tbuckley/cabot-search huggingface dataset:
Abstract 9420: Detection Of No-Reflow Phenomenon by Three-Dimensional (3D) Myocardial Contrast Echocardiography in Patients with Acute Myocardial Infarction
Authors: Katsuomi Iwakura, Atsunori Okamura, Yasushi Koyama, Motoo Date, Yoshiharu Higuchi, Koichi Inoue, Ryusuke Kimura, Hiroyuki Nagai, Yuko Toyoshima, Makito Ozawa, Shigemiki Omiya, Daisuke Morisawa, Takashi Takagi, Masaharu Masuda, Shimpei Nakatani, Yohei Sotomi, Kenshi Fujii
Journal: Circulation (2011)

Backgrounds: No-reflow phenomenon observed after percutaneous coronary intervention (PCI) determines clinical and functional outcomes in patients with acute myocardial infarction (AMI). Myocardial contrast echocardiography (MCE) is one of the established methods to detect no-reflow after AMI. However, MCE using 2D echocardiography has only limited view of left ventricle, and it might evaluate myocardial perfusion inappropriately. We investigated the feasibility of MCE using three-dimensional echocardiography (3D-MCE) to assess myocardial perfusion after AMI. Methods and Results: We performed MCE study in 50 patients with AMI 15 minutes after successful primary PCI, using iE33 (Philips Medical Systems). We injected 3 mL of sonicated contrast agent containing microbubbles into a culprit coronary artery, and recorded an apical 2D-MCE image. Then, we recorded a full-volume 3D-MCE image with another injection of contrast agent. We obtained 7 short axis (SAX) images from one 3D data set, as shown in Figure. Myocardial perfusion in each segment was scored as good=0, poor=1, no-reflow=2, and sum of the score was calculated as a perfusion defect (PD) score. We determined ejection fraction (EF) and wall motion score index (WMSI), as an average of segmental score (0=normokinesis to 4=dyskinesis), on echocardiography recorded at 7.4±4.6 month later. Myocardial perfusion was successfully evaluated in 673/767 (87.7%) segments within risk area in SAX images on 3D-MCE. PD score in 2D-MCE showed no correlation with CK-MB (R 2 =0.08, p=0.06), EF (R 2 =0.03, p=0.26) and WMSI (R 2 =0.04, p=0.19) on follow-up echocardiography. On the other hand, PD score on 3D-MCE was significantly correlated with CK-MB (R 2 =0.56, p&lt;0.0001), WMSI (R 2 =0.40, p&lt;0.0001). It was also weakly but significantly correlated with EF (R 2 =0.10, p=0.02). Conclusions: 3D-MCE detected no-reflow after PCI and predicted functional recovery in patients with AMI more precisely than 2D-MCE.
Abstract 4667: The use of fragment-based screening approaches to improve the specificity of inhibitors targeting malignant melanoma
Authors: Sreya Mukherjee, Shardell Spriggs, Paul Wilder, Wenbo Yu, Kristen Varney, Alexander D. MacKerell, David J. Weber
Journal: Cancer Research (2018)

Abstract S100B belongs to the S100 protein family of Ca2+-binding proteins. Prior studies have shown that S100B is a biological marker for malignant melanoma. Increases in S100B levels are predictive of disease progression, recurrence, and overall low survival in the patients. It was shown previously that S100B binds to p53 and down-regulates its tumor suppression activities including growth arrest and apoptosis. Chemical biology and structure-based drug design methods are underway to inhibit S100B and restore p53 function. However, highly specific S100B inhibitors are required, so S100B can be blocked in melanoma without impairing S100A1 function in skeletal and cardiac muscle. With this goal in mind, a fragment-based screening approach using NMR and computational approaches is being applied. Results to date indicate that these methods can be used to identify specific small molecule fragments that target S100B and not S100A1. The fragments that uniquely bind S100B will then be considered with structural data of existing S100B-SBiX complexes to improve their specificity for binding S100B (i.e. versus S100A1). The inhibitor design strategy will also include improving the stability of the compounds their cell permeability, and their overall drug-like properties. The most promising of these new inhibitors will ultimately be used to target high levels of S100B found in malignant and rescue p53-dependent tumor suppression pathways in vivo with the goal of them having therapeutic value for treating malignant melanoma. Citation Format: Sreya Mukherjee, Shardell Spriggs, Paul Wilder, Wenbo Yu, Kristen Varney, Alexander D. MacKerell, David J. Weber. The use of fragment-based screening approaches to improve the specificity of inhibitors targeting malignant melanoma [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 4667.
Low-level ozone has both respiratory and systemic effects in African American adolescents with asthma despite asthma controller therapy
Authors: Michelle L. Hernandez, Radhika Dhingra, Allison J. Burbank, Krista Todorich, Ceila E. Loughlin, Marcia Frye, Kelly Duncan, Carole Robinette, Katherine Mills, Robert B. Devlin, David B. Peden, David Diaz-Sanchez
Journal: Journal of Allergy and Clinical Immunology (2018)
The Efficacy of Tenofivir to Prevent Perinatal Transmission in Chronic Hepatitis B Mothers. A Clinical Perspective
Authors: Ghassan Mubarak, Richard Ferstenberg
Journal: Hepatology (2018)

To the Editor: With great satisfaction, we read the April 2018 American Association for the Study of Liver Diseases (AASLD) guidelines for the management of chronic hepatitis B propose that pregnant women with hepatitis B virus (HBV) receive tenofovir in the third trimester, for viral loads greater than 200,000 IU/mL.1 Surprisingly, the first double‐blinded, randomized, controlled trial on this subject, released in the March 8 issue of the New England Journal of Medicine, found no significant difference between fetal viral loads of a group of 147 women who received tenofovir beginning at 28 weeks and those of a control group who did not. The researchers concluded that there was no benefit to prescribing tenofovir in the third trimester of pregnancy.2 These results contrast with the thinking that the AASLD has carefully substantiated and cultivated in the hepatology community in recent years. The conclusion reached by the researchers of this study is counterintuitive, because 3 patients in their placebo group developed hepatitis B, whereas none in the treated group became infected. It is noteworthy that the mothers of all 3 infected infants in the treated group had HBV‐DNA levels of more than 7.8 log10 IU/mL. Such high viral loads may well be refractory to antiviral rescue during pregnancy. However, there are certainly a substantial number of mothers with viral loads somewhere between 200,000 and 1 million who can benefit from tenofovir. This particular trial simply cannot define the most precise group of potential beneficiaries. A randomized, open‐label trial published in 2016 studied 200 mothers with viral loads greater than 200,000 IU/mL and concluded that the rate of mother‐to‐child transmission was lower among those who received tenofovir disoproxil fumarate therapy than among those who received care without antiviral therapy. The researchers endorsed the use of tenofovir as outlined in the recent AASLD guidelines. We are not told viral loads of the mothers of tenofovir failures in this 2016 study, but it is possible that these mothers had initial viral loads that were several orders of magnitude greater than other viremic mothers who may have responded.3 It is therefore not reasonable to conclude from the March 2018 controlled trial that tenofovir is of no benefit to mothers with viral loads greater than 200,000 IU/mL. There may be, however, a higher threshold beyond which tenofovir will no longer do the job. For the time being, the new AASLD guidelines must be followed. Perhaps, in the future, there will be a more potent antiviral agent that can eradicate much higher viral loads during pregnancy. Potential conflict of interest Nothing to report.
Tumor Mutation Burden as a Biomarker in Resected Non–Small-Cell Lung Cancer
Authors: Siddhartha Devarakonda, Federico Rotolo, Ming-Sound Tsao, Irena Lanc, Elisabeth Brambilla, Ashiq Masood, Ken A. Olaussen, Robert Fulton, Shingo Sakashita, Anne McLeer-Florin, Keyue Ding, Gwénaël Le Teuff, Frances A. Shepherd, Jean-Pierre Pignon, Stephen L. Graziano, Robert Kratzke, Jean-Charles Soria, Lesley Seymour, Ramaswamy Govindan, Stefan Michiels
Journal: Journal of Clinical Oncology (2018)

The survival benefit with adjuvant chemotherapy for patients with resected stage II-III non-small-cell lung cancer (NSCLC) is modest. Efforts to develop prognostic or predictive biomarkers in these patients have not yielded clinically useful tests. We report findings from the Lung Adjuvant Cisplatin Evaluation (LACE)-Bio-II study, in which we analyzed next-generation sequencing and long-term outcomes data from > 900 patients with early-stage NSCLC treated prospectively in adjuvant landmark clinical trials. We used a targeted gene panel to assess the prognostic and predictive effect of mutations in individual genes, DNA repair pathways, and tumor mutation burden (TMB).
Abstract 2887: Evaluating the effectiveness of MAPK, AKT, and mTOR inhibitors in reducing proliferation in cellular models of papillary and follicular thyroid cancer
Authors: Brianna LeBoeuf, Braxton Anderson, Margaret Young, Aime Franco, Laura MacDonald
Journal: Cancer Research (2018)

Abstract Thyroid cancer is the most common endocrine malignancy, and incidence has been steadily increasing, suggesting occurrence will exceed that of colon cancer by 2030. Papillary and follicular thyroid cancer subtypes are most common, which are activated by BRAF and HRAS mutations, respectively. Interestingly, papillary and follicular thyroid cancers are associated with different pathologies and metastases. Currently, both papillary and follicular thyroid cancers are treated by surgical removal of the thyroid, followed by radioactive iodine treatment to eliminate any remaining tumor cells. Unfortunately, for individuals with progressive thyroid cancer, these treatment options are not effective, highlighting a need for increased investigation into mechanisms of drug sensitivity. In this study, we sought to evaluate mechanisms of differential drug sensitivity through RNA-seq analysis of cell lines derived from mouse models of papillary and follicular thyroid cancer. Additionally, we evaluated the effects of MAPK, AKT, and mTOR inhibitors on murine papillary and follicular thyroid cancer cell proliferation. To accurately assess drug efficacy, we calculated GR50 concentrations for each inhibitor in six papillary and follicular thyroid cancer cell lines. We discovered that papillary and follicular thyroid cancer cell lines responded differently to MAPK and AKT inhibitors, suggesting that treatment approaches should be tailored to subtype despite having mutations in the same signaling pathway. Citation Format: Brianna LeBoeuf, Braxton Anderson, Margaret Young, Aime Franco, Laura MacDonald. Evaluating the effectiveness of MAPK, AKT, and mTOR inhibitors in reducing proliferation in cellular models of papillary and follicular thyroid 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 2887.
Platelet-Derived Nitric Oxide Signaling and Regulation
Authors: EugeniaGkaliagkousi, JamesRitter, AlbertFerro
Journal: Circulation Research (2007)

Nitric oxide (NO) exerts important vasodilatory, antiplatelet, antioxidant, antiadhesive, and antiproliferative effects. Although endothelium derived NO has been shown to be of prime importance in cardio- and vasculoprotection, until recently little was known about the role of platelet-derived NO. New evidence suggests that NO synthesized by platelets regulates platelet functions, in particular suppressing platelet activation and intravascular thrombosis. Moreover, platelet NO biosynthesis may be decreased in patients with cardiovascular risk factors or with coronary heart disease, and this may contribute to arterial thrombotic disease in these patients. Here, we review the current state of knowledge as regards the role of platelet-derived NO, both in normal physiology and in cardiovascular disease states, and compare platelet NO signaling and regulation with that in endothelial cells.
Angiotensin II Type 2 Receptor Is Upregulated in Human Heart With Interstitial Fibrosis, and Cardiac Fibroblasts Are the Major Cell Type for Its Expression
Authors: YoshiakiTsutsumi, HiroakiMatsubara, NaohikoOhkubo, YasukiyoMori, YoshihisaNozawa, SatoshiMurasawa, KazuhisaKijima, KatsuyaMaruyama, HiroyaMasaki, YasutakaMoriguchi, YasunobuShibasaki, HiroshiKamihata, MitsuoInada, ToshijiIwasaka
Journal: Circulation Research (1998)

Abstract—The expression pattern of angiotensin (Ang) II type 2 receptor (AT2-R) in the remodeling process of human left ventricles (LVs) remains poorly defined. We analyzed its expression at protein, mRNA, and cellular levels using autopsy, biopsy, or operation LV samples from patients with failing hearts caused by acute (AMI) or old (OMI) myocardial infarction and idiopathic dilated cardiomyopathy (DCM) and also examined functional biochemical responses of failing hearts to Ang II. In autopsy samples from the nonfailing heart group, the ratio of AT1-R and AT2-R was 59% and 41%, respectively. The expression of AT2-R was markedly increased in DCM hearts at protein (3.5-fold) and mRNA (3.1-fold) levels compared with AMI or OMI. AT1-R protein and mRNA levels in AMI hearts showed 1.5- and 2.1-fold increases, respectively, whereas in OMI and DCM hearts, AT1-R expression was significantly downregulated. AT1-R–mediated response in inositol phosphate production was significantly attenuated in LV homogenate from f...
Abstract 17132: Characteristics, Therapeutic Efficacy, and Clinical Implications of Ventricular Tachycardias Detected Early After Implant of Continuous-flow Left Ventricular Assist Device
Authors: Janice YChyou, WilliamWhang, JoseDizon, AngeloBiviano, HasanGaran, YoshifumiNaka, PaoloColombo, Arthur RGaran
Journal: Circulation (2016)

Introduction: Ventricular tachycardias (VTs) frequently occur early after implant of continuous-flow left ventricular assist device (LVAD). Efficacy and optimal programming of implantable cardioverter-defibrillator (ICD)-based therapies in this population are not well understood. We aimed to assess the characteristics, ICD efficacy, and clinical implications of ICD-detected VTs within 30 days after LVAD implant. Methods: Thirty-four patients, of 160 consecutive patients who received first LVAD implant at our institution between January 1, 2012 and March 1, 2014, had VTs within 30 days after LVAD implant. Of these, 21 patients had ICD intracardiac electrograms of ICD-treated VTs within 30 days after LVAD implant and were included in this study. Results: There were 28 ICD-treated VTs in 21 study subjects (age 63±11 years, 76% male, 24% ischemic, 76% with prior VT). Most VTs (82%) were monomorphic. A minority (11%) of VTs initiated with short-long-short sequence; the remaining initiated with a single prematu...
Lung cancer staging: imagine fewer images
Authors: Ivan Vollmer, Marcelo Sánchez, Ramón Rami-Porta
Journal: European Respiratory Journal (2018)

We would like to thank K.G. Tournoy and J.P. Van Meerbeeck for their interest in our article [1]. In their letter, they raise important points that highlight the controversy surrounding the value of preoperative brain magnetic resonance imaging (MRI) in patients who can be considered for curative therapeutic option. We agree with them that accurate staging is essential for an optimal outcome. Brain imaging with MRI is recommended for all lung cancer patients candidates for radical treatment <http://ow.ly/FkgL30l6b6o>
Sex Differences in Authorship of Academic Cardiology Literature Over the Last 2 Decades
Authors: Mariam Asghar, Muhammad Shariq Usman, Rafi Aibani, Hamza Tahir Ansari, Tariq Jamal Siddiqi, Kaneez Fatima, Muhammad Shahzeb Khan, Vincent M. Figueredo
Journal: Journal of the American College of Cardiology (2018)
Assessment of Atrioventricular Junction Ablation and VVIR Pacemaker Versus Pharmacological Treatment in Patients With Heart Failure and Chronic Atrial Fibrillation
Authors: MicheleBrignole, CarloMenozzi, LorellaGianfranchi, GiacomoMusso, RobertoMureddu, NicolaBottoni, GinoLolli
Journal: Circulation (1998)

Background—Uncontrolled studies have suggested that atrioventricular junction ablation and pacemaker implantation have beneficial effects on quality of life in patients with chronic atrial fibrillation (AF). Methods and Results—We performed a multicenter, controlled, randomized, 12-month evaluation of the clinical effects of atrioventricular junction ablation and VVIR pacemaker (Abl+Pm) versus pharmacological (drug) treatment in 66 patients with chronic (lasting >6 months) AF who had clinically manifest heart failure and heart rate >90 bpm on 3 standard ECGs recorded at rest during stable clinical conditions on different days. Before completion of the study, withdrawals occurred in 8 patients of the drug group and in 4 patients of the Abl+Pm group. At the end of the 12 months, the 28 Abl+Pm patients who completed the study showed lower scores in palpitations (−78%; P=0.000) and effort dyspnea (−22%; P=0.05) than the 26 of the drug group. Lower scores, although not significant, were also observed for exerc...
Abstract 3348: The role of SOX2 in promoting resistance to AR-targeted therapies in prostate cancer
Authors: Larischa de Wet, Anthony Williams, Marc Gillard, Steve Kregel, Tzintzuni Garcia, Erin McAuley, Ryan Brown, Donald Vander Griend
Journal: Cancer Research (2018)

Abstract Prostate cancer is the most common type of cancer in men, with approximately 181,000 new cases diagnosed in 2016. Due to the central role of the androgen receptor (AR) in prostate development and more importantly prostate cancer cell survival and proliferation, strategies targeting AR have been the mainstay therapy for over 70 years. However, despite potent inhibition of AR pathway activation, many patients develop castration-resistant prostate cancer (CRPC). Second-line therapies, such as enzalutamide, has increased overall survival in CRPC, but resistance to these therapies inevitably emerges, suggesting that other pathways apart from AR signalling are contributing to the failure of treatments. We have previously demonstrated that SOX2 [SRY (sex determining region Y)-box 2] is an AR-repressed gene that is expressed in a large percentage of high Gleason grade prostate tumours, as well as in most metastases. Additionally, expression of SOX2 within a castration-sensitive cell line is sufficient to enable castration-resistant tumor formation in vivo, and enzalutamide resistance in vitro. In prostate cancer, SOX2 is not found with its normal stem cell co-factors, NANOG and OCT4, leading to the hypothesis that SOX2 is interacting with a novel co-factor in prostate cancer to regulate expression of genes promoting castration-resistance. A chromatin-immunoprecipitation experiment in a castration-resistant prostate cancer cell line was performed to determine if SOX2 binds the same genes and activates similar pathways in prostate cancer as in embryonic stem cells. Approximately half of the SOX2 bound genes in the CRPC cell line were shared with the embryonic stem cell line, and these genes are involved in signalling pathways and maintenance of stem cell pluripotency; the genes bound uniquely in the CRPC cell line are present in pathways involved with metabolic processes. To identify potential binding partners of SOX2, computational analysis of the sites bound by SOX2 in the promoter regions of target genes determined the FOXA1 motif is within close proximity to the SOX2 motif, and the physical interaction of these proteins was confirmed through co-immunoprecipitation. Further understanding of SOX2 target genes and the pathways that SOX2 activates in the presence of enzalutamide will be crucial to identify mechanisms of resistance and enable the development of novel therapies for castration-resistant prostate cancer. Citation Format: Larischa de Wet, Anthony Williams, Marc Gillard, Steve Kregel, Tzintzuni Garcia, Erin McAuley, Ryan Brown, Donald Vander Griend. The role of SOX2 in promoting resistance to AR-targeted therapies in 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 3348.
Abstract 5460: Discovery and evaluation of WX047, a potent and oral active phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitor
Authors: Ning Li, Amy Guan, Lei Huang, Dongling Hao, Bo Gao, Jikui Sun, Nengyang Shih, Lingwei Kong, Peipei Jiang, Yi Li, Dan Yao, Yuxin Qin, Tao Yu, Chengde Wu, Shuhui Chen, Hongyu Yuan, Xiulian Lu
Journal: Cancer Research (2018)

Abstract Background: The PI3K/AKT/mTOR signaling pathway is important in regulating cell cycle, which is directly related to cellular quiescence, proliferation and longevity. Dysfunctional signaling of the PI3K/AKT/mTOR pathway in cancer, and its crucial role in cell growth and survival have made it a much desired target for cancer therapeutics. Methods: By using structure-based design, the 4H-pyrido[1,2-a]pyrimidin-4-one derivative as an early lead was discovered. Further SAR studies optimized the in vitro and PK properties and led to the identification of WX047 as a potent dual inhibitor of PI3K and mTOR. Antitumor efficacy of WX047 was evaluated in the PC-3M xenograft tumor model. Results: A series of 7-(pyridin-3-yl)-4H-pyrido[1,2-a]pyrimidin-4-one derivatives were synthesized and evaluated for in vitro and in vivo activities. Among them, WX047 was identified as a potent dual PI3K and mTOR inhibitor with IC50 for mTOR of 19.17 nM and IC50 for PI3Kα of 3.13 nM. The cellular activity of WX047 was determined in PC-3M cells by western blot analysis of p-Akt and p-70S6K with p-Akt and p-70S6K inhibition IC50 of 16 nM and 65 nM respectively. WX047 had low clearance and high oral bioavailability relative to those of the reference compound GSK2126458. In addition, WX047 also demonstrated significant antitumor efficacy in the PC-3M xenograft tumor models (79% TGI@10mpk, PO, QD). Conclusions: WX047 has been identified as an orally active PI3K and mTOR dual inhibitor. It displays significant antitumor efficacy in the PC-3M xenograft tumor model. These support moving the compound forward to clinical investigation. Citation Format: Ning Li, Amy Guan, Lei Huang, Dongling Hao, Bo Gao, Jikui Sun, Nengyang Shih, Lingwei Kong, Peipei Jiang, Yi Li, Dan Yao, Yuxin Qin, Tao Yu, Chengde Wu, Shuhui Chen, Hongyu Yuan, Xiulian Lu. Discovery and evaluation of WX047, a potent and oral active phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) dual inhibitor [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 5460.
Persistent Opioid Use After Wisdom Tooth Extraction
Authors: Calista M. Harbaugh, Romesh P. Nalliah, Hsou Mei Hu, Michael J. Englesbe, Jennifer F. Waljee, Chad M. Brummett
Journal: JAMA (2018)

This pharmacoepidemiology study uses commercial claims database data to describe the rate of persistent opioid use among patients aged 13 to 30 years prescribed perioperative opioids for wisdom tooth extraction.
Interventional Therapy Versus Medical Therapy for Secundum Atrial Septal Defect: A Systematic Review (Part 2) for the 2018 AHA/ACC Guideline for the Management of Adults With Congenital Heart Disease
Authors: Matthew Oster, Ami B. Bhatt, Elisa Zaragoza-Macias, Nandini Dendukuri, Ariane Marelli
Journal: Journal of the American College of Cardiology (2018)