tbuckley/cabot-search huggingface dataset:
Abstract 5111: Gene editing in the NSG mouse strain and its genetic derivatives
Authors: David S. Grass, F William Buaas, Michael V. Wiles, Benjamin E. Low, Peter Kutny
Journal: Cancer Research (2018)

Abstract Mouse models continue to be powerful tools in preclinical oncology and immuno-oncology studies. The development of the inbred highly immunocompromised mouse strain NSG (NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ) has dramatically improved the ability to work with human tumors in an organismal context using xenograft approaches. Furthermore, technical innovations have expanded the utility of this personalized tumor platform via the reconstitution of parts of the human immune system. An example of this is the NSG-SGM3 inbred mouse strain, in which transgenes expressing human IL3, GMCSF and SCF have been stably integrated into the NSG background. This NSG “derivative” strain can effectively support the stable engraftment of human myeloid lineages and the regulatory T cell populations. Direct genetic modification of the NSG genome in mouse embryos was a key technical capability to attain this NSG “derivative” strain rapidly and avoid extensive breeding. Modification of NSG and derivative strains represent an opportunity to optimize the engraftment of other human lineages. The ability to apply modern genome modification technology to different inbred mouse strains is highly desirable but must overcome two major technical hurdles - 1) Reproductive biology constraints that prevent live born progeny after reagent delivery methods such as microinjection or electroporation and 2) Cell intrinsic DNA-repair processes that are a prerequisite enabling gene editing tools. Given the SCID mutation (Prkdcscid) in the NSG background compromises some DNA repair pathways, it was not clear whether nuclease assisted recombination technologies would be a robust tool to modify NSG (and derivatives) genomes at the zygote stage. Here, we demonstrate that CRISPR-Cas9 is an effective tool for introducing genome modifications in NSG and present a specific example using the Hprt locus. Furthermore, we will present general experience with genomic modifications using NSG, and its derivatives, to emphasize direct modification of these genomes is technically feasible and is enabling the rapid sequential genetic tailoring in this high value cancer model strain. Citation Format: David S. Grass, F William Buaas, Michael V. Wiles, Benjamin E. Low, Peter Kutny. Gene editing in the NSG mouse strain and its genetic derivatives [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 5111.
Abstract 3498: Regulation of AR through an FGF5 driven mechanism
Authors: Dalton McLean
Journal: Cancer Research (2018)

Abstract Purpose To investigate the role of increasing FGF5 expression in the progression of prostate cancer and emergence of castration resistant prostate cancer. Methods Utilizing a cell line model representing different stages of prostate cancer progression, we assessed FGF5 expression and function in vitro and in vivo. We analyzed both an outcomes and progression tissue microarray (TMA) containing ~400 prostate cancer patient cores to assess FGF5 expression in a clinical setting. Results There was a significant increase in the both RNA and protein expression of FGF5 in tumorigenic cell lines compared to nontumorigenic. In TMAs that were analyzed, there was a significant increase of FGF5-positive cells across progression of prostate cancer from benign to metastatic, with the highest percentage occurring in cases of cancer. When performing gain of function experiments with recombinant FGF5 (rFGF5) or overexpression plasmids, we found that FGF5 significantly increased the proliferation of AR-positive cell lines. Conversely, in AR-negative cell lines, FGF5 inhibited proliferation. Because FGF5 is associated with stem cells and differentiation events, we next asked whether the population of FGF5 cells that increases through cancer progression could lead to molecular changes in the total population. In addition to inhibiting proliferation of AR-negative nontumorigenic BPH1 cells, rFGF5 resulted in a robust AR expression. In LNCaP, C4-2, and C4-2B rFGF5 resulted in an increase in AR expression. In C4-2 and C4-2B cells an increase in AR protein coincided with an increase in nuclear YAP1, a potent transcriptional regulator. We hypothesized that androgens could be regulating FGF5 expression in the prostate. When androgen dependent LNCaP cells are subjected to an androgen-depleted environment, FGF5 protein and RNA significantly increased within 24hrs. Additionally, when AR is stimulated using dihyrotestosterone, FGF5 protein and RNA levels significantly decreased. These effects are not observed in cell lines that do not express AR. Conclusions These results suggest that FGF5 is increased in prostate cancer progression cell lines as well as patient samples, with highest expression in aggressive cancer cores. Data also suggests that AR plays a role in the regulation of FGF5 and vice versa. These data suggest that FGF5 driven AR expression could be driven by YAP1 nuclear localization. This mechanism will be further interrogated. Citation Format: Dalton McLean. Regulation of AR through an FGF5 driven mechanism [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 3498.
Selection of a Suitable Patient Population for New Antiplatelet Therapy From the Large Clinical Trial Database of the Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–Thrombolysis in Myocardial Infarction 50 (TRA-2P–TIMI50) Trial
Authors: ShinichiGoto, ShinyaGoto
Journal: Circulation (2015)
Losartan and Its Metabolite E3174 Modify Cardiac Delayed Rectifier K+ Currents
Authors: RicardoCaballero, EvaDelpón, CarmenValenzuela, MónicaLongobardo, JuanTamargo
Journal: Circulation (2000)

Background—The effects of type 1 angiotensin II receptor antagonist losartan and its metabolite E3174 on transmembrane action potentials, hKv1.5, HERG, and IKs currents were analyzed. Methods and Results—Guinea pig ventricular action potentials were recorded with microelectrode techniques and hKv1.5 and HERG currents with the whole-cell patch-clamp technique. IKs was recorded in guinea pig ventricular myocytes with the perforated-nystatin-patch configuration. Losartan and E3174 transiently increased the hKv1.5 current by 8.0±1.4% and 7.4±1.6%, respectively. Thereafter, they produced a voltage-dependent block, E3174 being more potent than losartan (P<0.05) for this effect. Losartan decreased HERG currents elicited at 0 mV (23.3±4.8%), whereas E3174 increased the current (30.5±6.2%). Both drugs shifted the midpoint of the activation curve of HERG channels to more negative potentials. In ventricular myocytes, losartan and E3174 inhibited the IKs (18.4±3.2% and 6.5±0.7%, respectively). Losartan-induced block ...
Abstract 4703: The inhibitor of apoptosis protein (IAP) antagonist Debio 1143 enhances the immune response to anti-PD1/L1 inhibitors in vitro and in vivo
Authors: Antoine Attinger, Bruno Gavillet, Anne Vaslin Chessex, Norbert Wiedemann, Gregoire Vuagniaux
Journal: Cancer Research (2018)

Abstract Background: Debio 1143 is an oral antagonist of IAPs, currently in clinical development, which sensitizes tumor cells to radiation- or chemotherapy-induced apoptosis. IAPs inhibitors modulate NF-κB signaling and drive the expression of genes relevant for inflammation and immunity. Here, we hypothesized that Debio 1143 could improve antitumor immunity by directly enhancing T-lymphocyte activation and by improving the effects of immune checkpoint inhibitors in vitro and in vivo. Methods: Ex vivo human PBMC anti-CD3/CD28 stimulation and modified mixed-lymphocyte reaction assays were performed to evaluate the immunostimulatory potential of Debio 1143 alone or in combination with the anti-PD-1 antibody nivolumab (N= 5 donors). T cells' proliferation and activation were measured by flow cytometry and cytokine release was measured by ELISA. The antitumor activity of an anti-PD-L1 antibody (5 mg/kg BIW IP) was tested either alone or in combination with Debio 1143 (100 mg/kg QD1-5 PO) in MBT-2 immunocompetent mouse model of bladder cancer over 3 weeks (n=8 /group). Results: Debio 1143 significantly enhanced CD4+ and CD8+ intracellular IFNγ expression in a concentration-dependent manner following anti-CD3/CD28 stimulation. This result was confirmed using a mixed-lymphocyte reaction assay, where Debio 1143 at concentrations achieved in clinical studies significantly increased IFNγ expression by activated CD4+ cells, and this effect was even further increased in presence of nivolumab. In MBT-2 tumor-bearing mice, the combination of Debio 1143 and anti-PD-L1 antibody significantly decreased tumor growth (P=0.001 using two-sided t-test) and increased survival, whereas monotherapies only displayed moderate activities (median survival time of 42 days vs. 33 or 28 days for Debio 1143 or anti-PD-L1 alone, respectively). Conclusion: These data show a key mechanistic role for future combination therapy of the IAP antagonist Debio 1143 and immune-checkpoint agents in cancer patients. This synergy will be further explored in a phase-Ib dose-finding clinical study combining Debio 1143 and Avelumab (anti-PD-L1) in patients with advanced solid malignancies and non-small cell lung cancer (CT# 03270176). Citation Format: Antoine Attinger, Bruno Gavillet, Anne Vaslin Chessex, Norbert Wiedemann, Gregoire Vuagniaux. The inhibitor of apoptosis protein (IAP) antagonist Debio 1143 enhances the immune response to anti-PD1/L1 inhibitors 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 4703.
Preterm Heart in Adult Life
Authors: Adam J. Lewandowski, Daniel Augustine, Pablo Lamata, Esther F. Davis, Merzaka Lazdam, Jane Francis, Kenny McCormick, Andrew R. Wilkinson, Atul Singhal, Alan Lucas, Nic P. Smith, Stefan Neubauer, Paul Leeson
Journal: Circulation (2012)

Preterm birth leads to an early switch from fetal to postnatal circulation before completion of left ventricular in utero development. In animal studies, this results in an adversely remodeled left ventricle. We determined whether preterm birth is associated with a distinct left ventricular structure and function in humans. A total of 234 individuals 20 to 39 years of age underwent cardiovascular magnetic resonance. One hundred two had been followed prospectively since preterm birth (gestational age=30.3±2.5 week; birth weight=1.3±0.3 kg), and 132 were born at term to uncomplicated pregnancies. Longitudinal and short-axis cine images were used to quantify left ventricular mass, 3-dimensional geometric variation by creation of a unique computational cardiac atlas, and myocardial function. We then determined whether perinatal factors modify these left ventricular parameters. Individuals born preterm had increased left ventricular mass (66.5±10.9 versus 55.4±11.4 g/m(2); P<0.001) with greater prematurity associated with greater mass (r = -0.22, P=0.03). Preterm-born individuals had short left ventricles with small internal diameters and a displaced apex. Ejection fraction was preserved (P>0.99), but both longitudinal systolic (peak strain, strain rate, and velocity, P<0.001) and diastolic (peak strain rate and velocity, P<0.001) function and rotational (apical and basal peak systolic rotation rate, P =0.05 and P =0.006; net twist angle, P=0.02) movement were significantly reduced. A diagnosis of preeclampsia during the pregnancy was associated with further reductions in longitudinal peak systolic strain in the offspring (P=0.02, n=29). Individuals born preterm have increased left ventricular mass in adult life. Furthermore, they exhibit a unique 3-dimensional left ventricular geometry and significant reductions in systolic and diastolic functional parameters. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01487824.
Disseminated Volvariella volvacea infections in patients with haematological malignancies: a case series
Authors: K.L. Chew, D.H.L. Ng, J.W.P. Teo, K.B. Tan, L.M. Poon, P.A. Tambyah, C.W.M. Ong
Journal: Clinical Microbiology and Infection (2018)
Doctors are given go ahead to extract sperm from unconscious man in legal first
Authors: Clare Dyer
Journal: BMJ (2018)

A High Court judge has made an emergency ruling allowing doctors to extract sperm from an unconscious man with a catastrophic brain injury, to store it and use it to try to impregnate his widow after his death.1

In a legal first, Mrs Justice Knowles ruled in the Court of Protection that the move would be in the best interests of the man, named only as Z, who was hit by a van while driving his motorcycle to work on 5 July. He and his wife, Y, who had one child, had undergone tests before starting in vitro fertilisation (IVF) treatment to …
Endoglin Targeting in Colorectal Tumor Microenvironment
Authors: Lisa M. Becker, Valerie S. LeBleu
Journal: Clinical Cancer Research (2018)

On endothelial cells, the TGFβ/BMP-9 coreceptor, endoglin, emerged as a promising antiangiogenic target in colorectal cancer. Its promiscuous expression by cancer-associated fibroblasts (CAF) emerges to facilitate metastasis. The multitarget impact of neutralizing endoglin may offer added benefit in controlling colorectal cancer.See related article by Paauwe et al., p. 6331.
Abstract 10821: The Presence of Non-obstructive Coronary Artery Disease on Coronary Computed Tomography Angiography Re-classifies Guideline-based Statin Eligibility
Authors: Hamed Emami, Richard Takx, Thomas Mayrhofer, Sumbal Janjua, Jakob Park, Amit Pursnani, Michael T Lu, Maros Ferencik, Udo Hoffmann
Journal: Circulation (2015)

Background: AHA/ACC guidelines advise using 7.5% threshold of 10-year risk for atherosclerotic cardiovascular disease (ASCVD) events to determine eligibility for statin therapy. Coronary Computed Tomography Angiography (CTA) provides prognostic information for ASCVD events as well. We tested the hypothesis whether presence of non-obstructive CAD (&lt;50% stenosis) as detected by CTA could be used to improve risk assessment per AHA/ACC guidelines in stable patients. Methods: We performed a systematic literature review to identify studies that assessed the prognostic value of coronary CTA findings for ASCVD events. The characteristics of study subjects at baseline, follow-up information, and outcomes were collected. We selected studies that provided hazard ratio (HR) for ASCVD events in patients with non-obstructive CAD and performed a meta-analysis. We incorporated the pooled HR into the standard 10-year ASCVD pooled cohort equation and derived equivalents for the 7.5% 10 year event risk for those with and without non-obstructive CAD and performed a sensitivity analysis using the lower and upper bounds of the confidence intervals of the pooled HR from the meta-analysis. Results: We identified 20 studies (22,036 subjects, 53% male, median follow-up 31 months) that assessed the prognostic value of CAD as detected by CTA. The studies that provided HR for ASCVD events were used for the meta-analysis. The pooled HR for incident ASCVD was 3.2 (95% CI 1.5-6.7). Equivalents for the 7.5% 10 year event risk for those with non-obstructive CAD were as low as 2.0% (African American women) and for those with no CAD as high as 33.8% (African American men). (Table 1) Conclusions: Non-obstructive CAD is an independent predictor of ASCVD events. Incorporating information on the presence of non-obstructive CAD into the AHA/ACC ASCVD risk calculator provides gender and ethnicity specific equivalents for the 7.5% threshold, which may improve efficiency and accuracy of statin therapy.
Abstract 1466: DAXX localizes ATRX to suppress alternative lengthening of telomeres in osteosarcoma
Authors: Sarah Faith Clatterbuck Soper, Kathryn E. Yost, Robert L. Walker, Marbin A. Pineda, Yuelin J. Zhu, Joshua J. Waterfall, Paul S. Meltzer
Journal: Cancer Research (2018)

Abstract To maintain genome stability, proliferating cells must add telomere sequence to counteract the chromosome end replication problem. In normal cells, telomeres are lengthened through the action of the enzyme telomerase. In about 10-15% of tumors, however, telomeres are lengthened through a telomerase-independent mechanism known as Alternative Lengthening of Telomeres or ALT. Many tumors that use ALT have poor prognoses, so ALT represents an appealing therapeutic target. It has been previously observed that ALT tumors frequently carry mutations in ATRX, which partners with the protein DAXX in a chromatin remodeling complex that deposits histone variant H3.3. How these mutations facilitate the ALT pathway is not well understood. Previous work in our lab identified an ALT-positive osteosarcoma cell line, G292, in which ATRX is wild-type but DAXX has undergone a fusion event with the non-canonical kinesin KIFC3. The DAXX-KIFC3 fusion leads to a loss of DAXX function, and inducible restoration of wild-type DAXX reversibly abrogates ALT in this cell line. We observe that expression of wild-type DAXX results in localization of ATRX to PML bodies, increased occupancy of ATRX at telomeric chromatin, and higher levels of histone H3.3 at telomeres. We conclude that full-length DAXX is required for the functional localization of ATRX to telomeres. Leveraging this our inducible system, we continue to probe the role of the ATRX/DAXX complex in suppressing ALT. Citation Format: Sarah Faith Clatterbuck Soper, Kathryn E. Yost, Robert L. Walker, Marbin A. Pineda, Yuelin J. Zhu, Joshua J. Waterfall, Paul S. Meltzer. DAXX localizes ATRX to suppress alternative lengthening of telomeres in osteosarcoma [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 1466.
Severe Left Ventricular Outflow Tract Calcification Is Associated With Poor Outcome in Patients Undergoing Transcatheter Aortic Valve Replacement
Authors: David Jochheim, Simon Deseive, Bernhard Bischoff, Magda Zadrozny, Sebastian Hausleiter, Moritz Baquet, Christian Tesche, Hans Theiss, Christian Hagl, Steffen Massberg, Julinda Mehilli, Jörg Hausleiter
Journal: JACC. Cardiovascular imaging (2018)
Abstract 209: Different Reaction To Lactate Between The Atrial And The Ventricular Muscle In Excitation-contraction Coupling
Authors: DaisukeShimura, YoichiroKusakari, NobuhitoGoda, SusumuMinamisawa
Journal: Circulation Research (2014)

Background: The effect of a metabolic change on excitation-contraction (EC) coupling is poorly understood in the atrial myocardium, while the previous studies have mainly focused on EC coupling in the ventricular myocardioum. Although the myocardium mostly uses fatty acid as an energy source, we have reported that metabolic substrate, includes lactate, can be used for energy production and that the metabolomic profile is different between the atria and the ventricles in mouse heart. In addition, it is still under discussion whether lactate can be an energy source for muscles. In the present study, we aimed to investigate the effect of lactate exposure on EC coupling in the atrial and the ventricular myocardium. Methods: We micro-injected aequorin (a Ca2+-sensitive photoprotein) into superficial cells of the left atrium and/or the left ventricular papillary muscle isolated from mice (C57/BL6, 12 - 17 weeks of age), and simultaneously measured intracellular Ca2+ concentration and tension (1 Hz at 36 °C). We...
Abstract P248: Green Space and Mortality Following Ischemic Stroke
Authors: ElissaWilker, Chih-DaWu, EileenMcNeely, ElizabethMostofsky, JohnSpengler, GregoryWellenius, MurrayMittleman
Journal: Circulation (2014)

Background: Residential proximity to green space has been associated with physical and mental health benefits, but whether green space is associated with post-stroke survival is not well understood. Methods: We identified patients ≥21 years of age admitted to the Beth Israel Deaconess Medical Center (BIDMC) between April 1, 1999 and October 31, 2008 with neurologist-confirmed acute ischemic stroke. Demographics, presenting symptoms, medical history and imaging results were abstracted from medical records at the time of hospitalization for stroke onset. The time of stroke symptom onset or time last seen normal was documented by the attending stroke neurologist at the time of hospital presentation. Participant addresses were geocoded and linked to average Normalized Difference Vegetation Index (NDVI) derived from satellite-based estimates within a 250x250m grid (July 2000-2012), distance to roadways with more than 10,000 cars/day, and 2000 US census block group. We identified deaths through June 2012 using ...
The Genetic Architecture of Diet‐Induced Hepatic Fibrosis in Mice: A Public Health Perspective
Authors: Saumya Pandey
Journal: Hepatology (2018)

To the Editor: The recently published article by Hui et al. emphasizes the public health significance of diet‐induced hepatic fibrosis; the research group elegantly highlighted the sophisticated and high‐throughput genetic analysis of a "humanized" hyperlipidemic mouse model for progressive nonalcoholic steatohepatitis (NASH) and fibrosis.1 A well‐designed study protocol adhering to ethical animal research involving mice carrying transgenes for human apolipoprotein E*3‐Leiden and cholesteryl ester transfer protein was described; briefly, "Western" diet–fed inbred mouse strains (over 100 inbred strains with distinct genetic background) developed significant hepatic inflammation and fibrosis (at approximately 12 weeks with elevated triglyceride levels) with vast differences in the degree of fibrosis as validated by histological analysis with characteristic features of human NASH (macrovesicular steatosis, hepatocellular ballooning, inflammatory foci, and pericellular collagen deposition). A major study strength was accuracy in the complex genetic data sets, with well‐defined genome‐wide association analyses identifying distinct genetic loci contributing to steatosis and NASH; moreover, genetic variation predisposing to NASH and fibrosis differed significantly from that predisposing to simple steatosis, consistent with a multistep model in which distinct genetic factors were involved. I would like to suggest that hepatic expression data from the mouse panel and 68 bariatric surgery patients with normal liver, steatosis, or NASH meaningfully identified enriched biochemical signaling pathways with substantial overlap between the mouse model and human disease; magnetic resonance imaging and computed tomography immunodiagnostic tools coupled with gene epidemiology‐based studies from well‐defined patient population subsets would further provide critical research insights in the cost‐effective management of NASH and hepatic fibrosis in contemporary times. I wish to add that the data appear bias‐free and accurate with appreciable statistical power so as to draw definitive conclusions. Replicative studies with the participation of age‐matched, healthy, disease‐free controls/volunteers of same genetic background/ethnicity as nonalcoholic fatty liver disease/fibrosis cases are warranted for a cost‐effective, strategic public health research model.2 Future translational research strategies targeting interrelated biological pathways and genetic networks in animal models (porcine, equine, murine, bovine, etc.) and clinically confirmed histopathological cases of NASH and fibrosis would certainly aid in identifying predictive biomarkers with subsequent design of pharmacological scaffolds and drug targets in overall disease management for stratification of asymptomatic and symptomatic "at‐risk" disease‐susceptible individuals. Potential conflict of interest Nothing to report.