tbuckley/cabot-search huggingface dataset:
Abstract 2829: Targeting the DNA damage response and DNA-PK signaling via small molecule Ku inhibitors
Authors: John J. Turchi, Navnath S. Gavande, Pamela S. VanderVere-Carozza, Tyler Vernon, Katherine S. Pawelczak
Journal: Cancer Research (2018)

Abstract Normal 0 false false false EN-US X-NONE X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin-top:0in; mso-para-margin-right:0in; mso-para-margin-bottom:10.0pt; mso-para-margin-left:0in; line-height:115%; mso-pagination:widow-orphan; font-size:11.0pt; font-family:"Calibri","sans-serif"; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin;} The DNA dependent protein kinase (DNA-PK) is a validated target for cancer therapeutics that drives the DNA damage response (DDR) and plays a critical role as a primary sensor in the non-homologous end joining (NHEJ) DNA double strand break (DSB) repair pathway. Various anti-cancer therapeutic strategies mediate their cytotoxic effects by inducing DSBs, including ionizing radiation (IR), and clinical outcomes are directly related to the repair of DNA damage. Modulating the pathway responsible for repairing DSBs will have a profound impact on the efficacy of DNA damaging agents in the clinic. To date, development of inhibitors for DNA-PK has focused on targeting the active site with ATP mimetics. We have taken the novel and innovative approach to inhibiting DNA-PK via blocking the Ku 70/80 heterodimer interaction with DNA, a necessary step in DNA-PK activation. Exploiting this unique mechanism of kinase activation, we have identified a series of highly potent and specific DNA-PK inhibitors that impart their inhibitory activity via disruption of the binding of Ku protein to DNA ends. This novel approach affords significant advantages to current approaches in kinase inhibition. Novel derivatives of our initial hit inhibit DNA-PK catalytic activity at nanomolar concentrations and potentiate cellular sensitivity to DSB-inducing agents like etoposide and bleomycin. Data demonstrate that the cellular effects observed are a function of Ku inhibition and that this novel class of DNA-PK inhibitors can be further developed as anti-cancer therapeutics that can be used as an adjuvant to, or concomitant with radiotherapy and other cancer therapies that induce DNA damage. Citation Format: John J. Turchi, Navnath S. Gavande, Pamela S. VanderVere-Carozza, Tyler Vernon, Katherine S. Pawelczak. Targeting the DNA damage response and DNA-PK signaling via small molecule Ku 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 2829.
Abstract 5027: Heterocellular 3D scaffolds as biomimetic to recapitulate the tumor microenvironment of peritoneal metastases in vitro and in vivo
Authors: Olivier De Wever, Emiel Dejaeghere, Elly De Vlieghere
Journal: Cancer Research (2018)

Abstract Peritoneal metastases cause cancer mortality and preclinical models are urgently needed to boost therapeutic progress. This study reports on a hybrid hydrogel-polylactic acid (PLA) scaffold that mimics the architecture of peritoneal metastases at the qualitative, quantitative and spatial level. Porous PLA scaffolds with controllable pore size, shape, and surface properties are functionalized by type I collagen hydrogel and co-seeding of cancer-associated fibroblast (CAF) increases cancer cell adhesion, recovery, and exponential growth by in situ heterocellular spheroid formation. Scaffold implantation at the peritoneal wall allows long-term follow-up (&amp;gt;14 weeks) and results in a time-dependent increase in vascularization, which correlates with cancer cell colonization in vivo. CAF, endothelial cells, macrophages and cancer cells show spatial and quantitative aspects as similarly observed in patient-derived peritoneal metastases. CAF provide long-term secretion of complementary paracrine factors implicated in spheroid formation in vitro as well as in recruitment and organization of host cells in vivo. In conclusion, the multifaceted heterocellular interactions that occur within peritoneal metastases are reproduced in this tissue-engineered implantable scaffold model. Citation Format: Olivier De Wever, Emiel Dejaeghere, Elly De Vlieghere. Heterocellular 3D scaffolds as biomimetic to recapitulate the tumor microenvironment of peritoneal metastases in vitro and in vivo [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 5027.
Abstract 2075: Whole genome sequence analysis informs precision medicine of pediatric cancers
Authors: Bogdan Tanasa, Alex Lee, Marcus Breese, Avanthi Shah, Stan Leung, Heng-Yi Liu, Aviv Spillinger, Kimberly Hazard, Arun Rangaswami, Sheri Spunt, Norm Lacayo, Tabitha Cooney, Eric Alejandro Sweet-Cordero
Journal: Cancer Research (2018)

Abstract Several recent studies (including BASIC3, iCAT, INFORM, PEDS-MIONCOSEQ) have used whole exome sequencing (WES) and RNA-seq in order to identify targetable chromosomal alterations in a large variety of pediatric cancers. Few studies have attempted to evaluate whether a more comprehensive approach including WGS and RNA-seq could be used to identify novel events relevant to the pathogenesis of advanced pediatric cancer. We analyzed a total of 59 patients (37 solid tumors, 11 brain tumors, and 10 leukemia/lymphomas) to determine the feasibility of using whole-genome sequencing (WGS) technology in conjunction with RNA-seq in order to identify actionable/druggable alterations in the pediatric cancer genomes. WGS analysis has been performed on 75 samples, that were collected from 45 patients, either at diagnosis or at relapse. For WGS analysis of germline-tumor pairs, after performing the sequence alignment with BWA-MEM to gender-specific hg38 genomes, we have used and verified a set of computational methods: 1) MuTect2 for SNV calling, 2) cn.mops for CNV calling, 3) DELLY and LUMPY for SV calling. Here we present our findings on the sets of SNV, CNV, SV, and gene fusions that we have identified by WGSA and RNA-seq, respectively, with a particular emphasis on the druggable alterations, and on the tumor response in the murine PDX models of the pediatric cancers. Consistent with previous observations, the mutational burden across pediatric cancers was low. While common mutations were identified, there was a long-tail of mutations that occurred at a low frequency. As anticipated, samples obtained post-chemotherapy had a higher mutational burden than treatment naive samples. TP53 was the most commonly mutated gene, but we also identified SNVs in other genes commonly mutated in cancer, such as ASXL1, NOTCH2, and RB1. Other novel recurring variants were discovered, further analysis of which is ongoing. Our results indicate that integrated WGS and RNA-seq analysis is feasible in the clinical setting and can reliably identify variants reported on commercially available gene panel testing. However, this approach also resulted in additional clinically relevant findings and allows for novel discovery that will further advance our understanding of these rare and highly aggressive pediatric malignancies. Citation Format: Bogdan Tanasa, Alex Lee, Marcus Breese, Avanthi Shah, Stan Leung, Heng-Yi Liu, Aviv Spillinger, Kimberly Hazard, Arun Rangaswami, Sheri Spunt, Norm Lacayo, Tabitha Cooney, Eric Alejandro Sweet-Cordero. Whole genome sequence analysis informs precision medicine of pediatric cancers [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 2075.
Substrate Preference and Metabolic Activity of the Aerobic and the Hypoxic Turtle Heart
Authors: NormanBrachfeld, YoshinagaOhtaka, IrwinKlein, MasakaKawade
Journal: Circulation Research (1972)

Substrate utilization by the isolated aerobic (Po2 500 mm Hg) and hypoxic (Po2 50 mm Hg) turtle (Pseudemys scripta) heart was evaluated by retrograde perfusion. During aerobic perfusion, the heart demonstrated active extraction and oxidation of free fatty acid (FFA) even in the presence of exogenous glucose. FFA metabolism was similar to that seen in the mammalian heart and was adequate to meet most of the myocardial energy requirements. When hypoxia supervened, FFA utilization did not compete with, but rather enhanced, concomitant carbohydrate metabolism, and glycogenolysis provided sufficient substrate to meet myocardial energy requirements with little change in observed hemodynamic function. During hypoxia, both rat and turtle demonstrated enhanced myocardial esterification of extracted [1-14C]-palmitate into neutral lipid. Exogenous glucose provided the glycerophosphate skeleton for FFA esterification in the hypoxic rat heart; endogenous glycogen served this function in the turtle myocardium. Extracti...
Superoxide Released to High Intra-arteriolar Pressure Reduces Nitric Oxide–Mediated Shear Stress– and Agonist-Induced Dilations
Authors: AnHuang, DongSun, GaborKaley, AkosKoller
Journal: Circulation Research (1998)

Abstract—It is thought that elevated levels of reactive oxygen metabolites contribute to the dysfunction of vascular endothelium in hypertension. We hypothesized that high intravascular pressure itself elicits production of superoxide, which then interferes with nitric oxide (NO)–mediated responses of arterioles. Thus, isolated arterioles (≈80 μm in diameter) from gracilis muscle of normotensive Wistar rats were cannulated and exposed to 140 mm Hg perfusion pressure for 30 minutes (in the absence of perfusate flow). After high intravascular pressure treatment, dilations to increases in perfusate flow (0 to 30 μL/min) were significantly reduced (from 39±2.2 to 19±2.1 μm at 30 μL/min), eliciting an increase in wall shear stress from ≈20 to ≈60 dyne/cm2. Nω-nitro-l-arginine (10−4 mol/L) did not affect, whereas indomethacin eliminated, flow-induced dilations after pressure treatment. In control, substance P (SP, 10−9 to 5×10−8 mol/L), sodium nitroprusside (SNP, 10−8 to 10−6 mol/L), and adenosine (ADO, 10−6 to...
Changes in Lung Clearance Index in Preschool-aged Patients with Cystic Fibrosis Treated with Ivacaftor (GOAL): A Clinical Trial
Authors: Felix Ratjen, Michelle Klingel, Philip Black, Michael R. Powers, Hartmut Grasemann, Melinda Solomon, Scott D. Sagel, Scott H. Donaldson, Steven M. Rowe, Margaret Rosenfeld
Journal: American Journal of Respiratory and Critical Care Medicine (2018)
Lipoprotein(a) and Coronary Heart Disease
Authors: JohnDanesh, RoryCollins, RichardPeto
Journal: Circulation (2000)

Background—Studies of the association between the plasma concentration of lipoprotein(a) [Lp(a)] and coronary heart disease (CHD) have reported apparently conflicting findings. We report a meta-analysis of the prospective studies with at least 1 year of follow-up published before 2000. Methods and Results—The following information was abstracted for each study: geographical location of study, size, type of cohort (population-based or selected because of previous disease), mean age, follow-up duration, blood storage temperature and duration, assay methods, degree of adjustment for potential confounders, and relationship of baseline Lp(a) measurement with subsequent CHD risk. There were 5436 deaths from CHD or nonfatal myocardial infarctions during a weighted mean follow-up of 10 years in the 27 eligible studies. Comparison of individuals in the top third of baseline plasma Lp(a) measurements with those in the bottom third in each study yielded a combined risk ratio of 1.6 (95% CI 1.4 to 1.8, 2P<0.00001), w...
Integration of magnetic resonance imaging and protein and metabolite CSF measurements to enable early diagnosis of secondary progressive multiple sclerosis
Authors: Stephanie Herman, Payam Emami Khoonsari, Andreas Tolf, Julia Steinmetz, Henrik Zetterberg, Torbjörn Åkerfeldt, Per-Johan Jakobsson, Anders Larsson, Ola Spjuth, Joachim Burman, Kim Kultima
Journal: Theranostics (2018)

Molecular networks in neurological diseases are complex. Despite this fact, contemporary biomarkers are in most cases interpreted in isolation, leading to a significant loss of information and power. We present an analytical approach to scrutinize and combine information from biomarkers originating from multiple sources with the aim of discovering a condensed set of biomarkers that in combination could distinguish the progressive degenerative phenotype of multiple sclerosis (SPMS) from the relapsing-remitting phenotype (RRMS). Methods: Clinical and magnetic resonance imaging (MRI) data were integrated with data from protein and metabolite measurements of cerebrospinal fluid, and a method was developed to sift through all the variables to establish a small set of highly informative measurements. This prospective study included 16 SPMS patients, 30 RRMS patients and 10 controls. Protein concentrations were quantitated with multiplexed fluorescent bead-based immunoassays and ELISA. The metabolome was recorded using liquid chromatography-mass spectrometry. Clinical follow-up data of the SPMS patients were used to assess disease progression and development of disability. Results: Eleven variables were in combination able to distinguish SPMS from RRMS patients with high confidence superior to any single measurement. The identified variables consisted of three MRI variables: the size of the spinal cord and the third ventricle and the total number of T1 hypointense lesions; six proteins: galectin-9, monocyte chemoattractant protein-1 (MCP-1), transforming growth factor alpha (TGF-α), tumor necrosis factor alpha (TNF-α), soluble CD40L (sCD40L) and platelet-derived growth factor AA (PDGF-AA); and two metabolites: 20β-dihydrocortisol (20β-DHF) and indolepyruvate. The proteins myelin basic protein (MBP) and macrophage-derived chemokine (MDC), as well as the metabolites 20β-DHF and 5,6-dihydroxyprostaglandin F1a (5,6-DH-PGF1), were identified as potential biomarkers of disability progression. Conclusion: Our study demonstrates, in a limited but well-defined and data-rich cohort, the importance and value of combining multiple biomarkers to aid diagnostics and track disease progression.
Inhibition of Myosin Phosphatase by Upregulated Rho-Kinase Plays a Key Role for Coronary Artery Spasm in a Porcine Model With Interleukin-1β
Authors: TadashiKandabashi, HiroakiShimokawa, KenjiMiyata, IkukoKunihiro, YojiKawano, YukoFukata, TaikiHigo, KensukeEgashira, ShosukeTakahashi, KozoKaibuchi, AkiraTakeshita
Journal: Circulation (2000)

Background—We recently demonstrated that the Rho-kinase–mediated pathway plays an important role for coronary artery spasm in our porcine model with interleukin-1β (IL-1β). In this study, we examined whether or not Rho-kinase is upregulated at the spastic site and if so, how it induces vascular smooth muscle hypercontraction. Methods and Results—Segments of the left porcine coronary artery were chronically treated from the adventitia with IL-1β–bound microbeads. Two weeks after the operation, as reported previously, intracoronary serotonin repeatedly induced coronary hypercontractions at the IL-1β–treated site both in vivo and in vitro, which were markedly inhibited by Y-27632, one of the specific inhibitors of Rho-kinase. Reverse transcription–polymerase chain reaction analysis demonstrated that the expression of Rho-kinase mRNA was significantly increased in the spastic compared with the control segment. Western blot analysis showed that during the serotonin-induced contractions, the extent of phosphory...
Abstract 4868: BI 907828: A novel, potent MDM2 inhibitor that is suitable for high-dose intermittent schedules
Authors: Dorothea Rudolph, Andreas Gollner, Sophia Blake, Jörg Rinnenthal, Andreas Wernitznig, Ulrike Weyer-Czernilofsky, Christian Haslinger, Pilar Garin-Chesa, Jens Quant, Darryl B. McConnell, Jürgen Moll, Kraut Norbert
Journal: Cancer Research (2018)

Abstract MDM2 inhibitors block the interaction between the Tumor Protein p53 (TP53) and MDM2, its key negative regulator, and represent a new therapeutic concept for cancer therapy. MDM2 inhibitors are designed to restore p53 activity in TP53 wild-type tumors. Several MDM2 inhibitors are currently being evaluated in early clinical development with mainly daily dosing regimens. However, recent clinical data suggest myelosuppression as an on-target, dose-limiting toxicity for this class of inhibitors. Particularly, thrombocytopenia could limit the clinical utility of MDM2 inhibitors. Hence there is a need to mitigate these side effects and to improve the therapeutic window. One approach is less frequent dosing to allow bone marrow recovery while still maintaining efficacious exposure levels and clinical activity. Here we present data on BI 907828, a novel and potent MDM2 inhibitor with optimized drug-like properties including a reliable, dose-linear PK across species with good bioavailability after oral dosing that allows various dose schedules. Remarkably, a single oral dose of 2 mg/kg led to tumor regressions in a SJSA-1 xenograft model in all treated mice, as did treatment on a daily low dose schedule. Data on PK, PD and efficacy relationships in this xenograft model will be presented including dose-dependent induction of TP53 target genes and markers of apoptosis. Moreover, BI 907828 significantly prolonged the survival by more than 50 days with a daily oral dose of 2.5 mg/kg in a difficult to treat disseminated MOLM-13 AML model, as noted by profiling of a clinical-stage MDM2 inhibitor. In summary, BI 907828 is a novel, potent, orally bioavailable MDM2 inhibitor that shows excellent efficacy with daily low dose but also intermittent high dose schedules in preclinical models of cancer. Citation Format: Dorothea Rudolph, Andreas Gollner, Sophia Blake, Jörg Rinnenthal, Andreas Wernitznig, Ulrike Weyer-Czernilofsky, Christian Haslinger, Pilar Garin-Chesa, Jens Quant, Darryl B. McConnell, Jürgen Moll, Kraut Norbert. BI 907828: A novel, potent MDM2 inhibitor that is suitable for high-dose intermittent schedules [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 4868.
Bioluminescence imaging and two-photon microscopy guided laser ablation of GBM decreases tumor burden
Authors: Yingwei Fan, Yu Sun, Wei Chang, Xinran Zhang, Jie Tang, Liwei Zhang, Hongen Liao
Journal: Theranostics (2018)

Brain tumor delineation and treatment are the main concerns of neurosurgeons in neurosurgical operations. Bridging the gap between imaging/diagnosis and treatment will provide great convenience for neurosurgeons. Here, we developed an optical theranostics platform that helps to delineate the boundary and quantitatively analyze glioblastoma multiforms (GBMs) with bioluminescence imaging (BLI) to guide laser ablation, and we imaged the GBM cells with two-photon microscopy (TPM) to visualize the laser ablation zone in vivo. Methods: Laser ablation, using the method of coupled ablated path planning with the guidance of BLI, was implemented in vivo for mouse brain tumors. The mapping relationship between semi-quantitative BLI and the laser ablation path was built through the quantitative tumor burden. The mapping was reflected through coupled ablated path planning. The BLI quantitatively and qualitatively evaluated treatment using laser ablation with the appropriate laser parameters and laser-tissue parameters. These parameters were measured after treatment. Furthermore, histopathological analysis of the brain tissue was conducted to compare the TPM images before and after laser ablation and to evaluate the results of in vivo laser ablation. The local recurrences were measured with three separate cohorts. The weights of all of the mice were measured during the experiment. Results: Our in vivo BLI data show that the tumor cell numbers were significantly attenuated after treatment with the optical theranostics platform, and the delineation of GBM margins had clear views to guide the laser resection; the fluorescence intensity in vivo of GBMs quantitatively analyzed the rapid progression of GBMs. The laser-tissue parameters under guidance of multimodality imaging ranged between 1.0 mm and 0.1 mm. The accuracy of the laser ablation reached a submillimeter level, and the resection ratio reached more than 99% under the guidance of BLI. The histopathological sections were compared to TPM images, and the results demonstrated that these images highly coincided. The weight index and local recurrence results demonstrated that the therapeutic effect of the optical theranostics platform was significant. Conclusion: We propose an optical multimodality imaging-guided laser ablation theranostics platform for the treatment of GBMs in an intravital mouse model. The experimental results demonstrated that the integration of multimodality imaging can precisely guide laser ablation for the treatment of GBMs. This preclinical research provides a possibility for the precision treatment of GBMs. The study also provides some theoretical support for clinical research.
Abstract 17230: Respiratory Sinus Arrhythmia Quantified from Standard ECG for Risk Stratification of Post-Infarction Patients
Authors: DanielSinnecker, PetraBarthel, AlexanderMüller, Karl-LudwigLaugwitz, GeorgSchmidt
Journal: Circulation (2014)

Objectives: Respiratory sinus arrhythmia (RSA) reflects modulation of the sinoatrial node discharge frequency by the autonomic nervous system. Impaired autonomic function is associated with adverse outcome in cardiac patients. We developed a method for calculating RSA from standard ECG recordings and investigated its association with mortality in survivors of acute myocardial infarction. Methods: Consecutive patients (n=941, mean age 61 years, 19% female) presenting with acute myocardial infarction and sinus rhythm were enrolled between May 2000 and March 2005 and followed up until August 2010. The main study outcome was 5-year all-cause mortality. Patients underwent 30-minute ECG recordings. Auxiliary respiratory muscle activity derived from high pass-filtered ECG signal was used to define respiratory phase. The influence of expiration on RR intervals (RRI) was assessed by bivariate phase-rectified signal averaging (PRSA), and RSAPRSA was quantified by Haar wavelet analysis. RSAPRSA ≤0 was defined as abn...
Extensive Primary Repair of the Thoracic Aorta in Acute Type A Aortic Dissection by Means of Ascending Aorta Replacement Combined With Open Placement of Triple-Branched Stent Graft
Authors: Liang-WanChen, Xiao-FuDai, LinLu, Gui-CanZhang, HuaCao
Journal: Circulation (2010)

Background—To simplify extensive primary repair of the thoracic aorta in acute type A aortic dissection, we developed the open triple-branched stent graft placement technique. The early results of this new technique are reported. Methods and Results—Between June 2008 and November 2009, 30 patients with acute Stanford type A aortic dissection underwent extensive primary repair of the thoracic aorta by means of ascending aorta replacement combined with open placement of triple-branched stent graft. Placement of the triple-branched stent graft into the true lumen of the descending aorta, arch, and 3 arch vessels was technically successful in all patients. The mean cardiopulmonary bypass time, aortic cross-clamp time, and lower body arrest time were 151.8±16.69, 84.1±6.97, and 31.17±5.34 minutes, respectively. The postoperative mechanical ventilation support period and duration of intensive care unit stay were 17.93±2.35 and 62.10±9.24 hours, respectively. All implanted stent grafts were fully opened and not ...