tbuckley/cabot-search huggingface dataset:
Abstract 837A: Combining CRISPR/Cas9 mutagenesis and a small-molecule inhibitor to probe the function of MELK in cancer
Authors: Christopher J. Giuliano, Ann Lin, Joan C. Smith, Ann C. Palladino, Jason M. Sheltzer
Journal: Cancer Research (2018)

Abstract The Maternal Embryonic Leucine Zipper Kinase (MELK) has been identified as a promising therapeutic target in multiple cancer types. MELK over-expression is associated with aggressive disease, and MELK has been implicated in numerous cancer-related processes, including chemotherapy resistance, stem cell renewal, and tumor growth. Based on these preclinical results, the MELK inhibitor OTS167 is currently being tested as a novel chemotherapy agent in several clinical trials. Here, we report that cancer cell lines harboring CRISPR/Cas9-induced null mutations in MELK exhibit wild-type growth in vitro, under environmental stress, in the presence of cytotoxic chemotherapies, and in vivo. Furthermore, MELK-knockout lines remain sensitive to OTS167, suggesting that this drug blocks cell division through an off-target mechanism. By combining our MELK-knockout clones with a new highly-specific MELK inhibitor, we further demonstrate that the acute inhibition of MELK results in no specific anti-proliferative phenotype. Analysis of gene expression data from cancer patients identifies MELK expression as a correlate of mitotic activity, explaining its association with poor prognosis. In total, our results demonstrate the power of CRISPR/Cas9-based genetic approaches to investigate cancer drug targets, and call into question the rationale for treating patients with anti-MELK monotherapies. Citation Format: Christopher J. Giuliano, Ann Lin, Joan C. Smith, Ann C. Palladino, Jason M. Sheltzer. Combining CRISPR/Cas9 mutagenesis and a small-molecule inhibitor to probe the function of MELK in 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 837A.
Abstract 3366: APOBEC3 family of cytidine deaminases in sensitizing triple-negative breast cancer cells to cisplatin and carboplatin
Authors: Kayla L. Conner, Asra N. Shaik, Jordan White, Wen Lei, Michele L. Cote, Steve M. Patrick
Journal: Cancer Research (2018)

Abstract Cisplatin is a DNA damaging chemotherapeutic which forms interstrand crosslinks (ICL) and intrastrand adducts that induce replication fork collapse and lead to apoptosis. These adduct sites can be repaired through several repair pathways, the most important being nucleotide excision repair (NER). Cisplatin and carboplatin ICLs form a unique structure that forces cytosines flanking the adduct site to become extrahelical. Our lab has previously shown that base excision repair (BER) and mismatch repair (MMR) mediate sensitivity to cisplatin and carboplatin as a consequence of nonproductive processing of DNA flanking the ICL structure. The APOBEC3 (A3) protein family of cytidine deaminases have recently been implicated in cancer development and have potential to deaminate the extrahelical cytosines formed by cisplatin ICLs. Polβ knockdown MDA-MB-231 cells are resistant to cisplatin in vivo compared to wild-type cells (p&amp;lt;0.001). Knockdown of APOBEC3 family members in MDA-MB-231 breast cancer cells results in a resistant phenotype to cisplatin and carboplatin treatment compared to the control. Utilizing CRISPR-Cas9 genome editing, we generated knockouts of A3 members. A3D knockdown in the APOBEC3C (A3C) knockout results in resistance to cisplatin compared to the control, suggesting that multiple A3 enzymes can deaminate the ICL induced extrahelical cytosine. APOBEC3A (A3A) knockdown in a cell line with high expression of A3A (SK-BR-3) shows no difference in cisplatin and carboplatin treatment, suggesting that A3A does not deaminate extrahelical cytosines. Overexpression of A3C or A3D in cell lines with low expression of A3 proteins (SK-BR-3) results in sensitivity to cisplatin. These results together suggest that A3C, A3D, and A3G can deaminate the ICL extrahelical cytosines, resulting in the activation of BER. The subsequent nucleotide misincorporation by Polβ followed by MMR protein binding would physically block NER proteins from repairing the ICL, therefore conferring sensitivity to cisplatin and carboplatin. Citation Format: Kayla L. Conner, Asra N. Shaik, Jordan White, Wen Lei, Michele L. Cote, Steve M. Patrick. APOBEC3 family of cytidine deaminases in sensitizing triple-negative breast cancer cells to cisplatin and carboplatin [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 3366.
A prospective analysis for prevalence of complications in Thai nontransfusion‐dependent Hb E/β‐thalassemia and α‐thalassemia (Hb H disease)
Authors: Supachai Ekwattanakit, Noppadol Siritanaratkul, Vip Viprakasit
Journal: American Journal of Hematology (2018)

Abstract Recently, complications in patients with nontransfusion‐dependent thalassemia (NTDT), in particular those with β‐thalassemia intermedia (β‐TI), were found to be significantly different from those in patients with transfusion dependent thalassemia (TDT), mainly β‐thalassemia major (β–TM). However, this information is rather limited in other forms of NTDT. In this prospective study, adult Thai NTDT patients were interviewed and clinically evaluated for thalassemia related complications. Fifty‐seven NTDT patients (age 18‐74 years), 59.6% Hb E/β‐thalassemia and 40.4% Hb H disease, were recruited; 26.4% were splenectomized. The most common complications were gallstones (68.4%), osteoporosis (26.3%), and pulmonary hypertension (15.8%). Splenectomy was associated with higher rate of gallstones and serious infection ( P = .001 and .052, respectively), consistent with a multivariate analysis (RR = 9.5, P = .044, and RR = 15.1, P = .043, respectively). In addition, a higher hemoglobin level was inversely associated with gallstones in both univariate and multivariate analyses ( P = .01 and .022, respectively). Serum ferritin was associated with abnormal liver function ( P = .002). In contrast to the previous study, the prevalence of thrombosis was less common in our population (1.7%), probably due to differences in transfusion therapy, ethnicity, and underlying genotypes. For the first time, this prospective study provided the current prevalence of NTDT related complications in a Southeast Asian population with a different underlying genetic basis compared with previous studies. Although individual prevalence of each complication might differ from other studies, several important clinical factors such as splenectomy, degree of anemia, and iron overload seem to be determining risks of developing these complications consistently across different ethnicities.
Pulsatility of Ascending Aortic Pressure Waveform Is a Powerful Predictor of Restenosis After Percutaneous Transluminal Coronary Angioplasty
Authors: YasunoriNakayama, KeiTsumura, NaotoshiYamashita, KiyomichiYoshimaru, TomoshigeHayashi
Journal: Circulation (2000)

Background—Because ascending aortic pressure has a greater effect on coronary perfusion during diastole than systole, we hypothesized that a high coronary diastolic-to-systolic pressure ratio prevents coronary lesions from restenosing after percutaneous transluminal coronary angioplasty (PTCA) and that ascending aortic pulsatility relative to mean pressure is higher in patients with restenosis than in those without restenosis. The purpose of this study was to evaluate prospectively whether the morphology of the ascending aortic pressure wave can be used to predict restenosis after PTCA. Methods and Results—We measured the coronary artery diameter and the aortic pressure before PTCA. To quantify the relative magnitude of the pulsatile-to-mean aortic pressure, we normalized the pulse pressure to mean pressure and referred to this value as the fractional pulse pressure (PPf). We prospectively investigated the effect of PPf in relation to subsequent risk of restenosis after PTCA in patients with coronary arte...
Congenital Heart Defects in Europe
Authors: HelenDolk, MariaLoane, EsterGarne
Journal: Circulation (2011)

Background—This study determines the prevalence of Congenital Heart Defects (CHD), diagnosed prenatally or in infancy, and fetal and perinatal mortality associated with CHD in Europe. Methods and Results—Data were extracted from the European Surveillance of Congenital Anomalies central database for 29 population-based congenital anomaly registries in 16 European countries covering 3.3 million births during the period 2000 to 2005. CHD cases (n=26 598) comprised live births, fetal deaths from 20 weeks gestation, and terminations of pregnancy for fetal anomaly (TOPFA). The average total prevalence of CHD was 8.0 per 1000 births, and live birth prevalence was 7.2 per 1000 births, varying between countries. The total prevalence of nonchromosomal CHD was 7.0 per 1000 births, of which 3.6% were perinatal deaths, 20% prenatally diagnosed, and 5.6% TOPFA. Severe nonchromosomal CHD (ie, excluding ventricular septal defects, atrial septal defects, and pulmonary valve stenosis) occurred in 2.0 per 1000 births, of wh...
Abstract 11589: Comorbidity and Medication Use Are Risk Factors of Non-shockable Rhythm in Patients With Out-of-hospital Cardiac Arrest
Authors: Asger Granfeldt, Mads Wissenberg, Steen M Hansen, Christian Torp-Pedersen, Erika F Christensen, Christian F Christiansen
Journal: Circulation (2015)

Introduction: Non-shockable rhythm (NSR) is the most prevalent heart rhythm for both in- and out-of-hospital cardiac arrest (OHCA). While survival from OHCA patients with a shockable rhythm (SR) has increased over time, survival following NSR remains low. Thus, identification of risk factors for NSR is important to reduce mortality. We hypothesize that patients with NSR and SR are two disparate groups where patients with NSR are characterized by a high non-cardiac disease burden when compared to patients with SR. Methods: Using data from the nationwide Danish Cardiac Arrest Registry (2001–2012), we identified 33,617 OHCA patients ≥18 years old. The Danish National Registry of Patients was used to identify comorbidities while the National Prescription Registry was used to identify drug prescriptions (within 180 days). A multivariable logistic regression model was used to estimate odds ratios for risk factors associated with NSR. Results: Patients with NSR were characterized by a higher median age 71 years (IQR 60-81) vs. 67 years (IQR 58-77), higher proportion of women (38% vs. 21%), lower proportion of witnessed collapse (50% vs. 79%) and bystander CPR (27% vs. 50%) than patients with SR. A higher proportion of NSR occurred in private homes (77% vs. 58%) and time from recognition of OHCA to first rhythm analysis was longer: 13 min (IQR 7-22) vs. 9 min (IQR 6-14). In a fully adjusted model (patient-related and cardiac arrest-related characteristics included) a higher degree of comorbidity, psychiatric disease, chronic obstructive lung disease and the use of antidepressants, antipsychotics, anxiolytics, analgesics, corticosteroids, and antibiotics (within 14 days) where associated with NSR (Table). In contrast, the use of cardiovascular specific drugs and history of cardiovascular disease was associated with a lower risk of NSR. Conclusion: A history of non-cardiac disease and non-cardiac drug use are risk factors of NSR when compared to patients with SR.
Abstract 20284: Cardiac Ankyrin Repeat Protein Expression Is Impacted By Ventricular Loading Conditions In Chronic Heart Failure
Authors: Amber Kempton, Ben Canan, Faith Kline, Paul Janssen, Peter J Mohler, Sakima A Smith
Journal: Circulation (2016)

Introduction: Ankyrin repeat domain 1 (ANKRD1), the gene encoding CARP, a transcription co-factor that translocates to the nucleus in response to mechanical stretch, is up-regulated in heart failure (HF). Left Ventricular Assist Devices (LVADs) for end-stage HF unloads the ventricle and reduces wall stress and wall stretch, and could have a direct impact on ANKRD1 expression. Hypothesis: LVAD support will lead to decreased expression of ANKRD1 in heart. Methods: Left ventricular (LV) apical core specimens were acquired at the time of LVAD implantation (pre-LVAD HF samples). LV tissue was also obtained from explanted hearts of patients undergoing heart transplantation at the Ohio State University (post-LVAD samples). Approval for use of human subjects was obtained from the IRB. LV tissue from healthy donor hearts not suitable for transplantation was obtained through Lifeline of Ohio (control non-failure samples). Patients who received LVAD support and had a subsequent transplantation (pre- and post-LVAD sa...
Abstract 298: Low-dose Interleukin-18 is Necessary to Adapt to Pressure Overload in Mice
Authors: IwasakuToshihiro, HirotaniShinichi, EguchiAkiyo, SuminatniNaoki, OkuharaYoshitaka, MorisawaDaisuke, SawadaHisashi, NaitoYoshiro, MasuyamaTohru
Journal: Circulation Research (2014)

Background: We previously reported that circulatory Interleukin-18 (IL-18) level elevates in heart failure (HF) patients. However, the roles of circulatory IL-18 in HF have not been fully elucidated. Continuous infusion of IL-18 induces cardiomyocyte hypertrophy and fibrosis, whereas IL-18 null mice were fragile to pressure overload. We hypothesized that systemic (circulatory) and local (cardiac) IL-18 have distinct effects on HF and cardiac remodeling. Purpose: The purpose of this study was to elucidate the role of circulatory IL-18 in adaptation to pressure overload in IL-18 null mice. Methods: Wild type (WT) mice and IL-18 null (IL-18-/-) were subjected to transaortic constriction (TAC). Sequential serum IL-18 levels myocardial IL-18 mRNA expressions were determined by ELISA and qRT-PCR in WT mice. After two week of TAC, IL-18 null mice were administered either (IP) saline or recombinant IL-18 intraperitoneally (10ng/20g every other day). Cardiac function was assessed by transthoracic echocardiography....
Endothelial Function Predicts Future Development of Coronary Artery Disease
Authors: RaffaeleBugiardini, OliviaManfrini, CarminePizzi, FiorellaFontana, GianluigiMorgagni
Journal: Circulation (2004)

Background— The prognosis for women with chest pain and angiographically normal coronary arteries is believed to be totally benign. Previous studies, however, did not account for the delay of a decade or so in the development of coronary artery disease that women may experience. Methods and Results— This study assessed long-term follow-up of 42 women with de novo angina, evidence of reversible myocardial perfusion defects on SPECT, and normal coronary angiograms. At recruitment, all women underwent endothelial function testing (intracoronary acetylcholine) during catheterization. Patients were followed up for >10 years. Angiography was repeated at the end of the follow-up in 37 patients. At recruitment, 22 patients developed diffuse vasoconstriction during acetylcholine in the absence of identifiable focal coronary spasm (acetylcholine-positive group). The remaining 20 patients showed vasodilation (acetylcholine-negative group). At the end of follow-up, in the acetylcholine-positive group, 1 patient devel...
Abstract 251: Luteolin-mediated increase in miR-26a inhibits prostate cancer cell growth and induces cell cycle arrest targeting EZH2
Authors: Rajnee Kanwal, Stephen Moreton, Daniel Franco, Sanjay Gupta
Journal: Cancer Research (2018)

Abstract Luteolin (3',4',5,7-tetrahydroxyflavone), a flavonoid found in several vegetables and fruits, has been reported to possess anticancer and apoptosis inducing properties. However, the molecular targets of luteolin action are presently unknown. The enhancer of zeste homolog 2 (EZH2) is a catalytic subunit of polycomb repressive complex 2 (PRC2), which catalyzes the trimethylation of histone H3 on Lysine 27 (H3K27) and is involved in chromatin remodeling and gene silencing. EZH2-mediated epigenetic gene silencing plays an important role in several human cancers including prostate neoplasm. Emerging studies demonstrate that miR-26a, a non-coding microRNA, regulates EZH2 expression and is frequently lost during cancer progression. Here we investigated the potential involvement of luteolin-mediated miR-26a upregulation and EZH2 suppression leading to cell cycle arrest and apoptosis in cancer cells. Human prostate cancer DU145 and PC-3 cells, which possess high constitutive EZH2 expression, were treated with 5-20 µM luteolin at various times significantly inhibited EZH2 and H3K27 trimethylation in dose and time dependent manner. Luteolin treatment further resulted in increased expression of miR-26a in both cell lines, as exhibited by EZH2 inhibitor GSK126. Mechanistic investigations revealed that miR-26a overexpression suppressed cell cycle regulatory molecules such as cyclin D and E, cyclin dependent kinases CDK4 and CDK6, and CDK inhibitors p14/ARF, p16/INK4A and p21/WAF1 in EZH2-dependent manner. Interestingly, similar observations were noted in prostate cancer cells with a marked decrease in cyclins and CDKs along with concomitant increase in CDK inhibitors after luteolin treatment resulting in G0/G1 phase cell cycle arrest. In plasma specimens, obtained from healthy individuals, high-risk subjects and prostate cancer patients exhibit a progressive decrease in miR-26a expression. Taken together, our results indicate that miR-26a functions as a growth suppressive miRNA lost in prostate cancer, whereas luteolin is a promising agent which demonstrate anti-proliferative effects mediated by upregulation of miR-26 repressing EZH2 in prostate cancer cells. Citation Format: Rajnee Kanwal, Stephen Moreton, Daniel Franco, Sanjay Gupta. Luteolin-mediated increase in miR-26a inhibits prostate cancer cell growth and induces cell cycle arrest targeting EZH2 [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 251.
Screening for Urinary Incontinence in Women: A Systematic Review for the Women's Preventive Services Initiative
Authors: Heidi D. Nelson, Amy Cantor, Miranda Pappas, Liev Miller
Journal: Annals of Internal Medicine (2018)

Urinary incontinence is infrequently addressed during routine health care despite its high prevalence and adverse effects on health.To evaluate whether screening for urinary incontinence in women not previously diagnosed improves outcomes (symptoms, quality of life, and function) and to evaluate the accuracy of screening methods and potential harms of screening.English-language searches of Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews (1 January 1996 to 30 March 2018); ClinicalTrials.gov (April 2018); and reference lists of studies and reviews.Randomized trials, cohort studies, systematic reviews of studies that enrolled nonpregnant women without previously diagnosed urinary incontinence and compared clinical outcomes and adverse effects between women who were and were not screened, and diagnostic accuracy studies that reported performance measures of screening tests.Dual extraction and quality assessment of individual studies.No studies evaluated the overall effectiveness or harms of screening. Seventeen studies evaluated the diagnostic accuracy of 18 screening questionnaires against a clinical diagnosis or results of diagnostic tests. Of these, 14 poor-quality studies were based in referral clinics, enrolled only symptomatic women, or had other limitations. One good-quality and 2 fair-quality studies (evaluating 4 methods) enrolled women not recruited on the basis of symptoms. Areas under the receiver-operating characteristic curve for stress, urge, and any type of incontinence in these studies were 0.79, 0.88, and 0.88 for the Michigan Incontinence Symptom Index; 0.85, 0.83, and 0.87 for the Bladder Control Self-Assessment Questionnaire; and 0.68, 0.82, and 0.75 for the Overactive Bladder Awareness Tool. The Incontinence Screening Questionnaire had a sensitivity of 66% and specificity of 80% for any type of incontinence.Studies enrolled few participants, often from symptomatic referral populations; used various reference standards; and infrequently reported CIs.Evidence is insufficient on the overall effectiveness and harms of screening for urinary incontinence in women. Limited evidence in general populations suggests fairly high accuracy for some screening methods.Health Resources and Services Administration.
Abstract 17185: Dose-response Gradient Between Levels of Newly Revealed, Asymptomatic Abnormal Ankle-Brachial Index and Clinical Events in Patients With Significant Coronary Artery Disease
Authors: Jong-Young Lee, Hyun Woo Park, Jung-Min Ahn, Won-Jang Kim, Duk-Woo Park, Seung-Whan Lee, Young-Hak Kim, Cheol Whan Lee, Seong-Wook Park, Seung-Jung Park
Journal: Circulation (2013)

Objectives: The aim of the present study was to evaluate dose-association between levels of newly revealed abnormal ankle-brachial index (ABI) and clinical outcomes in patients with significant cor...
Abstract 10363: Cardio-Protective Effects of Pentraxin 3 Produced From Bone Marrow-Derived Cells Against Ischemia/Reperfusion Injury
Authors: Takeshi Shimizu, Satoshi Suzuki, Akihiko Sato, Yuichi Nakamura, Shu-ichi Saitoh, Alberto Mantovani, Tetsuro Shishido, Isao Kubota, Yasuchika Takeishi
Journal: Circulation (2015)

Background: Pentraxin 3 (PTX3), produced in response to inflammatory signals, acts as a humoral arm of the innate immunity. Although a cardio-protective role of PTX3 against myocardial ischemia/reperfusion (I/R) injury has been reported experimentally, the origins of PTX3 functioning for protection of myocardium remain unclear. We examined the role of PTX3 produced from bone marrow (BM)-derived cells in myocardial I/R injury. Methods and Results: PTX3 deficient (PTX3 -/- ) and wild-type littermate (WT) mice were lethally irradiated and injected with BM cells, generating 4 types of mice (WT/WT BM, WT/PTX3 -/- BM, PTX3 -/- /WT BM and PTX3 -/- /PTX3 -/- BM). Six weeks after BM transplantation, the myocardial I/R procedure was performed. Infarct size was greater in WT and PTX3 -/- mice with BM from PTX3 -/- donor (WT/PTX3 -/- BM and PTX3 -/- /PTX3 -/- BM) compared with WT and PTX3 -/- mice with BM from WT donor (WT/WT BM and PTX3 -/- /WT BM) (P&lt;0.05 and P&lt;0.01, respectively). Localization of PTX3 was observed in neutrophils and macrophages in WT and PTX3 -/- mice with BM from WT donor (WT/WT BM and PTX3 -/- /WT BM), while only in endothelial cells in WT mice with BM from PTX3 -/- donor (WT/PTX3 -/- BM). Infiltration of neutrophils and generation of reactive oxygen species (ROS) at ischemic border zones were greater in PTX3 -/- mice with BM from PTX3 -/- donor (PTX3 -/- /PTX3 -/- BM) than PTX3 -/- mice with BM from WT donor (PTX3 -/- /WT BM) (P&lt;0.01 and P&lt;0.01, respectively). Plasma levels and cardiac expressions of IL-6 were higher in PTX3 -/- mice with BM from PTX3 -/- donor (PTX3 -/- /PTX3 -/- BM) than PTX3 -/- mice with BM from WT donor (PTX3 -/- /WT BM) (P&lt;0.05 and P&lt;0.05, respectively). However, no significant differences in infarct size, infiltration of neutrophils, generation of ROS and production of IL-6 were observed between WT and PTX3 -/- mice with BM from WT donor and between WT and PTX3 -/- mice with BM from PTX3 -/- donor. These results indicate that the lack of PTX3 produced from BM-derived cells, but not from cardiac resident cells, contributes to neutrophil infiltration, ROS generation and IL-6 production in response to I/R, resulting in the increment of infarct size. Conclusion: PTX3 produced from BM-derived cells plays a crucial role in cardiac protection against myocardial I/R injury.