tbuckley/cabot-search huggingface dataset:
Abstract 1764: Neurovascular-targeting antibodies discovered using yeast biopanning enhance drug delivery and improve survival for glioblastoma
Authors: Paul A. Clark, Benjamin J. Umlauf, Eric V. Shusta, John S. Kuo
Journal: Cancer Research (2018)

Abstract INTRODUCTION: Median survival for newly diagnosed glioblastoma (GBM) patients remains less than two years despite aggressive clinical interventions. Antibody-based GBM-targeting could improve brain delivery and accumulation of therapies, but it has been challenging to identify universal tumor cell antigens due to intra-tumor and inter-patient GBM heterogeneity. We hypothesized that antigens of the neurovascular extracellular matrix (nvECM) within GBM-disrupted blood-brain barrier (BBB) may localize and enhance efficacy of therapeutic agents. METHODS: Yeast surface display biopanning and high throughput screening identified Variable Lymphocyte Receptors (VLR, i.e. jawless vertebrate lamprey antibodies) that preferentially accumulate at nvECM. Lead VLR candidates were tested for tumor targeting via combination with chemotherapeutic doxorubicin (DOX) liposomes and assessed for anti-GBM effects in vitro and against orthotopic mouse xenografts in vivo. RESULTS: VLR clones were enriched for binding to mouse brain endothelial cell (bEnd.3 line) ECM with two rounds of biopanning, then screened for preferential binding to brain-derived ECM. Lead VLR clone P1C10 was chosen for further testing for nvECM specificity vs. fibroblast (3T3 line) ECM in a high throughput screen, high affinity (Kd=48±6.1 nM), and immunolabeling of normal mouse and human brain, and GBM samples. Clone P1C10 demonstrated tumor-specific targeting in orthotopic U87 GBM xenografts, with 50% more DOX fluorescence detected at GBM after intravenous injection of P1C10-DOX liposomes compared to control, non-specific VLR-DOX. Finally, administration of P1C10-DOX liposomes (15 mg/kg, i.p., 1/week) significantly improved survival of mice bearing U87 xenografts, compared to non-targeted VLR-DOX (Kaplan-Meier, p&amp;lt;0.01). CONCLUSIONS: We report combining yeast surface display biopanning and screening to identify VLRs that preferentially accumulate at disrupted nvECM of GBM-disrupted BBB, and demonstrate GBM-targeting specificity in vitro and in vivo with significant survival benefit. These results support the nvECM immune-targeting strategy to improve anti-GBM therapeutic efficacy, potentially improving survival and quality-of-life in brain cancer patients. Citation Format: Paul A. Clark, Benjamin J. Umlauf, Eric V. Shusta, John S. Kuo. Neurovascular-targeting antibodies discovered using yeast biopanning enhance drug delivery and improve survival for glioblastoma [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 1764.
Abstract 17461: Clinical Significance of No Pulmonary Vein Potential at Redo-procedure After Catheter Ablation for Atrial Fibrillation
Authors: Tae-Hoon Kim, Jae-Sun Uhm, Boyoung Joung, Moon-Hyoung Lee, Hui-Nam Pak
Journal: Circulation (2015)

Introduction: Long-lasting pulmonary vein isolation (PVI) has been shown to be the key determinants for clinical outcome in both patients with paroxysmal and persistent atrial fibrillation (AF). Hypothesis: Although reconnected PV potential (PVP) has been regarded as a main mechanism of AF recurrence after catheter ablation, PVIs are well preserved in some patients at redo-procedure after recurrence. Therefore, we explored the characteristics and clinical outcome of the patients with negative PVP at redo-procedure. Methods: Among 1522 patients with AF who underwent catheter ablation, 143 patients (79.0% male, 56.1±10.0 years old, 65.0% paroxysmal AF) refractory to antiarrhythmic drug underwent redo-procedure. PVP was not shown in 52 patients (PVP- group, 36.4%), but remaining 91 patients showed PVP (PVP+ group, 234/364 (64.3%) of PVs). We mapped triggers with isoproterenol infusion in both groups (after PVI in PVP+ group). Depending on mapping finding, we ablated non-PV foci and added linear ablation or complex fractionated atrial electrogram (CFAE)-guided ablation. Results: 1. PVP- group was independently associated with female gender (OR 2.64 95%CI 1.13~6.21, p=0.026) and later de novo clinical recurrence timing (OR 1.02 95% CI 1.00~1.04, p=0.047). 2. Additional linear ablations were more likely to be performed in PVP- group (92.2% vs. 61.5%, p&lt;0.001), but total ablation time (2411.3±1082.8 vs. 3144.8 ± 1412.5 sec, p=0.003) and procedure time (164.2± 51.4 vs. 144.2±47.1 min, p=0.027) were shorter in PVP- group than in PVP+ group. 3. During 18.4±10.2 months follow-up after redo-ablation, PVP- group showed significantly higher clinical recurrence rate than PVP+ group regardless of redo-ablation strategies (Kaplan Meier, Log Rank p=0.011). The presence of recurred PV connection (PVP+) was independently associated with lower recurrence of AF after repeat ablation (HR 0.46, 95% CI 0.21 - 0.98, p=0.043). Conclusions: AF patients with well-preserved PVI recurred later timing after de novo ablation, but showed poor clinical outcome after redo-ablation procedure, suggesting a potential AF progression.
Monoclonal Anti-CD18 Antibody Prevents Transcellular Biosynthesis of Cysteinyl Leukotrienes In Vitro and In Vivo and Protects Against Leukotriene-Dependent Increase in Coronary Vascular Resistance and Myocardial Stiffness
Authors: AngeloSala, GiuseppeRossoni, FerruccioBerti, CarolaBuccellati, AlbinoBonazzi, JacquesMaclouf, GiancarloFolco
Journal: Circulation (2000)

Background—Cysteinyl leukotrienes (cys-LT) can constrict small and large vessels and increase vascular permeability. Formation of cys-LT arising from polymorphonuclear leukocytes (PMNL) and endothelial cell cooperation (transcellular synthesis) led to the hypothesis that PMNL–endothelial cell adhesion may represent a key step toward the formation of vasoactive cys-LT. Methods and Results—We studied the effect of pretreatment with a monoclonal antibody directed against the CD18 subunit of PMNL β2-integrin on the synthesis of cys-LT in a PMNL-perfused isolated rabbit heart in vitro and in a model of permanent ligature of the left descending coronary artery in the rabbit in vivo. Challenge of PMNL-perfused rabbit hearts with formyl-met-leu-phe (0.3 μmol/L) caused synthesis of cys-LT and increase in coronary perfusion pressure that were prevented by the anti-CD18 antibody. Similar results were obtained with the use of A-23187 (0.5 μmol/L) as a challenge. Persistence of PMNL-associated myeloperoxidase activity...
Abstract 1055: Lymphotoxin-alpha plays key roles in lymphoproliferative lesions arising in patient-derived cancer xenografts
Authors: Tsuyoshi Chijiwa, Daisuke Komura, Mizuha Haraguchi, Haruo Hashimoto, Hiroshi Suemizu, Makoto Katayama, Yoshiyasu Nakamura, Daisuke Furukawa, Takayuki Isagawa, Hiroto Katoh, Takashi Moriya, Shumpei Ishikawa, Yohei Miyagi, Masato Nakamura
Journal: Cancer Research (2018)

Abstract Patient-derived xenograft (PDX) mouse models from engrafting fresh surgical specimens directly onto immunodeficient mice have enabled the development of more relevant in vivo models for human cancers. PDX models retain similar morphology, heterogeneities, and molecular signatures with the original cancers. Moreover, PDXs with clinical information, termed “cancer xenopatients”, are remarkable systems in personalized medicine for cancer. During the establishment process, a transplantable lymphoproliferative lesion (LPL) that replaces the original tumor cells sometimes occurs in severely immunodeficient mice. Although the occurrence of LPL is the most problematic aspect of the establishment of PDX, its mechanisms are unknown. We previously reported that the LPL phenomenon resembled the graft-versus-host disease (GVHD)-like mechanism and was suppressed by anti-GVHD agents. In the present study, we genomically analyzed the detailed mechanism of LPL in PDX mouse models. In our previous study, we established three LPL-PDX/NOG lines. These LPL-PDX lines were re-transplanted onto NOG mice and the xenograft tumors were then harvested for study. Genome sequencing and comprehensive analyses of tumor-stroma interactions (CAncer-STromal INteractome analysis, CASTIN) were performed on mRNA of these LPL-PDX/NOGs. Immunohistochemistry demonstrated that LPL tissues consisted of B-cells, T-cells, and differentiated plasma cells. CASTIN revealed tumor-stroma interactions in PDX/NOG comprehensively and quantitatively at the gene expression level by distinguishing gene arrangements in human tissue (cancer or LPL) from mouse tissue (stroma) by signal strength and dependency. Some strong interactions were found for these LPL-PDX/NOGs; VEGFB-FLT1, LTA-LTBR, LTA-TNFRSF1A, IL13-IL4R, IL13-IL13RA1, and SEMA4F-NRP2. Suppression of LPL-PDX/NOG by the anti-GVHD agent FK506 (1.0 mg/kg/day, 4 weeks) decreased interactions of LTA-LTBR and LTA-TNFRSF1A. Based on these results, LPLs during establishment of PDX occur due to a lymphotoxin-alpha-related mechanism. Controlling lymphotoxin-alpha related interactions may improve the establishment rate of PDX in severely immunodeficient mice. Citation Format: Tsuyoshi Chijiwa, Daisuke Komura, Mizuha Haraguchi, Haruo Hashimoto, Hiroshi Suemizu, Makoto Katayama, Yoshiyasu Nakamura, Daisuke Furukawa, Takayuki Isagawa, Hiroto Katoh, Takashi Moriya, Shumpei Ishikawa, Yohei Miyagi, Masato Nakamura. Lymphotoxin-alpha plays key roles in lymphoproliferative lesions arising in patient-derived cancer xenografts [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 1055.
Abstract P264: Association of D-dimer with Incident Cardiovascular Disease Events and F3 Gene Variants in African Americans: Results From the Jackson Heart Study
Authors: Laura M Raffield, Russell P Tracy, Qing Duan, Peter Durda, James G Wilson, Ethan M Lange, Leslie A Lange, Alex P Reiner
Journal: Circulation (2016)

Plasma D-dimer, a fibrin degradation product, is a biomarker of both coagulation and fibrinolysis and a risk factor for both arterial and venous thrombosis. African Americans (AAs) have increased risk of thrombosis and higher levels of D-dimer as compared to European populations, but little is known about the genetic architecture of D-dimer in AAs. D-dimer was assessed in 4163 AAs from the Jackson Heart Study (mean age 55 years, 62.1% female). We hypothesized that D-dimer levels would associate with incident cardiovascular disease events and with both coding and noncoding genetic variants. Median (interquartile range) D-dimer in the cohort was 0.40 (0.26-0.64) μg/ml. D-dimer was associated with increased risk of coronary heart disease (hazard ratio (HR) per standard deviation (SD)=1.26, p=0.012), stroke (HR=1.27, p=0.018), heart failure (HR=1.33, p=0.001), and mortality (HR=1.25, p&lt;0.0001) in models adjusted for age, sex, BMI, current smoking, diabetes, hypertension, systolic blood pressure, and low-density lipoprotein cholesterol. Using data from the Affymetrix Genome-Wide Human SNP Array 6.0, imputation based on the 1000 Genomes project reference panel (Phase I, Version 3, March 2012 release) was completed using MACH 1.0 and minimac in 2709 participants with D-dimer. Associations were assessed using MACH2QTL v.1.13, with models adjusted for age, sex, and the first ten principal components for global ancestry calculated using EIGENSOFT. The most significant signal was for an intergenic locus near F3 (top variant rs2022030, p=5.71x10 -12 , minor allele frequency=10.6%, imputation r 2 =1). F3 codes for tissue factor, a necessary co-factor for factor VIIa in the initiation of the extrinsic blood coagulation pathway. The F3 locus had been previously associated with D-dimer levels in European populations but has not been reported for AAs. Data were also available from the Illumina HumanExome Beadchip, version 1.1, in 2502 individuals; single variant analyses and gene-based tests for nonsynonymous, splicing, and nonsense variants with a minor allele frequency &lt;5% were performed using RAREMETAL, adjusted for age, sex, and the first ten principal components. For single variant analyses, a nonsynonymous variant in GPRASP1 (G protein-coupled receptor associated sorting protein 1, rs145805077, p= 1.84x10 -7 , minor allele frequency=0.3%) was significantly associated with decreased D-dimer. No gene-based test result met the strict multiple comparison significance threshold; the top gene-based result with the sequence kernel association test (SKAT) was for six variants in PPM1M (protein phosphatase, Mg2+/Mn2+ dependent, 1M, p=6.09x10 -6 ). These results highlight D-dimer as an important predictor of cardiovascular disease risk in AAs and that levels of this biomarker are associated with the F3 locus.
Abstract 3901: Characterizing antibody-drug conjugate cytotoxicity using four different real-time assays
Authors: Andrew L. Niles, Kevin Kupcho, Sarah Duellman, Jolanta Vidugiriene, Dan Lazar, James J. Cali
Journal: Cancer Research (2018)

Abstract Recent clinical successes using antibody drug conjugates (ADC) directed to hematological or solid tumor cancers have re-invigorated immunotherapeutic drug development interest. Unfortunately, efficacious ADC are inherently complex entities comprised of a targeting antibody, a stable but cleavable linker, and a toxic payload, for which the best combinations are often identified through iterative trial and error. Therefore, an efficient and systematic method for rank ordering ADC candidates is sought to evaluate their intrinsic pharmacodynamic properties. We chose SKBR3 (Her2+) and T47D (Her2-) cell models to define the on- and off-target cytotoxic potential of trastuzumab emtansine. We employed a suite of four, newly developed real-time assays to measure exposure-dependent changes in viability, caspase activation, phosphatidylserine (PS) exposure and loss of membrane integrity to define potency and magnitude of response, as well as primary mode of cell death. We discovered that trastuzumab emtansine mediated dose-dependent effects on SKBR3, with cytostasis beginning at 17h near 1μg/ml, caspase induction at 20h, which led to PS exposure at about 21h and secondary necrosis at 30h. During this same time course, full dose-response curves were generated for each biomarker as EC50 values evolved and matured to their respective maximal responses. Conversely, the T47D non-target cell population exhibited only minor cytotoxicity at the latest time points, presumably owing to linker degradation and non-specific payload release. Taken together, these data define the in vitro pharmacological disposition of trastuzumab emtansine, including the kinetic component of functionality related to antigen/antibody engagement, internalization, linker mediated payload release and resulting toxicity. This study may provide a tangible roadmap for the critical evaluation of other ADC under development. Citation Format: Andrew L. Niles, Kevin Kupcho, Sarah Duellman, Jolanta Vidugiriene, Dan Lazar, James J. Cali. Characterizing antibody-drug conjugate cytotoxicity using four different real-time assays [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 3901.
Abstract 1113: PODXL1 as a critical accelerator for pancreatic cancer metastasis
Authors: Eisaku Kondo, Ken Saito
Journal: Cancer Research (2018)

Abstract Podocalyxin-like 1 (PODXL1) is an anti-adhesive transmembrane protein belonging to the CD34 family and also stem cell marker that has been associated with an aggressive tumor phenotype and poor prognosis in several forms of cancer. In this study, we report the biological role of PODXL1 in progression of pancreatic invasive ductal adenocarcinoma (PDAC), especially focusing to invasion and metastasis of PDAC cells. Knockout of PODXL1 gene in three different human PDAC lines, MiaPaCa-2, AsPC1 and Panc-1, almost completely abrogated metastatic lesion in liver-metastatic mouse model in vivo. Molecular analysis revealed that PODXL1 functioned as a critical activator to multiple cytokine receptors expressed on cancer cells, and its interaction facilitated PDAC cell invasion. Endogenous expression of PODXL1 was strongly detected on cancer cells at the invasive front of the PDAC tissues, where coincidently expressed specific cytokine receptor that critically mediates cancer metastasis in vivo. Thus, we identify the novel functional aspect of PODXL1 and its biological role on PDAC as one of the most intractable malignancies. Citation Format: Eisaku Kondo, Ken Saito. PODXL1 as a critical accelerator for pancreatic cancer metastasis [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 1113.
Abstract 1277: 3-Isothiocyanato-1-propene as biomodulatory agent in ameliorating phenobarbital induced alterations in profile of detoxifying enzymes in different metabolic sites of Wistar rats
Authors: Saroj Arora, Sakshi Bhushan, Adarsh Pal Vig, Pardeep Kaur, Robin Shergill
Journal: Cancer Research (2018)

Abstract Backgound: Human exposure to xenobiotics is responsible for increased susceptibility to genetic and epigenetic changes. These changes are further accountable for disruption of pathways involved in cell proliferation, apoptosis, differentiation and senescence. Among array of plant products, that play an imperative role against such adverse catastrophes, the naturally occurring isothiocyanate known as 3-Isothiocyanato-1-propene (AITC) possesses abundant biological activities of therapeutic interest. Purpose of the study: Hence, considering these facts, the present study was planned to analyse four metabolic sites viz., liver, kidneys, stomach and lungs for protective activities of AITC against phenobarbital induced damage in Wistar rats. Methodology: The rats were divided into eight groups and treatments were given intraperitoneally for five days followed by sacrificing of animals on sixth day. The organs were homogenized and analysed for biochemical parameters and histopathology. Results: AITC in all the metabolic sites attenuated the levels of cytochrome dependent oxygenases, phase II detoxifying enzymes (DT-diaphorase, γ-glutamyltranspeptidase and glutathione-S-transferase), cascade of antioxidant enzymes (superoxide dismutase, catalase, ascorbate peroxidase, guaiacol peroxidase), membrane bound ATPases (Na+/K+-ATPase, Mg2+-ATPase, Ca2+-ATPase) and serum marker enzymes (SGOT, SGPT, direct bilirubin, indirect bilirubin, alkaline phosphastase, creatinine, blood urea nitrogen). Futhermore, the different doses of AITC (50, 100 and 150 µM/kg bw) resumed the necroinflammatory score by improving the piecemeal necrosis, focal lytic necrosis and portal inflammation. Conclusion: The maximum efficacy of amelioration by AITC was observed in liver due to the fact that amount of these enzymes in metabolic sites other than liver is quantitatively low. Hence, AITC emerged as potent candidate for ameliorating the harmful effects of non genotoxic carcinogen (phenobarbital) by regulating its metabolism efficiently in rats. Owing to its useful functions, AITC can act as an important bioprotective agent. Citation Format: Saroj Arora, Sakshi Bhushan, Adarsh Pal Vig, Pardeep Kaur, Robin Shergill. 3-Isothiocyanato-1-propene as biomodulatory agent in ameliorating phenobarbital induced alterations in profile of detoxifying enzymes in different metabolic sites of Wistar rats [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 1277.
Abstract 19156: Gene Expression Profiles Underlying the Cardioprotective Effects of Mechanical Primary Unloading of the Left Ventricle Before Reperfusion in Acute Myocardial Infarction
Authors: Yali Zhang, Gavin Schnitzler, Michele Esposito, Xiaoying Qiao, Shiva Annamalai, Emily Mackey, Kevin Morine, Andrew Mullin, Robert Pedicini, Catalina Breton, Richard Karas, Navin K Kapur
Journal: Circulation (2016)

We recently reported that compared to Primary Reperfusion (PR), first unloading the left ventricle (LV) by activating an mechanical circulatory support pump while delaying coronary reperfusion (Pri...
Cerebral Protection During Surgery for Acute Aortic Dissection Type A
Authors: TobiasKrüger, ErnstWeigang, IsabellHoffmann, MariaBlettner, HermannAebert
Journal: Circulation (2011)

Background—Cerebral protection during surgery for acute aortic dissection type A relies on hypothermic circulatory arrest, either alone or in conjunction with cerebral perfusion. Methods and Results—The perioperative and intraoperative conditions of 1558 patients submitted from 44 cardiac surgery centers in German-speaking countries were analyzed. Among patients with acute aortic dissection type A, 355 (22.8%) underwent surgery with hypothermic circulatory arrest alone. In 1115 patients (71.6%), cerebral perfusion was used: Unilateral antegrade cerebral perfusion (ACP) in 628 (40.3%), bilateral ACP in 453 (29.1%), and retrograde perfusion in 34 patients (2.2%). For 88 patients with acute aortic dissection type A (5.6%), no circulatory arrest and arch intervention were reported (cardiopulmonary bypass–only group). End points of the study were 30-day mortality (15.9% overall) and mortality-corrected permanent neurological dysfunction (10.5% overall). The respective values for the cardiopulmonary bypass–only...