tbuckley/cabot-search huggingface dataset:
Abstract 5899: Genome-wide CRISPR-Cas9 screening identifies genetic vulnerabilities and potential therapeutic targets in castration resistant prostate cancer
Authors: Jakob Haldrup, Linnéa Schmidt, Jakob S. Pedersen, Karina D. Sørensen
Journal: Cancer Research (2018)

Abstract Background: Treatment options for castration-resistant prostate cancer (CRPC) are limited and only a few agents (e.g. enzalutamide, docetaxel) are routinely used in the clinic. Unfortunately, CRPC tumors will invariable develop resistance to these agents and only a subset of patients will respond. Thus, novel predictive biomarkers are urgently needed to ensure that an expensive and potentially harmful agent is given only to patients who will benefit from it. Furthermore, to enable new treatment strategies, a better understanding of drug resistance mechanisms is required. Methods: To identify novel drug resistance genes and mechanisms of therapy resistance, we performed genome-wide CRISPR-Cas9 knockout screens in LNCaP (hormone naïve) and in the isogenic C4 (castration resistant) PC cell line, respectively. Using 77,441 unique sgRNAs (Brunello library), a total of 19,114 protein-coding genes were tested for their potential functional role in enzalutamide or docetaxel resistance. Both IC50 and IC90 values were used for selection. MAGeCK was used to identify enriched and depleted sgRNAs (treatment vs. DMSO). Results: Among the highest ranked hits for the C4 dropout screens, several potential genetic vulnerabilities and mechanisms of resistance were identified, as knockout of specific genes sensitized C4 cells to enzalutamide. None of these hits were observed in LNCaP, which suggest CRPC-specific resistance mechanisms. For the positive screens, increased enzalutamide resistance was observed after knockout of genes encoding e.g. phosphokinases and specific solute carriers (SLCs) for C4 and LNCaP, respectively. Lastly, our results suggest that knockout of specific zinc finger nucleases (ZFNs), posttranslational modification enzymes or microtubule components may modulate docetaxel resistance in C4 cells. Conclusion: Drug resistance is a major clinical problem. Here, we identified genetic vulnerabilities that may be translated into predictive biomarkers, combination therapies and/or novel drug development strategies for CRPC. Citation Format: Jakob Haldrup, Linnéa Schmidt, Jakob S. Pedersen, Karina D. Sørensen. Genome-wide CRISPR-Cas9 screening identifies genetic vulnerabilities and potential therapeutic targets in castration resistant prostate cancer [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 5899.
Heart Homotransplantation in Puppies
Authors: Yoshiokondo, Franzgrädel, Adriankantrowitz
Journal: Circulation (1965)

A satisfactory technique for orthotopic homotransplantation of the heart, under profound hypothermia without a pump-oxygenator, has been presented. Of the 40 puppies in our series, 24 lived more than one day; 13 lived more than seven days. One is well and active on the 112th day. The rhythm of the transplanted hearts was often somewhat irregular shortly after surgery, but usually became fairly regular on the following day and maintained a constant rate even after exercise. Long survivors steadily gained weight and showed a proportional increase in heart size. The fate of the transplant could be forecast in some instances from the follow-up electrocardiograms. Although the histological findings were not uniform, acceptance of the homogous heart greatly exceeded our expectations. Unpredictable histocompatibility may possibly explain the long survivors.
Abstract 106: Shock and ROR! Targeting ROR1 and ROR2 in a preclinical patient-derived model of ovarian cancer
Authors: Claire E. Henry, Neville F. Hacker, Caroline E. Ford
Journal: Cancer Research (2018)

Abstract BACKGROUND: New targets for ovarian cancer treatment are critically needed. The Wnt receptors ROR1 and ROR2 are overexpressed in all histotypes of ovarian cancer and appear to play a role in both the tumour and the surrounding microenvironment. We have previously conducted an extensive suite of in vitro experiments, exploring the functional role of ROR1 and ROR2 in ovarian cancer. Silencing either receptor using siRNA inhibited ovarian cancer cell migration and invasion, and silencing both receptors had an even stronger inhibitory effect on the metastatic potential of ovarian cancer cellS. We have also shown that silencing ROR1 and ROR2 sensitises chemoresistant ovarian cancer cells to chemotherapy. Combined, these studies have confirmed the importance of RORs in ovarian cancer, and provided a strong argument for these receptors potential as clinical targets. However, these previous studies have utilised simple 2D in vitro models to investigate cancer cell growth and migration, which does not allow investigation of stromal involvement in ROR driven metastasis. AIM: To investigate targeting ROR1 and ROR2 in a 3D primary co-culture model of epithelial ovarian cancer dissemination to the omentum. METHODS: Primary fibroblasts (NOF) and mesothelial (HPMC) cells were isolated from fresh samples of omentum collected from women with benign or non-metastatic conditions and cultured with collagen to produce a organotypic 3D model. Stable shRNA knockdown of ROR1, ROR2 and double ROR1/ROR2 in OVCAR4 ovarian cancer cells were incorporated into the 3D model to measure adhesion, or using a transwell to measure invasion. Gene expression changes in primary cells upon OVCAR4 interaction was evaluated using indirect transwell co-culture. RESULTS: Double knockdown of ROR1 and ROR2 strongly inhibited cell adhesion (p&amp;lt;0.05) and invasion (P&amp;lt;0.05) to the omentum model. ROR2, but not ROR1, was up- regulated in primary fibroblasts when cultured with OVCAR4 (P=0.05) and ectopic overexpression of ROR2 in NOFs increased cell migration. CONCLUSION: The combination of ROR1 and ROR2 signalling influences ovarian cancer dissemination to the omentum, however ROR2 may also play a specific role in stromal activation during metastasis. Therefore, targeting both ROR1 and ROR2 may be a powerful approach to treating ovarian cancer. The development of a number of monoclonal antibodies targeting ROR1 currently in phase 1 trials for other tumour types makes this clinically feasible in the near future. Citation Format: Claire E. Henry, Neville F. Hacker, Caroline E. Ford. Shock and ROR! Targeting ROR1 and ROR2 in a preclinical patient-derived model of ovarian cancer [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 106.
Differential Effects of Oral and Transdermal Estrogen Replacement Therapy on Endothelial Function in Postmenopausal Women
Authors: SatuVehkavaara, TiinaHakala-Ala-Pietilä, AnttiVirkamäki, RobertBergholm, ChristianEhnholm, OutiHovatta, Marja-RiittaTaskinen, HanneleYki-Järvinen
Journal: Circulation (2000)

Background—We determined whether the vascular effects of estradiol depend on the route of administration by comparing the effects of oral estradiol and transdermal placebo, transdermal estradiol and oral placebo, and transdermal placebo and oral placebo on in vivo endothelial function in 27 postmenopausal women. Methods and Results—Endothelial function was assessed from blood flow responses to intrabrachial artery infusions of endothelium-dependent (7.5 and 15 μg/min acetylcholine) and endothelium-independent (3 and 10 μg/min of sodium nitroprusside) vasodilators at 0, 2, and 12 weeks. In the oral estradiol group, the increase in flow above basal during infusion of the low dose of acetylcholine at 0, 2, and 12 weeks averaged 6.0±0.8, 6.9±0.8, and 11.3±1.2 (P<0.01 versus 0 and 2 weeks) mL · dL−1 · min−1 at 0, 2, and 12 weeks. The percentage increases versus 0 weeks averaged 21±14% at 2 and 120±34% at 12 weeks. During the high-dose acetylcholine infusion, the increase in flow above basal averaged 8.6±1.3, 1...
Fibroblast Growth Factor-23 May Follow Cardiovascular Disease Rather than Causing It in Chronic Kidney Disease
Authors: Chenchen Zhou, Changlin Mei, Bing Dai, Cheng Xue
Journal: Journal of the American Society of Nephrology (2018)

We read the article "Fibroblast growth factor-23 and risks of cardiovascular and noncardiovascular diseases: A meta-analysis" by Marthi et al.1 with great interest. The study provided an important demonstration that serum higher fibroblast growth factor-23 (FGF-23) level was positively associated with cardiovascular and noncardiovascular outcomes in populations with or without CKD.1 In agreement with Marthi et al.,1 our previous meta-analysis also pointed out that there might be predictive effects of FGF-23 on cardiovascular diseases (CVDs; including myocardial infarction, atrial fibrillation, myocardial ischemia, heart failure, and stroke) and mortality in patients with CKD.2 However, the absence of an exposure-response relationship and similarly sized associations between FGF-23 and different outcomes may not be strong enough to suggest a noncausal relationship between FGF-23 and CVD. Indeed, interactions between FGF-23 and CVD are complicated and remain inconclusive. Experimental studies have revealed that FGF-23 could induce left ventricular hypertrophy.3 Both FGF-23 overexpression and Klotho deficiency showed cardiac remodeling effects in CKD.4 However, Slavic et al.5 found that genetic ablation of FGF-23 or Klotho did not modulate heart hypertrophy, indicating other mediators as the real culprits. Recently, left ventricular hypertrophy in transgenic mice was found to elevate myocardial and serum levels of FGF-23.3 Taken together, the mutual promotion between FGF-23 and CVD indicates a complex interaction between mineral metabolism and the cardiovascular system in CKD. FGF-23 may follow CVD rather than causing it in CKD. In conclusion, the finding of this meta-analysis1 is very important, because it brings us a deep and broad view of FGF-23 in CVD and mortality in patients with or without kidney disease. More mechanisms between FGF-23 and CVD will need to be studied to better understand the effect of FGF-23 on cardiovascular health in patients with CKD. Disclosures None.
Abstract 3161: The macrolide toxin mycalolide B disrupts actin-driven invasion and metastasis of HER2-positive cancers
Authors: Sarah Nersesian, Rodette Williams, Dr. Andrew Evans, Dr. John Allingham, Dr. Andrew Craig
Journal: Cancer Research (2018)

Abstract HER2 is a driver and clinical target in cancers afflicting women. HER2-positive (HER2+) cancers have high rates of metastasis and lower overall survival rates compared to other cancer subtypes. The goal of this study is to test the vulnerability of HER2+ cancer cells and tumors to disruption of their actin cytoskeleton using the marine macrolide toxin mycalolide B (Myc B), as these cells are highly dependent on rapid actin polymerization and remodeling for migration and invasion into new sites of tumor growth. The effects of Myc B treatment on HER2+ breast (HCC1954) and ovarian (SKOV3) cancer cell lines were profiled in assays of cell viability, motility, and invasion. Treatments of Myc B alone or in combination with Trastuzumab were also performed in HER2+ tumor xenograft assays. Myc B showed potent growth suppressive and cytotoxic effects on HER2+ cancer cells at doses in the 70-100 nM range. At sub-lethal doses, Myc B caused a rapid loss of leading edge protrusions, and sustained defects in HER2+ cancer cell motility and invasion. HER2 internalization and killing of HER2+ cancer cells by Trastuzumab-emtansine was not compromised with Myc B treatment. In a HER2+ tumor xenograft model, Myc B treatment alone, or in combination with Trastuzumab, led to significant reductions in tumor growth and metastasis. Together, these findings identify a major vulnerability in metastasis-initiating HER2+ cancer cells to the actin toxin Myc B, and provide a rationale to exploit this vulnerability with the development of new therapeutics targeting actin. Citation Format: Sarah Nersesian, Rodette Williams, Dr. Andrew Evans, Dr. John Allingham, Dr. Andrew Craig. The macrolide toxin mycalolide B disrupts actin-driven invasion and metastasis of HER2-positive 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 3161.
Abstract 356: KChIP2 Mediates Ion Channel Dysregulation by Novel Transcriptional Regulation of miR-34s
Authors: DrewNassal, HaiyanLiu, XiaopingWan, AngelinaRamirez-Navarro, EckhardFicker, IsabelleDeschenes
Journal: Circulation Research (2014)

Introduction: Cardiac ion channel dysregulation is a hallmark of heart failure. Consistently, the disease yields dramatic decline in Ito through loss in Kv4 and its auxiliary partner KChIP2. Notably, transcriptional changes in heart failure can be elicited through KChIP2 silencing without disease signaling, suggesting potential transcriptional capacity for KChIP2. Further, disparity between resulting transcript and protein patterns suggests a mechanism compatible with modified miRNA activity. Considering other members of the KChIP family behave as transcriptional repressors, we hypothesize that KChIP2 regulates discrete miRNAs which in turn regulate cardiac excitability. Methods and Results: A miRNA microarray was conducted on neonatal rat ventricular myocytes (NRVM) following in vitro silencing of KChIP2 by siRNA, identifying the miR-34 family as potential transcriptional targets of KChIP2. Regulation, confirmed by quantitative PCR, showed reduction in miR-34a/b/c when over-expressing KChIP2 and increase...
A New Concept: Pre‐HCC Disease
Authors: Yao Yang, Yuemin Feng, Xinya Zhao, Le Wang, Xiaoyu Xie, Jie Li, Mindie H. Nguyen, Qiang Zhu
Journal: Hepatology (2018)

Supported by the National Science Foundation of China (no. 81570551; 81770607) and Key Research project of Shandong Province (no. 2016GSF201008). TO THE EDITOR: The American Association for the Study of Liver Diseases recently updated the clinical practice guidelines on management of hepatocellular carcinoma (HCC).(1) The guidelines provide detailed recommendations in surveillance, diagnosis, and treatments for patients with HCC; we notice there is still a void in the recommendations for pre‐HCC disease, which is not yet overtly cancerous, but appears to be on the way to developing an HCC. Considering the high incidence and mortality of HCC worldwide, the prevention of HCC should be a high priority consideration, and there should be more focus on the pre‐HCC disease. Diagnosis of Pre‐HCC Disease Recent advances in liver imaging have improved the diagnosis of early stages of hepatocarcinogenesis, such as high‐grade dysplastic nodule (HGDN) and early HCC.(2) A cirrhotic lesion showing arterial phase nonhyperintensity, hepatobiliary phase hypointensity, and diffusion‐weighted imaging nonhyperintensity on the Gd‐EOB‐DTPA (gadoxeticacid) enhanced magnetic resonance imaging is most likely an HGDN,(3) and a patient with cirrhosis carrying such a lesion should be considered as having pre‐HCC disease and should be taken seriously, given the malignant potential of HGDN.(4) Treatment of Pre‐HCC Disease Although the noninvasive diagnosis of pre‐HCC disease seems to be achievable, what to do next is still a troublesome issue yet to be solved. Watchful follow‐up for patients who have pre‐HCC is widely accepted in current clinical practice, though precise surveillance strategy remains to be established and it might be limited by high‐cost imaging tests and poor compliance of patients.(5) Meanwhile, the efficacy of active interventions, such as surgery and local percutaneous therapy for pre‐HCC disease, is still unknown, so further studies about the treatment of pre‐HCC are needed. In summary, radiological advances have made it possible for practitioners to diagnose pre‐HCC disease without heavy reliance on invasive tissue diagnosis. And then, monitoring and treatment strategy for patients with pre‐HCC disease is urgently needed. Potential conflict of interest Nothing to report.
Optical Mapping Reveals That Repolarization Spreads Anisotropically and Is Guided by Fiber Orientation in Guinea Pig Hearts
Authors: AnthonyKanai, GuySalama
Journal: Circulation Research (1995)

Abstract Guinea pig hearts were stained with a voltage-sensitive dye and imaged on a photodiode array to record fluorescent action potentials (APs) from 124 sites. Activation and repolarization patterns were recorded from the epicardium during stimulation at different loci and correlated with the underlying fiber architecture. Endocardial APs were recorded by inserting a light guide into the ventricular cavity or by dissecting out the ventricular free wall to expose the endocardium. In hearts paced on the right atrium to simulate sinus rhythm, activation emerged synchronously over a large area of the ventricular epicardium and spread laterally in 5 to 7 ms. The apparent longitudinal and transverse velocities were 2.66±0.11 and 1.65±0.09 m/s (n=12). In contrast, repolarization began near the apex on the endocardium and spread transmurally in 6±1.3 ms (n=12) and then anisotropically along the epicardium in 25 to 30 ms with apparent maximum (0.53±0.11 m/s) and minimum (0.31±0.10 m/s) repolarization velocitie...
Guidance of Vascular Development
Authors: BrunoLarrivée, CatarinaFreitas, StevenSuchting, IsabelleBrunet, AnneEichmann
Journal: Circulation Research (2009)

The vascular system of vertebrates consists of an organized, branched network of arteries, veins, and capillaries that penetrates all the tissues of the body. One of the most striking features of the vascular system is that its branching pattern is highly stereotyped, with major and secondary branches forming at specific sites and developing highly conserved organ-specific vascular patterns. The factors controlling vascular patterning are not yet completely understood. Recent studies have highlighted the anatomic and structural similarities between blood vessels and nerves. The 2 networks are often aligned, with nerve fibers and blood vessels following parallel routes. Furthermore, both systems require precise control over their guidance and growth. Several molecules with attractive and repulsive properties have been found to modulate the proper guidance of both nerves and blood vessels. These include the Semaphorins, the Slits, and the Netrins and their receptors. In this review, we describe the molecula...
Involvement of Thromboxane Receptor in the Proatherogenic Effect of Isoprostane F2α-III
Authors: MyanTang, TillmannCyrus, YuemangYao, LuiginaVocun, DomenicoPraticò
Journal: Circulation (2005)

Background— Atherosclerosis is a chronic inflammatory disease of the arterial wall, where it associates with oxidative stress and formation of oxidized lipids. The lipid oxidation product isoprostane iPF2α-III, also known as 8-isoPGF2α and 15-F2t-IsoP, is elevated in patients with cardiovascular disease and present in atherosclerotic lesions. Several proatherogenic biological effects have been attributed to this isoprostane, suggesting that it could be an active factor in the pathogenesis of the disease. Methods and Results— In this study we show that iPF2α-III directly promotes atherogenesis in 2 different mouse models (ie, apolipoprotein E [apoE]– and LDL receptor–deficient mice) by activating the thromboxane receptor (TP). This effect is mediated by potent proinflammatory vascular reactions but is independent of thromboxane A2 levels, changes in blood pressure, or lipid profile. Pharmacological antagonism of TP suppresses the vascular proatherogenic effects of iPF2α-III. Endothelial cells genetically l...
Differential Effects of a Segment of Slow Conduction on Reentrant Ventricular Tachycardia in the Rabbit Heart
Authors: KaiHaberl, MauritsAllessie
Journal: Circulation (1999)

Background—The purpose of this study was to compare differential effects of a segment of slow conduction during ventricular tachycardia (VT) due to depression of the action potential and electrical uncoupling. Methods and Results—In 33 Langendorff-perfused rabbit hearts, a ring of anisotropic left ventricular subepicardium was created by a cryoprocedure. Reentrant VT was produced by incremental pacing. Slow conduction in a segment of the ring was created by selective perfusion of the LAD with 10 mmol/L potassium or 0.75 mmol/L heptanol. As a result, VT cycle length increased from 193±34 to 235±37 ms (potassium) and 227±42 ms (heptanol). Reset curves were made by applying premature stimuli proximal to the area of depressed conduction. In a ring of uniform anisotropic tissue, the reset curve was almost completely flat. Electrical uncoupling of part of the ring (nonuniform anisotropy) resulted in a mixed reset curve. In both substrates, early premature beats failed to terminate VT. Depression of part of the ...
Abstract 19031: Prediction and Incidence of Non-PV Trigger Foci of Atrial Fibrillation With Regard to Clinical Profile
Authors: YasushiMukai, ShujiroInoue, SusumuTakase, ShunsukeKawai, AkikoChishaki, KenjiSunagawa
Journal: Circulation (2015)

Introduction: Non-PV triggers play significant roles in initiating atrial fibrillation (Af). We hypothesized that location of non-PV Af triggers is predictable to some extent from clinical background and may have influence on clinical outcome after ablation. Methods: We analyzed consecutive 109 patients (76 men) with Af who underwent catheter ablation and investigation of Af triggers. Af was induced under recordings of intra-cardiac electrograms before ablation procedure in the following ways (1) watching spontaneous firing, (2) induction with intravenous infusion of isoproterenol and adenosine, (3) burst atrial pacing and/or intentional defibrillation to watch immediate recurrence of Af. Af triggers were analyzed and compared to clinical profiles and therapeutic outcome. Results: Eighty-four were paroxysmal Af and 25 were persistent. Any ectopic trigger of Af was identified in 73 patients (66%) with 99 foci. Seventy-eight foci were PVs (79%) whereas 21 (21%) were non-PV triggers. In general, non-PV foci ...
Abstract 20504: Dysfunctional cAMP-Dependent Protein Kinase (PKA) Signaling Causes Impaired Autonomic Control in Diabetic Heart Failure
Authors: LeeBockus, KennethHumphries
Journal: Circulation (2014)

Autonomic control of cardiac function primarily occurs through the regulation of cAMP-dependent protein kinase (PKA) via the adrenergic and muscarinic pathways. The diabetic heart has a suppressed β-adrenergic response that is classically attributed to β-adrenergic receptor internalization, but little is known about how the PKA signaling pathway is affected. We assessed the hypothesis that β-adrenergic impairment in diabetes occurs through PKA signaling dysfunction. Four-month streptozotocin (STZ)-induced diabetic mice were used in this study as a model of diabetic cardiomyopathy. Although the diabetic mice have substantial cardiac impairment, as measured by pressure catheter, cAMP levels are not reduced, suggesting the pathway upstream of PKA is intact. We next developed a novel system using acute 8-min treatments with a cAMP analog, 8Br-cAMP, to activate PKA in a receptor-independent manner and increase ventricular inotropy. Diabetic mice have an impaired response to 8Br-cAMP treatment as shown by minim...