tbuckley/cabot-search huggingface dataset:
Vascular Smooth Muscle Cell Sirtuin 1 Protects Against DNA Damage and Inhibits Atherosclerosis
Authors: IsabelleGorenne, SheetalKumar, KellyGray, NicholaFigg, HaixiangYu, JohnMercer, MartinBennett
Journal: Circulation (2013)

Background—Vascular smooth muscle cells (VSMCs) in human atherosclerosis manifest extensive DNA damage and activation of the DNA damage response, a pathway that coordinates cell cycle arrest and DNA repair, or can trigger apoptosis or cell senescence. Sirtuin 1 deacetylase (SIRT1) regulates cell ageing and energy metabolism and regulates the DNA damage response through multiple targets. However, the direct role of SIRT1 in atherosclerosis and how SIRT1 in VSMCs might regulate atherosclerosis are unknown. Methods and Results—SIRT1 expression was reduced in human atherosclerotic plaques and VSMCs both derived from plaques and undergoing replicative senescence. SIRT1 inhibition reduced DNA repair and induced apoptosis, in part, through reduced activation of the repair protein Nijmegen Breakage Syndrome-1 but not p53. Fat feeding reduced SIRT1 and induced DNA damage in VSMCs. VSMCs from mice expressing inactive truncated SIRT1 (Δex4) showed increased oxidized low-density lipoprotein–induced DNA damage and sen...
Effective cross-sector collaborations create sustainability
Authors: Jessica Kritz
Journal: The Lancet Global Health (2018)

Despite the focus on programme sustainability, the implementation of this idea has proved to be challenging, particularly in developing countries.1,2 The goal of this comment is to put forth a modest suggestion for expanding sustainability through cross-sector collaboration. This idea is being tested with an ongoing project in the Old Fadama urban slum in Accra, Ghana. This project is designed to build upon the fragmentary cross-sector collaboration evidence base of developing countries.3 The approach incorporates new ideas and research from the cross-sector collaboration literature from developed countries.
Stimulation of Bradykinin B1 Receptors Induces Vasodilation in Conductance and Resistance Coronary Vessels in Conscious Dogs
Authors: Jin BoSu, RémiHoüel, FrançoisHéloire, FabriceBarbe, FabrizioBeverelli, LucienSambin, AlainCastaigne, AlainBerdeaux, BertrandCrozatier, LucHittinger
Journal: Circulation (2000)

Background—Constitutive bradykinin B1 receptors have been identified in dogs; however, their physiological implications involving the coronary circulation remain to be determined. This study examined, in conscious dogs, the coronary response to des-Arg9-bradykinin (a B1 receptor agonist) and the mechanisms involved. Methods and Results—Eleven dogs were instrumented with a left ventricular micromanometer, a circumflex coronary catheter, a cuff occluder, a Doppler flow probe, and ultrasonic crystals to measure coronary blood flow velocity (CBFv) and coronary diameter (CD). Intracoronary des-Arg9-bradykinin (3 to 100 ng/kg) and bradykinin (0.1 to 10 ng/kg) did not modify systemic hemodynamics but dose-dependently increased CBFv and CD. Des-Arg9-bradykinin was less potent than bradykinin. Hoe 140 (a B2 antagonist, 10 μg/kg) abolished the effects of bradykinin but did not influence the effects of des-Arg9-bradykinin. When CBFv increase was prevented by the cuff occluder, CD responses to bradykinin and des-Arg9...
Glycogen-Synthase Kinase3β/β-Catenin Axis Promotes Angiogenesis Through Activation of Vascular Endothelial Growth Factor Signaling in Endothelial Cells
Authors: CarstenSkurk, HenrikeMaatz, EdwardRocnik, AnnBialik, ThomasForce, KennethWalsh
Journal: Circulation Research (2005)

Glycogen-Synthase Kinase 3β (GSK3β) has been shown to function as a nodal point of converging signaling pathways in endothelial cells to regulate vessel growth, but the signaling mechanisms downstream from GSK3β have not been identified. Here, we show that β-catenin is an important downstream target for GSK3β action in angiogenesis and dissect the signal transduction pathways involved in the angiogenic phenotype. Transduction of human umbilical vein endothelial cells (HUVECs) with a kinase-mutant form of the enzyme (KM-GSK3β) increased cytosolic β-catenin levels, whereas constitutively active GSK3β (S9A-GSK3β) reduced β-catenin levels. Lymphoid enhancer factor/T-cell factor promoter activity was upregulated by KM-GSK3β and diminished by S9A-GSK3β, whereas manipulation of Akt signaling had no effect on this parameter. β-Catenin transduction induced capillary formation in a Matrigel-plug assay in vivo and promoted endothelial cell differentiation into network structures on Matrigel-coated plates in vitro. β...
Abstract 5356: Robust gene fusion detection in formalin-fixed tissue sample with QIAseq RNAscan Oncology Panel
Authors: Jeffrey Falk, Parth Sitlani, Claire Orosco, Maya Panjikaran, Dana Weiner, Song Tian, Raed Samara, John DiCarlo, Yexun Wang, Eric Lader, Frank Reinecke
Journal: Cancer Research (2018)

Abstract Introduction: Gene fusions are frequently associated with tumorigenesismalignant tumors. Highly sensitive and reproducible detection of gene fusions in clinical samples, especially formalin-fixed paraffin-embedded (FFPE) specimens, is important for diagnosis, prognosis, and treatment guidance. Although many clinical tests utilize next-generation-sequencing (NGS) for detection of genetic alterations, reliable detection of gene fusions by NGS in FFPE samples remains a challenge. Methods: Five FFPE non-small cell lung cancer samples confirmed by FISH to contain EML4-ALK or KIF5B-RET fusions were selected for testing along with the Seraseq™ FFPE Tumor Fusion RNA Reference Material, v1, which evaluates forcontains 12 known fusions. Four operators prepared NGS libraries for each sample (89-250ng input) using the commercially available QIAseq RNAscan Oncology Panel, which targets 223 fusion gene pairs or 576 unique breakpoints. The resulting libraries were sequenced on an Illumina® NextSeq 500 sequencer. Demultiplexed FASTQ files were analyzed using cloud-based QIAseq RNAscan Analysis pipeline v1.7.20.2. Detected fusions that are on the panel's target list were reported as curated gene fusions and assigned a score based on unique molecules supporting the transcript. Results: For the Seraseq™ FFPE Tumor Fusion RNA Reference v1 sample, all 12 expectedknown fusions were detected in each of the libraries generated by four different operators. The analysis pipeline correctly called the expected fusion in all four replicates of the five clinical FFPE samples tested, which varied in both input quantityamount and quality. Reproducibility was evaluated by comparing the score values across replicate libraries for each sample; expected fusion detection was 100% consistent between users, and the average correlation coefficient for the fusion score was 0.995. Conclusions: The commercially available QIAseq RNAscan Oncology panel is a highly sensitive and robust product for detection of gene fusions in FFPE samples. QIAseq RNAscan methodology provides a useful tool for studying gene fusions in tumor samples and with optimization, customization, and validation can further fit the specific needs for of clinical laboratories. Citation Format: Jeffrey Falk, Parth Sitlani, Claire Orosco, Maya Panjikaran, Dana Weiner, Song Tian, Raed Samara, John DiCarlo, Yexun Wang, Eric Lader, Frank Reinecke. Robust gene fusion detection in formalin-fixed tissue sample with QIAseq RNAscan Oncology Panel [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 5356.
Abstract 1835: PPARγ agonist in combination with <i>bcr/abl</i> tyrosine kinase inhibitors in patients of chronic myeloid leukemia in chronic phase with suboptimal molecular response
Authors: Hemant Malhotra, Ajay Yadav, Ashwin Mathur, Debashish Biswas, Bharti Malhotra
Journal: Cancer Research (2018)

Abstract Introduction &amp; background: Ten to 20 % of patients of Chronic Myeloid Leukemia in chronic phase (CML CP) have suboptimal molecular response (MR) to first line Imatinib maleate (IM). Treatment options include IM dose increase or switch to a 2nd generation tyrosine kinase inhibitor (TKI), Nilotinib or Dasatinib. Recently, synergy has been demonstrated when PPAR γ agonists are added to TKIs. We describe our initial results on 15 patients of CML CP treated with the combination of IM and pioglitazone, a PPAR γ agonist. Patients and methods: Fifteen patients of CML CP with suboptimal MR (bcr/abl:abl RQ-PCR between 1 to 10) after more than two years of IM were recruited in this pilot study. Because of economic considerations, these patients were not candidates for 2nd gen. TKIs. Patients given IM 600 mg/day and pioglitazone 30 mg/day. Blood counts and biochemistry monitored monthly, bcr/abl tested every 3 months using a cartridge based IS assay using the Cepheid GenXpert. Results &amp; conclusions: Twelve of the 15 patients achieved significant MR, with 6/16 achieving a major MR at 9 months. Only 3/15 did not show a response (Table). Treatment with pioglitazone was well tolerated. One patient was not analysed due to intolerance to pioglitazone are first dose. Two patients had grade 1 elevation of hepatic enzymes which returned to normal after one week treatment cessation. We conclude that the combination of imatinib with pioglitazone is effective and well tolerated in patients with a sub-optimal MR to TKI in patients with CML-CP. The combination could be a cost-effective strategy in treating imatinib non/sub-optimal responders in the developing world. The combination needs further and larger studies for confirmation and evaluation of the mechanisms of the synergy. S. No.Patient ID/SexDiagnosis dateBCR-ABL (Before Pio)BCR-ABL (After Pio)At 3 monthAt 6 monthAt 9 month1SCM/MOct 20125.352.741.830.0052MD/FAug 20061.130.880.480.13GPJ/MJan 20142.860.43ND0.54RRC/MOct 20082.861.070.25ND5RK/MMar20081.390.770.350.416RDS/FOct 200010.15.994.870.677RDR/FApril 20039.045.780.360.058MM/MMay 20114.48NDND0.149RD/FJuly 20108.331.290.440.7310RB/FJuly 20153.253.022.891.3911BRR/MJan 20107.135.613.821.7712BK/FNov 20042.060.040.030.0713DPS/MJan 20116.155.471.020.8414JKM/MApril 20074.2215.49.117.6215CS/MOct 20121.721.170.840.08 Citation Format: Hemant Malhotra, Ajay Yadav, Ashwin Mathur, Debashish Biswas, Bharti Malhotra. PPARγ agonist in combination with bcr/abl tyrosine kinase inhibitors in patients of chronic myeloid leukemia in chronic phase with suboptimal molecular 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 1835.
Abstract 5194: In vivo capture of early metastatic cells through a CXCL12 loaded-dermal filler
Authors: Caterina Ieranò, Crescenzo D'Alterio, Simona Giarra, Maria Napolitano, Assunta Santagata, Antonio Barbieri, Virginia Campani, Antonio Luciano, Claudio Arra, Annamaria Anniciello, Gerardo Botti, Laura Mayol, Giuseppe De Rosa, Roberto Pacelli, Stefania Scala
Journal: Cancer Research (2018)

Abstract The chemokine CXCL12 and its receptor CXCR4 are critical for orienting and seeding cells in metastatic sites. To distract CXCR4 expressing circulating tumor cells (CTCs) a “fake” pre-metastatic niche was built with a hyaluronic acid based dermal filler hydrogel-CXCL12-loaded (CLG). CXCR4 expressing human T leukemia cells, CCRF-CEM, and murine melanoma cells human CXCR4 transduced, B16-hCXCR4-GFP, were evaluated for migration in vitro toward CLG. CLGs and EGs (empty gels) were subcutaneously injected in C57BL/6 mice and five days later B16-hCXCR4-GFP (5x105 cells) were intravenously injected. Twenty two days later mice were euthanized and hydrogels recovered. Gel trapped cells were recovered through ialuronidase digestion of the gels and lungs were analyzed to detect metastases. Circulating tumor cells (CD45neg/hCXCR4 plus/GFP plus) were assessed in the blood at day 10 and 22 from cells injection. In vitro, CEM and B16-hCXCR4-GFP cells more efficiently migrated toward CLG compared with EG. In vivo, a significantly higher number of B16-hCXCR4-GFP tumor cells was detected within the CLGs compared with EGs, indicating that the CXCL12 in hydrogel enabled recruitment of tumor cells. Concomitantly, lung metastases were significantly reduced in mice carrying CLG, but not EG, as assessed by reduced B16-hCXCR4-GFP positive tumor cells in the lung (75% reduction in lung metastases in mice carrying CLG; p&amp;lt;0.05). CLG recovered cells by hydrogel enzymatic digestion recapitulated the features of melanoma cell line B16-hCXCR4-GFP (epithelial, melanin rich, MELAN A/ S100/ c-kit/CXCR4 +; α-SMA -). CTCs, evaluated at 10 and at 22 days post cells injection, significantly increased in CLG carrying mice compared to EG carrying mice. Our study suggests that a hyaluronic acid (HA) hydrogel, commercially used as dermal filler, loaded with CXCL12 can divert CXCR4 positive circulating tumor cells B16-hCXCR4-GFP. The cells trapped in the CLG can be recovered and characterized. As a corollary, a reduction of CXCR4 dependent lung metastasis was detected. It suggests that hydrogel-CXCL12 trap may be a therapeutic and diagnostic tool to recover and analyze the biology of circulating tumor cells. Citation Format: Caterina Ieranò, Crescenzo D'Alterio, Simona Giarra, Maria Napolitano, Assunta Santagata, Antonio Barbieri, Virginia Campani, Antonio Luciano, Claudio Arra, Annamaria Anniciello, Gerardo Botti, Laura Mayol, Giuseppe De Rosa, Roberto Pacelli, Stefania Scala. In vivo capture of early metastatic cells through a CXCL12 loaded-dermal filler [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 5194.
Therapeutic Responses and Survival Effects of 177Lu-PSMA-617 Radioligand Therapy in Metastatic Castrate-Resistant Prostate Cancer
Authors: Yong Joong Kim, Yong-il Kim
Journal: Clinical Nuclear Medicine (2018)

We performed a meta-analysis on the therapeutic effects of prostate-specific membrane antigen (PSMA)-617 labeled with lutetium-177 (Lu-PSMA-617) in patients with metastatic castration-resistant prostate cancer (mCRPC).The primary outcome was the therapeutic responses after the first cycle of Lu-PSMA-617 radioligand therapy. The parameters studied were the pooled proportions of any prostate-specific antigen (PSA) decline and a greater than 50% PSA decline. The secondary outcome was the survival effects after Lu-PSMA-617 radioligand therapy. Studied parameters were pooled hazard ratios of the overall survival according to any PSA decline and a greater than 50% PSA decline after the first cycle of Lu-PSMA-617 radioligand therapy.In total, 10 eligible studies with 455 patients were finally included in this meta-analysis. The pooled proportions of any PSA decline was 68.00% (95% confidence interval [CI], 63.55%-72.22%], and those with a greater than 50% PSA decline was 34.45% (95% CI, 30.14%-38.97%). The pooled hazard ratios for the overall survival of any PSA decline was 0.29 (95% CI, 0.21-0.40) with significance (P < 0.00001); however, a greater than 50% PSA decline was 0.82 (95% CI, 0.54-1.25) with no significance (P = 0.39).We suggest that approximately two-thirds of any PSA decline and one-third of a greater than 50% PSA decline can be expected after the first cycle of Lu-PSMA-617 radioligand therapy in patients with mCRPC. Moreover, any PSA decline showed survival prolongation after the first cycle of the Lu-PSMA-617 radioligand therapy.
Activation of Sympathetic Vasodilator and Vasoconstrictor Neurons by Electric Stimulation in the Medulla of the Dog and Cat
Authors: Percylindgren, Börjeuvnäs
Journal: Circulation Research (1953)

Electric stimulation in the ventrolateral area of the medulla elicited vasodilation in skeletal muscles, and vasoconstriction in the skin and intestines. The vasodilation was accredited to activity in the cholinergic sympathetic vasodilator outflow previously shown to originate in the motor cortex of the dog. The possible functional significance of the vasodilator fibers in regulating muscle blood flow during exercise is discussed.
Noncanonical Activity of Seryl-tRNA Synthetase Is Involved in Vascular Development
Authors: HajimeFukui, RyukiHanaoka, AtsuoKawahara
Journal: Circulation Research (2009)

Vascular endothelial growth factor (Vegf) plays central roles in the establishment of stereotypic vascular patterning in vertebrates. However, it is not fully understood how the network of blood vessels is established and maintained during vascular development. A zebrafish ko095 mutant presented the disorganized vessels with abnormal branching of the established intersegmental vessels (ISVs) after 60 hours postfertilization. The gene responsible for ko095 encodes seryl-tRNA synthetase (Sars) with a nonsense mutation. The abnormal branching of ISVs in ko095 mutant was suppressed by the introduction of either wild-type Sars or a mutant Sars (T429A) lacking the enzymatic activity that catalyzes aminoacylation of transfer RNA for serine (canonical activity), suggesting that the abnormal branching is attributable to the loss of function of Sars besides its canonical activity. We further found the increased expression of vegfa in ko095 mutant at 72 hours postfertilization, which was also reversed by the introdu...
FcγRIIA H/R131 Polymorphism, Subclass-Specific IgG Anti-Heparin/Platelet Factor 4 Antibodies and Clinical Course in Patients With Heparin-Induced Thrombocytopenia and Thrombosis
Authors: Gowthami Arepally, Steven E. McKenzie, Xiao-Ming Jiang, Mortimer Poncz, Douglas B. Cines
Journal: Blood (1997)
CD40 Ligand–Dependent Tyrosine Nitration of Prostacyclin Synthase In Vivo
Authors: BradleyDavis, Ming-HuiZou
Journal: Circulation (2005)

Background— Cells in human atherosclerotic lesions express the immune mediator CD40 and its ligand, CD40L, but the mechanisms and the mediators by which CD40L contributes to atherosclerosis are poorly defined. Here, we show how CD40L increases vascular inflammation and thrombosis via tyrosine nitration and inhibition of prostacyclin synthase (PGIS), an enzyme with antithrombotic, antiproliferative, and dilatory functions in the normal vasculature. Methods and Results— Exposure of cultured human aortic endothelial cells to clinically relevant concentrations of CD40L (20 to 80 ng/mL) dose-dependently increased the production of superoxide (O2·−), decreased nitric oxide (NO) bioactivity, and increased PGIS nitration. Furthermore, inhibition of CD40 expression by small interfering RNA blocked the effects of CD40L on O2·−, NO bioactivity, and PGIS nitration, which indicates a specific effect of CD40L. In addition, either depletion of mitochondria (ρ0 cells, ie, mitochondria-depleted cells, to prevent mitochond...
Abstract 2085: Exploring mutation signatures in pediatric cancers
Authors: Francis A. San Lucas, Philip Lupo, Austin Brown, Michael Scheurer, Paul Scheet
Journal: Cancer Research (2018)

Abstract Background: Mutation signatures have been catalogued across most common cancers, providing insights into their underlying mutational processes and suggesting strategies for categorization and subphenotyping. However, these analyses have been limited to mostly adult cancers, likely due to the relative rarity of pediatric analogs and a corresponding lower mutation burden of these tumors. Here we attempted to compare mutation signatures across several pediatric cancers, given these constraints, with their corresponding adult versions. Data and Methods: From the ICGC data portal, we downloaded clinical and mutation data for pediatric brain (medulloblastoma, glioblastoma, neuroblastoma) and blood-based (acute lymphoblastic leukemia, acute myeloid leukemia) cancers. We also obtained data for related adult cancers, including glioblastoma and acute myeloid leukemia. For each cancer, we characterized mutation patterns using trinucleotides centered at somatic SNVs and then estimated the composition of underlying putative COSMIC mutation signatures. For cancers with low mutation rates (impeding estimates of mutation signatures), we grouped mutations from similar samples based on clinical and molecular statuses to infer mutation signatures. Results: Each of the pediatric cancer types strongly exhibited the common cancer mutation Signature 1 (spontaneous deamination of 5-methylcytosine), as might be expected since it has been described across all adult cancer types. Further, pediatric acute myeloid leukemia and glioblastoma both harbored mutation signatures seen in their adult counterparts in addition to unexpected patterns of defective DNA mismatch repair and DNA double-strand break repair. Interestingly, for pediatric glioblastoma we identified Signatures 3, 8, 15 and 16, which were previously unidentified in adult glioblastoma and have been recently implicated in pediatric medulloblastoma. Conclusion: Our findings may be influenced by the sparsity of mutations in pediatric cancers, highlighting the need for quantifying precision in measures of mutation signatures. This notwithstanding, from our initial observations, pediatric cancers appear to exhibit a more diverse set of mutation signatures than their adult counterparts. Further, pediatric cancers of different histologies, particularly those of brain cancers, may share molecular mechanisms more than currently believed. Citation Format: Francis A. San Lucas, Philip Lupo, Austin Brown, Michael Scheurer, Paul Scheet. Exploring mutation signatures in 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 2085.
Complication Rate of Right Ventricular Endomyocardial Biopsy via the Femoral Approach
Authors: MatthiasHolzmann, AlexanderNicko, UweKühl, MichelNoutsias, WolfgangPoller, WolfgangHoffmann, AndreasMorguet, BernhardWitzenbichler, CarstenTschöpe, Heinz-PeterSchultheiss, MatthiasPauschinger
Journal: Circulation (2008)

Background— An unequivocal diagnosis of myocarditis and cardiac virus persistence is based on histological, immunohistological, and molecular biological analyses of endomyocardial biopsies (EMBs). Biopsy-based diagnosis of myocarditis has become increasingly important because recent studies have demonstrated the beneficial effects of biopsy-based causal treatment strategies (immunosuppressive or antiviral). Because the risks of major complications caused by EMB procedures have not yet been well defined, we evaluated the incidence of major and minor complications of right ventricular EMB procedures in this retrospective and prospective single-center study. Methods and Results— With the use of a modified Cordis bioptome, 1919 patients underwent 2505 EMB procedures retrospectively over a 9-year period (January 1995 to December 2003), and 496 patients underwent 543 EMB procedures prospectively between January 2004 and December 2005. A total of 2415 patients had 3048 EMB procedures via the right femoral vein a...