tbuckley/cabot-search huggingface dataset:
Loss of p53 Accelerates Neointimal Lesions of Vein Bypass Grafts in Mice
Authors: UrsulaMayr, ManuelMayr, ChaohongLi, FlorianWernig, HermannDietrich, YanhuaHu, QingboXu
Journal: Circulation Research (2002)

The transcription factor p53 is essentially involved in regulation of cell death and proliferation. Recently, we have established a mouse model for vein graft arteriosclerosis by grafting autologous jugular veins or vena cava to carotid arteries. Using this model, we studied the role of p53 in the development of vein graft arteriosclerosis in p53−/− mice. Four weeks after grafting, neointimal hyperplasia of vein grafts in p53−/− mice was increased 2-fold compared with that of wild-type controls. Cell component analysis revealed that neointimal lesions in p53−/− mice consisted mainly of α-actin positive smooth muscle cells (SMCs), whereas the majority of cells in wild-type mice were MAC-1 (CD11b/18)-positive at 4 weeks. Importantly, SMC apoptosis as determined by TUNEL assay was significantly reduced in p53−/− vein grafts. TUNEL positive cells in wild-type vein grafts markedly increased from 0.5% to 6.4% of total cells 4 weeks postoperatively, but remained virtually unchanged in p53−/− grafts (0.8%). Immun...
Abstract 16889: Risk Factors for Bleeding Modify the Impact of CYP2C19 Genetic Test Results on Antiplatelet Drug Selection
Authors: Vindhya B Sriramoju, Nicholas Varunok, Lucius A Howell, Alexandra Cervantes, Melissa J Polasek, George A Stouffer, Craig R Lee
Journal: Circulation (2016)

Introduction: Our institution uses CYP2C19 genotype to enhance precision of antiplatelet drug selection in high risk patients following percutaneous coronary intervention (PCI). However, it is unkn...
Dynamic Electrophysiological Behavior of Human Atria During Paroxysmal Atrial Fibrillation
Authors: AlessandroCapucci, MauroBiffi, GiuseppeBoriani, FlaviaRavelli, GiandomenicoNollo, PaoloSabbatani, CarloOrsi, BrunoMagnani
Journal: Circulation (1995)

Background The aims of our study were to investigate the meaning of local atrial activation and its behavior during paroxysmal atrial fibrillation and to study the effect of overdrive pacing on local atrial activity. Methods and Results Twenty-five patients with lone paroxysmal atrial fibrillation underwent electrophysiological study. Functional and effective atrial refractoriness was determined. Mean and fifth percentile values of 100 consecutive atrial fibrillation intervals (FF) were evaluated at three atrial sites either at arrhythmia onset or at self-termination (or at minute 5). A high-voltage burst pacing was performed after 6 minutes of stable atrial fibrillation in 10 patients. Mean FF intervals were evaluated 5 seconds before and after atrial pacing. Forty-nine atrial fibrillation episodes were induced: 39 self-terminating within 5 minutes and 10 long-lasting. A significant correlation was found between mean FF and atrial functional refractory period (r=.73, P<.001) and between fifth percentile ...
Abstract 20204: CIED Malfunction in Patients Receiving Radiation is a Rare Event That Could Be Detected by Remote Monitoring
Authors: Vikram Samala, Katia Bravo, Genaro Fernandez, Michael J Moravan, Sughosh Dhakal, Abrar H Shah, Mehmet K Aktas
Journal: Circulation (2016)

Introduction: An increasing number of patients with cardiac devices require radiation therapy for treatment of a variety of cancers. The most recent guidelines from 1994 and small studies have tried to address the issue of radiation therapy in patients with cardiac implantable electronic devices (CIED). This study aimed to identify the incidence and predictors of CIED malfunction in a real-world population that has received radiation therapy. Hypothesis: CIED malfunction is a rare event that cannot be predicted by radiation data. Methods: This retrospective cohort study included 110 patients [61 with pacemakers (PM) and 49 with automatic implantable cardioverter defibrillators (AICDs) who received radiation therapy at the University of Rochester. Subjects received either high energy (16MV) and/or low energy (6MV) photon beams with or without electron beams (6-16 MeV). We included interrogations done from 1st day of radiation and up to three months post-radiation therapy. Outcomes analyzed were device-rela...
Remnant Lipoproteins Induce Proatherothrombogenic Molecules in Endothelial Cells Through a Redox-Sensitive Mechanism
Authors: HidekiDoi, KiyotakaKugiyama, HidekiOka, SeigoSugiyama, NobuhikoOgata, Shun-ichiKoide, Shin-ichiNakamura, HirofumiYasue
Journal: Circulation (2000)

Background—Triglyceride-rich lipoproteins (TGLs) are atherogenic. However, their cellular mechanisms remain largely unexplained. This study examined the effects of isolated remnant-like lipoprotein particles (RLPs) on the expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and tissue factor (TF), proatherothrombogenic molecules, in cultured human endothelial cells. Methods and Results—RLPs were isolated from plasma of hypertriglyceridemic patients by use of the immunoaffinity gel mixture of anti–apoA-1 and anti–apoB-100 monoclonal antibodies. The incubation of cells with RLPs significantly upregulated mRNA and protein expression of these molecules. Total TGLs (d<1.006) and LDL had fewer or minimal effects on expression of these molecules compared with RLPs. RLPs increased intracellular oxidant levels, as assessed with an oxidant-sensitive probe. Combined incubation with α-tocopherol or N-acetylcysteine, both antioxidants, suppressed RLP-induced increase in...
Abstract IA20: Therapeutic targeting of ARID1A mutation in ovarian cancer
Authors: Rugang Zhang
Journal: Clinical Cancer Research (2018)

Abstract SWI/SNF chromatin remodeling complexes regulate gene transcription by changing chromatin structure through hydrolyzing ATP. Cancer genome sequencing found that mutations in genes encoding for the subunits of the SWI/SNF complexes collectively occur in ~20% of all human cancers. For example, saturation analysis of The Cancer Genome Atlas (TCGA) cancer mutational profile reveals that the ARID1A subunit of the SWI/SNF complex shows one of the highest mutation rates among epigenetic regulators. Most notably, ARID1A is mutated in over 50% of ovarian clear cell carcinomas and 30% of ovarian endometrioid carcinomas. ARID1A mutation is a known genetic driver of ovarian cancer. Over 90% of the ARID1A mutations observed in ovarian cancer are frame-shift or nonsense mutations that result in loss of ARID1A protein expression. Loss of ARID1A correlates with late-stage disease and predicts early recurrence of ovarian clear cell carcinoma. Ovarian clear cell carcinoma ranks second as the cause of death from epithelial ovarian cancer and is associated with the worst prognosis among the major ovarian cancer subtypes when diagnosed at advanced stages. Additionally, for advanced-stage disease, there is currently no effective therapy. Here we will discuss emerging opportunities for therapeutic targeting of ARID1A mutation based on the genetic makeup of ARID1-mutated ovarian cancer with precision. They include synthetic lethality, the mutual exclusivity between ARID1A and TP53 mutations in ovarian cancer, and mechanism-guided combinatory approaches. Citation Format: Rugang Zhang. Therapeutic targeting of ARID1A mutation in ovarian cancer. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr IA20.
Adrenomedullin, an Endogenous Peptide, Counteracts Cardiovascular Damage
Authors: TatsuoShimosawa, YugoShibagaki, KotaroIshibashi, KazuoKitamura, KenjiKangawa, ShigeakiKato, KatsuyukiAndo, ToshiroFujita
Journal: Circulation (2002)

Background— Adrenomedullin (AM), a potent vasodilator peptide, is produced by posttranslational splicing of pro-adrenomedullin together with proadrenomedullin N-terminal 20 peptide (PAMP), another hypotensive peptide. Although both AM and PAMP have the potential not only to decrease blood pressure but also to protect organs from damage, there is no direct evidence for their individual physiological roles in vivo. Methods and Results— Using knockout mice with the disruption of AM peptide alone, we investigated the organ-protective effect of AM. Although the AM−/− mutation in mice was embryonic lethal without any apparent phenotypic changes, AM+/− mice were viable and fertile; plasma and organ AM concentrations were almost half of those in AM+/+ mice. With the administration of angiotensin II (Ang II) on a high-salt diet for 12 days, marked perivascular fibrosis and intimal hyperplasia were found in coronary arteries of Ang II/salt–treated AM+/− mice, without the AM upregulation that was observed in Ang II/...
Abstract 10979: ACE-inhibitor or ARB Therapy Reduces the Risk for GI Bleeding in LVAD Patients
Authors: Brian A Houston, Joban Vaishnav, Andrea L Schneider, P. E Miller, Kamil Faridi, Ashish Shah, Chris Sciortino, Gerin R Stevens, Ryan J Tedford, Daniel Judge, Rosanne Rouf, Stuart D Russell
Journal: Circulation (2015)

Introduction: Gastrointestinal bleeding (GIB) due to arteriovenous malformations (AVMs) is a major source of morbidity for patients supported with left ventricular assist devices (LVADs). Recent studies implicate angiogenesis mediated by vascular endothelial growth factor (VEGF) in AVM formation. Transforming growth factor-β is biochemically upstream of VEGF and is up-regulated after LVAD implantation. Angiotensin converting enzyme inhibitors (ACE-inhibitors) and angiotensin receptor blockers (ARBs) inhibit TGF-β. Hypothesis: ACE-inhibitor/ARB therapy will be independently associated with a reduced risk of GIB overall and GIB due to AVMs in LVAD patients. Methods: We reviewed the records of all patients aged 18 years or older receiving a continuous flow LVAD (HeartMate II or Heartware) at Johns Hopkins Hospital from 1/2004 to 9/2013 (n=186). We excluded patients for whom follow-up records were not available (n=3), those supported with a LVAD for less than 100 contiguous days (n=51), and those missing covariates included in statistical models (n=8), leaving 124 patients included for analyses. Cox proportional hazards models adjusted for demographic, cardiovascular, and laboratory variables were used to assess the association of ACE-inhibitor/ARB therapy with GIB. Results: Mean age of patients was 52 years and 75% were male. Ninety-seven patients received ACE-inhibitor and/or ARB therapy during LVAD support. Thirty-six patients (29%) had at least one GIB after discharge from their LVAD implantation; 15 of these 36 episodes (42%) were due to confirmed AVMs. Among ACE/ARB patients, 24% had a post-discharge GIB (23/97) versus 48% (13/27) of non-ACE/ARB patients. Fully adjusted Cox proportional hazards model demonstrated that ACE-inhibitor/ARB therapy was independently associated with a reduced risk of GIB after hospital discharge (HR 0.37, 95% CI 0.17-0.81, p=0.012) with suggestion of reduced risk of GIB due to AVMs (HR 0.32, 95% CI 0.10-1.06, p=0.06). Conclusions: ACE-inhibitor and ARBs are independently associated with a reduced risk of GIB in LVAD patients and should be considered for all LVAD patients without contraindications. Possible biologic mechanisms of this observation remain unexplored and warrant further investigation.
Abstract 1941: Constitutive IRAK4 activation contributes to NF-κB activity and chemoresistance in colorectal cancer
Authors: Qiong Li, Lin Li, Daoxiang Zhang, Hongmei Jiang, Andrea Wang-Gillam, Marianna B. Ruzinova, Kian-Huat Lim
Journal: Cancer Research (2018)

Abstract Aberrant activation of the NF-κB transcription factors is a major molecular mechanism that contributes to the aggressive behavior and treatment resistance of colorectal cancer (CRC). Understanding how these factors are activated will provide novel therapeutic opportunities to improve treatment response and outcome of CRC patients. In the present study, we showed that the Interleukin-1 Receptor-Associated Kinases 1 and 4 (IRAK1 and IRAK4) are constitutively activated by phosphorylation in a majority of CRC cell lines and patients samples. Notably, we observe significant positive correlation between phospho-IRAK4 and phospho-NF-kb/p65 staining by immunohistochemistry in patient CRC samples. Moreover, we showed that pharmacologic IRAK4 inhibitors dose-dependently suppressed phosphorylated -IRAK1, -IRAK4 and -IKKa/b by western blots, as well as significantly reducing NF-κB-driven luciferase activity in CRC cells. Furthermore, IRAK4 inhibitor dose dependently inhibit colony formation and anchorage-independent (AI) growth of CRC cells in soft agar. In three CRC cell lines, we observed various degrees of synergism between IRAK4 inhibitors and each chemotherapeutic agents including 5-FU, oxaliplatin and irinotecan, mainly through induction of apoptosis. Lastly, we showed that IRAK4 inhibitor augments the therapeutic effect of 5-FU and oxaliplatin in nude mice bearing CRC xenografts. Together, our data established IRAK4 kinase inhibitors as a promising novel class of targeted agent in CRC. Citation Format: Qiong Li, Lin Li, Daoxiang Zhang, Hongmei Jiang, Andrea Wang-Gillam, Marianna B. Ruzinova, Kian-Huat Lim. Constitutive IRAK4 activation contributes to NF-κB activity and chemoresistance in colorectal 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 1941.
Opioid Use Disorder Documented at Delivery Hospitalization — United States, 1999–2014
Authors: Sarah C. Haight, Jean Y. Ko, Van T. Tong, Michele K. Bohm, William M. Callaghan
Journal: MMWR Morbidity and Mortality Weekly Report (2018)

Opioid use by pregnant women represents a significant public health concern given the association of opioid exposure and adverse maternal and neonatal outcomes, including preterm labor, stillbirth, neonatal abstinence syndrome, and maternal mortality (1,2).State-level actions are critical to curbing the opioid epidemic through programs and policies to reduce use of prescription opioids and illegal opioids including heroin and illicitly manufactured fentanyl, both of which contribute to the epidemic (3).Hospital discharge data from the 1999-2014 Healthcare Cost and Utilization Project (HCUP) were analyzed to describe U.S. national and state-specific trends in opioid use disorder documented at delivery hospitalization.Nationally, the prevalence of opioid use disorder more than quadrupled during 1999-2014 (from 1.5 per 1,000 delivery hospitalizations to 6.5; p<0.05).Increasing trends over time were observed in all 28 states with available data (p<0.05).In 2014, prevalence ranged from 0.7 in the District of Columbia (DC) to 48.6 in Vermont.Continued national, state, and provider efforts to prevent, monitor, and treat opioid use disorder among reproductive-aged and pregnant women are needed.Efforts might include improved access to data in Prescription Drug Monitoring Programs, increased substance abuse screening, use of medication-assisted therapy, and substance abuse treatment referrals.Data were analyzed from the National Inpatient Sample (NIS; 1999-2014) and the State Inpatient Databases (SID; 1999-2014) of HCUP, Agency for Healthcare Research and Quality (4).NIS approximates a 20% stratified sample of all U.S. community hospital discharges participating in HCUP and is weighted to be nationally representative.Survey-specific analysis techniques were used to account for clustering, stratification, and weighting in NIS analyses (4).The SID contain state-specific data on hospital inpatient stays, regardless of payer; 30 states and DC had publically available data (Table ).
Restrictive Mitral Annuloplasty With or Without Surgical Ventricular Restoration in Ischemic Dilated Cardiomyopathy With Severe Mitral Regurgitation
Authors: YasuhiroShudo, KazuhiroTaniguchi, KojiTakeda, TaichiSakaguchi, ToshihiroFunatsu, HajimeMatsue, ShigeruMiyagawa, HaruhikoKondoh, SatoshiKainuma, KojiKubo, SeikiHamada, HironoriIzutani, YoshikiSawa
Journal: Circulation (2011)

Background—We assessed changes in left ventricular (LV) volume and function and in regional myocardial wall stress in noninfarcted segments after restrictive mitral annuloplasty (RMA) with or without surgical ventricular restoration (SVR). Methods and Results—Thirty-nine patients with ischemic cardiomyopathy (ejection fraction ≤0.35) and severe mitral regurgitation (≥3) were studied before and 2.8 months after surgery with cine-angiographic multidetector computed tomography (cine-MDCT). Eighteen underwent RMA alone (RMA group) and 21 underwent RMA and SVR (RMA+SVR group). In addition to measuring conventional parameters (LV end-diastolic volume index [LVEDVI], LV end-systolic volume index [LVESVI], and LV ejection fraction), we evaluated the regional circumferential end-systolic wall stress and mean circumferential fiber shortening in both the basal and mid-LV regions using 3-dimensional cine-MDCT images. LV end-diastolic and end-systolic volume indexes were significantly greater in the RMA+SVR group than...
Enhanced Survival of Transplanted Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes by the Combination of Cell Sheets With the Pedicled Omental Flap Technique in a Porcine Heart
Authors: MasashiKawamura, ShigeruMiyagawa, SatsukiFukushima, AtsuhiroSaito, KenjiMiki, EmikoIto, NagakoSougawa, TakujiKawamura, TakashiDaimon, TatsuyaShimizu, TeruoOkano, KoichiToda, YoshikiSawa
Journal: Circulation (2013)

Background—Transplantation of cardiomyocytes that are derived from human induced pluripotent stem cell–derived cardiomyocytes (hiPS-CMs) shows promise in generating new functional myocardium in situ, whereas the survival and functionality of the transplanted cells are critical in considering this therapeutic impact. Cell-sheet method has been used to transplant many functional cells; however, potential ischemia might limit cell survival. The omentum, which is known to have rich vasculature, is expected to be a source of blood supply. We hypothesized that transplantation of hiPS-CM cell sheets combined with an omentum flap may deliver a large number of functional hiPS-CMs with enhanced blood supply. Methods and Results—Retrovirally established human iPS cells were treated with Wnt signaling molecules to induce cardiomyogenic differentiation, followed by superparamagnetic iron oxide labeling. Cell sheets were created from the magnetically labeled hiPS-CMs using temperature-responsive dishes and transplanted...
Abstract 5588: Uneven distribution of CTCs in magnetic fields following binding with iron nanoparticles
Authors: Chengsen Xue, Christina D. Swenson, Thomas W. Mc Closkey
Journal: Cancer Research (2018)

Abstract Circulating tumor cell (CTC) detection and characterization have recently become an integral part of precision medicine. Several large, multicenter clinical studies confirmed that the prevalence of CTC is a useful predictor of treatment efficacy in metastatic breast cancer. The number of CTCs is strongly correlated with clinical progression. Oncology clinics widely use this biomarker to provide prognostic information. There are several platforms to isolate and measure CTCs. The only FDA-approved method is the CellSearch system developed by Veridex. The CellSearch System uses anti-EpCAM antibodies and polymer-coated iron nanoparticles in order to isolate CTC with the use of a magnetic field. The enriched CTC fraction is then placed in a MagNest chamber and the transparent slide is read by the automatic fluorescent CellTracks Analyzer. By using prelabeled breast cancer cells as quality control (QC) samples, we semiquantitated the distribution of CTC cells on slides in eleven QC samples. We found that CTC cells distribute unevenly on the slides. In order to count all CTCs, the whole area of the slide is divided into 175 small regions by the manufacturer. To better quantitate the CTC number, it is important to have all cells evenly spread over the slide. Our results showed that 41 out of 175 regions contained higher QC CTC counts. The heat map indicates that the magnetic field lines may have an effect on CTC localization. The CTC platforms are susceptible for underestimating actual CTC counts. Our findings indicate that cell concentration in certain regions caused by a magnetic field effect could be one of several contributing factors. Citation Format: Chengsen Xue, Christina D. Swenson, Thomas W. Mc Closkey. Uneven distribution of CTCs in magnetic fields following binding with iron nanoparticles [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 5588.
Reoxygenation of Hypoxic Coronary Smooth Muscle Cells Amplifies Growth-Retarding Effects of Ionizing Irradiation
Authors: AminaArab, ThorstenGrumann, RolandGuttenberger, ChristophBode, ChristophHehrlein
Journal: Circulation (2004)

Background— Hypoxic human coronary smooth muscle cells (HCSMCs) are possible targets for brachytherapy to prevent restenosis after percutaneous transluminal coronary angiography. It is unclear whether growth kinetics and gene expression of these cells undergoing γ-irradiation are changed by reoxygenation. Methods and Results— Hypoxic (H) and hypoxia-reoxygenated (H-R) HCSMCs were irradiated with γ-radiation at single doses of 4, 8, and 16 Gy using a 60Co-source. Vascular endothelial growth factor gene expression of HCSMCs was dramatically suppressed in H-R versus H cells independent of the radiation dose (15±7% versus 2183±2023%, P<0.01, H-R versus H cells). An oxygen enhancement ratio of 1.8 was calculated after irradiation from the retarded growth of H-R versus hypoxic HCSMCs. Production of reactive oxygen species by HCSMCs after irradiation increased by 15±2% in H-R cells versus 7±1% in H cells (P<0.05). Conclusions— Reoxygenation of hypoxic HCSMCs markedly amplifies growth-retarding effects of ionizin...
Wnt3a Regulates the Development of Cardiac Neural Crest Cells by Modulating Expression of Cysteine-Rich Intestinal Protein 2 in Rhombomere 6
Authors: XiaojingSun, RuilinZhang, XueyingLin, XiaoleiXu
Journal: Circulation Research (2008)

The cardiac neural crest is a subpopulation of neural crest cells (NCCs) that originates from the dorsal neural tube and later migrates to the heart and pharyngeal arch (PA), where they contribute to distinct aspects of cardiogenesis and PA patterning. Wnt family members have been implicated in general neural crest induction; however, the molecular mechanisms underlying the specification of distinct cell types such as cardiac NCCs remain unclear. Here, we have identified cysteine-rich intestinal protein 2 (crip2), a gene encoding for a LIM domain–containing protein, as a novel marker for cardiac NCCs in zebrafish. We observed a dynamic expression pattern for crip2, with expression being detected in the premigratory NCCs in rhombomere 6 (r6), migrating NCCs, ventricular cardiomyocytes, and aortic vessels in PAs 3 to 6. Interestingly, expression of wnt3a was detected in regions of the dorsal neural tube encompassing r6, and reduction of wnt3a led to disrupted expression of crip2 in r6, abnormal migration of...