myocardial ischemia and limit myocardial function. Recent studies indicate a genetic determination of α2-adrenergic coronary constriction.
Abstract 4855: Indotecan (LMP400), Imidotecan (LMP776) and LMP744: A new class of non-camptothecin TOP1 inhibitors selective for cancer cells with homologous recombination deficiencies and high SLFN11 expression
Authors: Yves Pommier, Laetitia Marzi, Zoe Waever Ohler, Ludmila Szabova, Shyam Sharan, Junko Murai, Mark Cushman
Journal: Cancer Research (2018)

Abstract To relax DNA supercoiling, topoisomerase I (TOP1) induces DNA cleavage complexes (TOP1cc). These TOP1cc can be trapped by camptothecin, leading to replication induced DNA double-strand breaks (DSB). Widely used, camptothecin derivatives have known limitations. It is now possible to overcome these limitations with the non-camptothecin indenoisoquinolines currently in clinical trials (LMP400, LMP776 and LMP744). Homologous recombination (HR) and its key components BRCA1, BRCA2 and PALB2 are needed to repair DSB induced by TOP1 inhibitors (Maede, Y et al. 2014). It has been shown that BRCA1 is a determinant of response to camptothecins in addition to Olaparib. Also, Schlafen11 (SLFN11) expression has been demonstrated to be a highly penetrant determinant of response to camptothecin derivatives (Zoppoli, G et al. 2012). To rationally select patients for phase 2 clinical trials based on cancer-specific genomic alterations, we have determined whether HR components deficiency or SLFN11 expression are determinants of LMPs response. Using isogenic cell lines, we assessed the survival after treatment with the LMPs. We found that SLFN11-positives cells are 10-times hypersensitive to LMPs compare to WT cells. Also, BRCA1-, BRCA2- and PALB2-deficient cells are 3- to 5- times hypersensitive to the LMPs. Adding Olaparib led to a greater cell death, especially in HR-deficient (HRD) cells. Our results show that the indenoisoquinolines are active at nanomolar concentrations and that HR deficiency and SLFN11 expression are strong drug response determinants. They also demonstrate that the LMPs synergize with Olaparib. These findings provide a rationale for personalized treatment and further clinical trials with the indenoisoquinolines in HR-deficient cancers. Citation Format: Yves Pommier, Laetitia Marzi, Zoe Waever Ohler, Ludmila Szabova, Shyam Sharan, Junko Murai, Mark Cushman. Indotecan (LMP400), Imidotecan (LMP776) and LMP744: A new class of non-camptothecin TOP1 inhibitors selective for cancer cells with homologous recombination deficiencies and high SLFN11 expression [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 4855.
Basilar Artery Insufficiency Secondary to Obstruction of Left Subclavian Artery
Authors: Gordonsproul
Journal: Circulation (1963)

Two cases are presented of basilar artery insufficiency with reversal of flow in the left vertebral artery secondary to obstruction of the subclavian artery at its origin. The symptoms have been relieved by restoration of pressure in the subclavian artery. The hemodynamics are reviewed, and the value of arteriography in cerebral vascular insufficiency is supported.
Abstract 5655: Biophysics in the cell—CETSA to study drug binding and cellular processes in cancer therapy
Authors: Ying Yu Liang, Anderson Ramos, Henriette Laursen, Olga Surova, Johan Lengqvist, Sara Lööf, Anette Langebäck, Smaranda Bacanu, Jonas Bergh, Pär Nordlund
Journal: Cancer Research (2018)

Abstract A key step of the action of most drugs is their binding (engagement) of the target protein(s). However, limitations in the available methods for directly accessing this critical step have added uncertainties in many stages of drug development. We have developed a generic method for evaluating drug binding to target proteins in cells and tissues (Martinez Molina et al. Science, 341:84). The technique is based on the physical phenomenon of ligand-induced thermal stabilization of target proteins; the method is therefore called the cellular thermal shift assay (CETSA). The technique allows for the first time to directly measure the biophysical interactions between a drug and protein target in non- engineered cells and tissues. We show that using CETSA a range of critical factors for drug action can be addressed at the target engagement level, including drug transport and activation, off-target effects, drug resistance as well as drug distribution in cells, patient and animal tissues. Although CETSA was first developed for evaluating drug binding to target proteins in cells it is also useful for characterizing physiological interactions, including protein-protein, protein-metabolite and protein-nucleic acid interactions (Martinez Molina &amp; Nordlund, Ann Rev Pharm Toxic 2016 56:141). In the proteome-wide CETSA experiment, interactions with more than 7000 proteins can be measured in parallel (Savitski, Science 2014 346;6205). This strategy therefore constitutes a novel mean for discovering key interactions determining the fate of cancer cells during therapy and resistance – interactions that can serve as biomarkers or candidates for novel drug targets in cancer therapy. Citation Format: Ying Yu Liang, Anderson Ramos, Henriette Laursen, Olga Surova, Johan Lengqvist, Sara Lööf, Anette Langebäck, Smaranda Bacanu, Jonas Bergh, Pär Nordlund. Biophysics in the cell—CETSA to study drug binding and cellular processes in cancer 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 5655.
Abstract 4652: Targeted nanomedicines improve therapeutic indices of RAF and MEK inhibitors
Authors: Daniel A. Heller, Yosi Shamay
Journal: Cancer Research (2018)

Abstract Potent kinase inhibitors have been developed to treat tumors, but they suppress signaling in normal cells so that their dosing and ability to inhibit the pathway are limited by toxicity, resulting in a narrow therapeutic index. We developed a novel drug delivery strategy which efficiently encapsulates and targets kinase inhibitors to the tumor microenvironment while obviating the sources of dose-limiting toxicities. The platform employs nanoparticle scaffolds that we modified to target caveolae and P-selectin, that can both be overexpressed on tumor vasculature. We assessed the targeted drug delivery properties of the nanoparticles, encapsulating the RAF inhibitor sorafenib and MEK inhibitor trametinib. Strikingly, we found selective tumor uptake and exceptional net anti-tumor efficacies in patient-derived xenografts and genetically modified mouse models. The nanomedicine strategy also prevented the inhibition of ERK phosphorylation in the skin, demonstrating that this targeting strategy may abrogate dose-limiting toxicities of kinase inhibitors to improve their therapeutic indices. Citation Format: Daniel A. Heller, Yosi Shamay. Targeted nanomedicines improve therapeutic indices of RAF and MEK inhibitors [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 4652.
17β-Estradiol Restores Endothelial Nitric Oxide Release to Shear Stress in Arterioles of Male Hypertensive Rats
Authors: AnHuang, DongSun, AkosKoller, GaborKaley
Journal: Circulation (2000)

Background—Endothelial nitric oxide (NO)–mediated responses are impaired in arterioles of male spontaneously hypertensive rats (SHR), but they are still present in female SHR. We hypothesized that in vitro incubation of arterioles of male SHR with estrogen will restore NO-mediated responses by upregulation of endothelial NO synthase. Methods and Results—Responses to increases in perfusate flow (from 0 to 25 μL/min) and to the calcium ionophore A23187 (5×10−8 to 10−6 mol/L), norepinephrine (NE; 10−7 to 3×10−7 mol/L), sodium nitroprusside (SNP; 10−8 to 10−6 mol/L), and adenosine (ADO; 10−6 to 5×10−5 mol/L) were studied in cannulated and pressurized gracilis muscle arterioles (≈75 μm in diameter) isolated from 12-week-old male SHR before and after incubation with 10−9 mol/L 17β-estradiol (17β-E2) for 16 to 18 hours. After incubation with 17β-E2, basal diameter of arterioles was significantly increased (by ≈10%), and flow-induced dilation was significantly enhanced (79.8±2.9 versus 103.7±3.7 μm at 25 μL/min),...
The Electrocardiogram in Duchenne Progressive Muscular Dystrophy
Authors: Cecyliaslucka
Journal: Circulation (1968)

Interpretation of the electrocardiogram in the Duchenne form of progressive muscular dystrophy (PMD) is still debated in the literature. The group studied consisted of 106 patients with the Duchenne type of PMD, aged 3 to 29 years. The duration of the disease varied from a few months to 15 years. One hundred one patients had abnormal electrocardiograms. These were of four types: type a (64 cases) showed tall R waves in V1 and deep Q waves in V4-6; type b (24 cases), RSr' and deep Q waves in V5-6; and type c (13 cases), polyphasic R waves in V1. The view that the electrocardiographic abnormalities in Duchenne dystrophy are a manifestation of the dystrophic process in the myocardium is discussed. The authors' material, however, failed to support this view but did support the view that the electrocardiographic abnormalities have an heredofamilial character.
Abstract 20913: Endothelial Cell Inflammation and Antioxidant Capacity Are Associated With 6-Minute Walk Performance in Patients With Symptomatic Peripheral Artery Disease
Authors: Andrew W Gardner, Polly S Montgomery, Yan D Zhao, Zoltan Ungvari, Anna Csiszar, William E Sonntag
Journal: Circulation (2017)

Introduction: The aim of the study was to determine whether 6-minute walk total distance and pain-free distance were associated with circulating biomarkers of antioxidant capacity and inflammation, and with endothelial cell inflammation, oxidative stress, and apoptosis in patients with symptomatic peripheral artery disease (PAD). Methods: Exercise performance in 251 patients was assessed by pain-free distance and total distance covered during a 6-minute walk test. Patients were further characterized on clinical characteristics, on circulating biomarkers of antioxidant capacity and inflammation, and on the endothelial effects of circulating factors present in the sera using a cell culture-based bioassay on primary human arterial endothelial cells. Results: In a multivariate regression model, pain-free distance during the 6-minute walk test was negatively associated with dyslipidemia (p&lt;0.001), chronic kidney disease (p=0.004), and NF-κB (p=0.007), and was positively associated with height (p=0.008). In multivariate analyses, total distance walked during the 6-minute walk test was negatively associated with NF-κB (p&lt; 0.001), coronary artery disease (p=0.009), and BMI (p=0.022), and was positively associated with ABI (p&lt;0.001), male sex (p&lt;0.001), and hydroxyl radical antioxidant capacity (p&lt;0.001). Conclusions: 6-minute walk performance in symptomatic patients with PAD was associated with vascular biomarkers, as walking distances were negatively associated with endothelial cell inflammation and positively associated with circulating antioxidant capacity. The clinical implication is that behavioral interventions designed to alleviate endothelial cell inflammation and increase circulating antioxidant capacity, such as exercise and antioxidant intake, may improve ambulatory ability in patients with PAD during submaximal exercise that is typically performed during daily activities.