tbuckley/cabot-search huggingface dataset:
Overdiagnosis and the cancer label
Authors: Richard Hurley
Journal: BMJ (2018)

Over-diagnosis and the cancer label.Concern about nomenclature in relation to cervical cancer has a long history, since Dr George Papanicolaou, a medical researcher in New York, announced his staining technique to identify pre-cancerous cells of the cervix in the 1940s.This was taken up enthusiastically by the American Cancer Society with its 'search and destroy' strategy.As American pathologist Lewis Robbins later told a researcher into the Cancer Society, 'The Pap smear isn't diagnosing cancer, it's diagnosing a precursor.Why did they call it cancer then?Because nobody would pay any attention if they called it dysplasia.If you call it carcinoma in situ, then they will examine it, do something with it.'In 1950 the International Congress of Obstetrics and Gynaecology altered the international classification of carcinoma of the cervix by adding a further stage, Stage 0, to include carcinoma in situ.By the early 1950s there were professional misgivings about the labelling, with one gynaecologist at a 1952 meeting of the American Society of Obstetricians and Gynecologists declaring: 'To call atypical lesions malignant and treat them as cancers is only to fog our own critical intellectual recesses and to harm the patient by putting the fear of cancer permanently in her mind.'Yet the interventionist lobby forged ahead, despite subsequent misgivings in the 1960s and 1970s by researchers such as Professor Archie Cochrane.At a time when there were strong screening and interventionist lobbies, Cochrane said he was considered 'a dangerous heretic'.He would be pleased by the current debates.
Abstract 20747: Systolic Blood Pressure Response is Eliminated by Alpha 1 Adrenergic Blockade in Human Subjects
Authors: Kristen E Cosselman, Karen Jansen, Cora Sack, Timothy V Larson, Joel D Kaufman
Journal: Circulation (2016)

Introduction: Exposure to traffic-related air pollution is associated with increased risk of cardiovascular disease and mortality. In controlled inhalation studies, exposure to diesel exhaust (DE) ...
Abstract 1915: Validation of ero1l as a therapeutic target for the treatment of multiple myeloma
Authors: Weichih Chen, Werner Geldenhuys, Lori Hazlehurst
Journal: Cancer Research (2018)

Abstract Validation of ERO1L as a therapeutic target for the treatment of multiple myeloma Wei-Chih Chen1, Werner Geldenhuys1 and Lori Hazlehurst1,2,3 1. Department of Pharmaceutical Sciences, School of Pharmacy. 2. Osborn Hematopoietic Malignancy and Transplantation Program, West Virginia University. 3. West Virginia University Cancer Institute, Morgantown, WV, USA. Multiple myeloma (MM) is a hematologic malignancy of plasma cells and remains an incurable disease. MM is exquisitely sensitive to agents which induce ER stress including inhibitors that target the proteasome such as Bortezomib. However, MM patients eventually relapse with drug resistant disease, indicating that additional therapies are required to improve patient outcomes. Endoplasmic reticulum oxidase 1-alpha (ERO1L) is an endoplasmic reticulum (ER) resident protein that plays a critical role in disulfide bonds formation and contributes to proper folding of secretory proteins. High expression of ERO1L has been reported to be associated with poor prognosis in several cancer indications. However, the role of ERO1L in MM remains unclear. Our data indicate the ERO1L expression is increased in MM cells compared to normal controls. Because MM cells are known to secrete high levels of paraprotein resulting in basal ER stress, we investigated the role of ERO1L in tumor growth. Our data indicate that overexpression of ERO1L in U266 MM cells enhanced cell growth using both in vitro and in vivo models. Moreover, inducible reduction of ERO1L using shRNA strategies inhibited colony formation in U266 cells. Using a pharmacological inhibitor of, ERO1L referred to as EN460, we show that inhibition of ERO1L induced markers of ER stress and triggered apoptosis. Together our findings indicate that ERO1L maybe a tractable strategy for the treatment of MM. Keywords: multiple myeloma (MM), endoplasmic reticulum oxidase 1 alpha (ERO1L) Citation Format: Weichih Chen, Werner Geldenhuys, Lori Hazlehurst. Validation of ero1l as a therapeutic target for the treatment of multiple myeloma [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 1915.
Medical cannabis on the NHS
Authors: Fiona Godlee
Journal: BMJ (2018)

Last week’s recognition by the UK government that cannabis has medicinal value and should be available on prescription is an important step (doi:10.1136/bmj.k3290). It offers the hope of potentially safe and effective treatment for thousands of children and adults with conditions that are currently beyond the help of licensed drugs, and it brings the UK in line with 40 other countries and 29 US states where medicinal use of cannabis is already legal. It also greatly opens up the …
Cyclin A Downregulation and p21cip1 Upregulation Correlate With GATA-6–Induced Growth Arrest in Glomerular Mesangial Cells
Authors: DaisukeNagata, EtsuSuzuki, HiroakiNishimatsu, MasaoYoshizumi, ToshiakiMano, KennethWalsh, MasatakaSata, MasaoKakoki, AtsuoGoto, MasaoOmata, YasunobuHirata
Journal: Circulation Research (2000)

Abstract—The GATA-6 transcription factor is reported to be expressed in vascular myocytes. Because glomerular mesangial cells (GMCs) and vascular myocytes have similar properties, we examined whether GATA-6 was expressed in cultured GMCs and whether overexpression of GATA-6 induced cell cycle arrest in GMCs, using a recombinant adenovirus that expresses GATA-6 (Ad GATA-6). GATA-6 expression in GMCs was downregulated when quiescent GMCs were stimulated by serum to reenter the cell cycle. [3H]thymidine uptake was inhibited in GMCs infected with Ad GATA-6 in a dose- and time-dependent manner. The expression of cyclin A protein was decreased and that of the cyclin-dependent kinase inhibitor p21cip1 was increased in GMCs infected with Ad GATA-6. Although the expression of p21cip1 transcripts did not change remarkably, p21cip1 protein was stabilized in GMCs infected with Ad GATA-6, suggesting a post-transcriptional regulation of p21cip1 expression. Northern blot analysis showed that expression of the cyclin A t...
Abstract 4804: Multitargeted kinase inhibition (AEE788) alleviates mTOR inhibitor drug resistance in triple-negative breast cancer
Authors: Jichao He, Ronan P. McLaughlin, Vera van der Noord, Gerard van Westen, Yinghui Zhang, Bob van de Water
Journal: Cancer Research (2018)

Abstract Triple negative breast cancer (TNBC), although accounting for 15-20% of breast cancer, is disproportionally responsible for female cancer death. Despite therapeutic strategies being advanced, the clinical outcome of mTOR-targeted chemotherapy remains poor in the past decades. Recent data have evidenced the interdependence of kinase signaling networks and their involvement in treatment refractory TNBC settings. Thus, a combinatorial therapy targeting multiple components of signaling cascade is urgently needed. We assessed drug response phenotype across 20 TNBC cell lines by profiling the effect of a kinase inhibitor library consisting of &amp;gt;350 different kinase inhibitors (KIs). A panel of TNBC cell lines clustered with resistance phenotype against rapalogues (rapamycin analogues). Rapamycin efficacy on TNBCs was detected by performing proliferation assays and calculating their IC50, respectively. Given the role of the mTOR pathway in translational control, the relationship between rapamycin responses (IC50) and translational factors expression in TNBC cell lines was studied by Pearson analysis. Notably, translation initiation factor EIF2B2, EIF2S3, EIF3S8 and EIF1AX positively correlated with rapamycin response, whereas EIF4EBP2 and EIF2AK2 displayed negative correlation. Next, a rapamycin combination KI library screen was performed to identify kinase inhibitors synergizing with mTOR inhibition. AEE788, a multiple kinase targeting inhibitor, synergistically enhanced inhibitory effect of rapamycin on TNBC cell proliferation. Moreover, AEE788 dose-dependently synergized with mTOR targeted therapy in several TNBC cell lines. The combination treatment significantly decreased phosphorylation level of mTOR and 4EBP1 as well as ERK, indicating downregulation of PI3K/AKT and MAPK pathways. ChEMBL-based cheminformatics analysis indicated that, besides VEGFR and EGFR, a number of other kinases were predicted as the targets of AEE788, including RPS6K1, AKT2 and CDK7. Altogether, our data reveals the essential role of rapamycin-associated translation factors in TNBC, and provides insight in the resistance of TNBC to rapamycin analogues as well as potential therapeutic approaches to alleviate rapamycin resistance. Citation Format: Jichao He, Ronan P. McLaughlin, Vera van der Noord, Gerard van Westen, Yinghui Zhang, Bob van de Water. Multitargeted kinase inhibition (AEE788) alleviates mTOR inhibitor drug resistance in triple-negative breast 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 4804.
Adiponectin, an Adipocyte-Derived Plasma Protein, Inhibits Endothelial NF-κB Signaling Through a cAMP-Dependent Pathway
Authors: NoriyukiOuchi, ShinjiKihara, YukioArita, YoshihisaOkamoto, KazuhisaMaeda, HiroshiKuriyama, KikukoHotta, MakotoNishida, MasahikoTakahashi, MasahiroMuraguchi, YasukazuOhmoto, TadashiNakamura, ShizuyaYamashita, TohruFunahashi, YujiMatsuzawa
Journal: Circulation (2000)

Background—Among the many adipocyte-derived endocrine factors, we found an adipocyte-derived plasma protein, adiponectin, that was decreased in obesity. We recently demonstrated that adiponectin inhibited tumor necrosis factor-α (TNF-α)–induced expression of endothelial adhesion molecules and that plasma adiponectin level was reduced in patients with coronary artery disease (Circulation. 1999;100:2473–2476). However, the intracellular signal by which adiponectin suppressed adhesion molecule expression was not elucidated. The present study investigated the mechanism of modulation for endothelial function by adiponectin. Methods and Results—The interaction between adiponectin and human aortic endothelial cells (HAECs) was estimated by cell ELISA using biotinylated adiponectin. HAECs were preincubated for 18 hours with 50 μg/mL of adiponectin, then exposed to TNF-α (10 U/mL) or vehicle for the times indicated. NF-κB–DNA binding activity was determined by electrophoretic mobility shift assays. TNF-α–inducible...
Abstract 815: New approach for old target: W0101 antibody drug conjugate effectively inhibits tumor growth in preclinical models of IGF-1R overexpressing solid tumors
Authors: Barbara Akla, Noureddine Loukili, Alain Robert, Charlotte Beau-Larvor, Martine Malissard, Jean-Francois Haeuw, Alain Beck, Michel Perez, Cyrille Dreyfus, Mariya Pavlyuk, Eric Chetaille, Nathalie Corvaia
Journal: Cancer Research (2018)

Abstract Insulin-like growth factor type 1 receptor (IGF-1R) has been recognized for decades for its role in tumorigenesis and growth1. In addition, overexpression of this receptor has been largely documented in numerous tumor tissues. However, so far, previous therapeutic approaches based on monoclonal antibodies and tyrosine kinase inhibitors failed to show clinical benefit in the overall patient population2. Here we disclose for the first time a novel IGF-1R targeted Antibody Drug Conjugate (ADC), W0101, designed to deliver highly potent cytotoxic drugs selectively to IGF-1R over-expressing tumor cells. The naked antibody for our ADC was selected on the basis of its specific binding properties to IGF-1R compared to insulin receptor (IR), and for its internalization properties. After coupling of a proprietary auristatin derivative to the naked antibody, neither the binding nor the internalization properties of W0101 evaluated by FACS analysis, were modified. Interestingly, the capacity of W0101 to induce cytotoxicity was evaluated in vitro in various cell lines and was demonstrated to be independent of effector functions. Mouse efficacy studies with various doses and schedules of administration were conducted in several models expressing different level of IGF-1Rin order to determine their sensitivity to W0101. The sensitivity of W0101 was correlated to the expression level of IGF-1R evaluated by IHC. And in a 3+ MCF-7 breast cancer model, a single injection of W0101 at 3mg/kg led to more than 90% tumor growth inhibition (TGI), associated with a modulation of the IGF-1R expression on the tumor cells (IHC study). The first in-human trial of W0101 is currently on going to address clinical safety. We believe that W0101 will bring a new therapeutic option for patients that overexpress IGF-IR. 1Pollak M. Insulin and insulin-like growth factor signaling in neoplasia. Nat Rev Cancer, 2008,8:915-928. 2Corvaia N, Beck A, Caussanel V, Goetsch L. Insulin-like growth factor receptor type I as a target for cancer therapy. Frontiers in Bioscience, Scholar, 5, 439-450, January 1, 2013 Citation Format: Barbara Akla, Noureddine Loukili, Alain Robert, Charlotte Beau-Larvor, Martine Malissard, Jean-Francois Haeuw, Alain Beck, Michel Perez, Cyrille Dreyfus, Mariya Pavlyuk, Eric Chetaille, Nathalie Corvaia. New approach for old target: W0101 antibody drug conjugate effectively inhibits tumor growth in preclinical models of IGF-1R overexpressing solid tumors [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 815.
Characterization of Different Subsets of Atrial Fibrillation in General Practice in France
Authors: SamuelLévy, MartineMaarek, PhilippeCoumel, LouisGuize, JeanLekieffre, Jean-LouisMedvedowsky, AlainSebaoun
Journal: Circulation (1999)

Background—The clinical presentation and causes of atrial fibrillation (AF) in the 1990s may differ from AF seen 2 to 3 decades ago. It was the objective of this prospective study to characterize various clinical presentations and underlying conditions of patients with AF observed in general practice in France. Methods and Results—The study population comprised 756 patients (19 to 95 years of age) with electrocardiographically documented AF subdivided into paroxysmal ( 1 month) and recent onset AF(persistent >7 days and<1 month). Symptoms were present in 670 patients (88.6%). The relative prevalences of paroxysmal, chronic, and recent onset AF were 22.1%, 51.4%, and 26.4%, respectively. Cardiac disorders, present in 534 patients (70.6%), included hypertension (39.4%), coronary artery disease (16.6%), and myocardial diseases (15.3%) as the most common. Rheumatic valvular disease represented a common cause in women (25.0%) but not in men (8.0%). The paroxysmal group differed ...
Myocardial Infarction Patterns in Young Subjects with Normal Coronary Arteriograms
Authors: Williamlikoff, Bernardsegal, Leonarddreifus
Journal: Circulation (1962)

For the present, the primary obligations of this communication are to acknowledge that the electrocardiographic patterns of myocardial ischemia, injury, and necrosis may appear in asymptomatic, young white males who have low-intensity systolic murmurs; to record that any implication that these electrical deviations result from obstructive coronary disease cannot be substantiated by coronary arteriography; and to suggest that individuals possessing these diagnostic features may represent a distant, recognizable clinical entity the etiology of which remains obscure.
Screening for Atrial Fibrillation With Electrocardiography
Authors: Susan J. Curry, Alex H. Krist, Douglas K. Owens, Michael J. Barry, Aaron B. Caughey, Karina W. Davidson, Chyke A. Doubeni, John W. Epling, Alex R. Kemper, Martha Kubik, C. Seth Landefeld, Carol M. Mangione, Michael Silverstein, Melissa A. Simon, Chien-Wen Tseng, John B. Wong
Journal: JAMA (2018)

<h3>Importance</h3> Atrial fibrillation is the most common type of cardiac arrhythmia (irregular heartbeat), and its prevalence increases with age, affecting about 3% of men and 2% of women aged 65 to 69 years and about 10% of adults 85 years and older. Atrial fibrillation is a major risk factor for ischemic stroke, increasing risk of stroke by as much as 5-fold. Approximately 20% of patients who have a stroke associated with atrial fibrillation are first diagnosed with atrial fibrillation at the time of stroke or shortly thereafter. <h3>Objective</h3> To issue a new US Preventive Services Task Force (USPSTF) recommendation on screening for atrial fibrillation with electrocardiography (ECG). <h3>Evidence Review</h3> The USPSTF reviewed the evidence on the benefits and harms of screening for atrial fibrillation with ECG in adults 65 years and older, the effectiveness of screening with ECG for detecting previously undiagnosed atrial fibrillation compared with usual care, and the benefits and harms of anticoagulant or antiplatelet therapy for the treatment of screen-detected atrial fibrillation in older adults. <h3>Findings</h3> Most older adults with previously undiagnosed atrial fibrillation have a stroke risk above the threshold for anticoagulant therapy and would be eligible for treatment. Anticoagulant therapy is effective for stroke prevention in symptomatic persons with atrial fibrillation and high stroke risk. However, the USPSTF found inadequate evidence to determine whether screening with ECG and subsequent treatment in asymptomatic adults is more effective than usual care. At the same time, the harms of diagnostic follow-up and treatment prompted by abnormal ECG results are well established and include misdiagnosis and invasive testing. Given these uncertainties, it is not possible to determine the net benefit of screening with ECG. <h3>Conclusions and Recommendation</h3> The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for atrial fibrillation with ECG. (I statement)
Cellular Senescence Impairs Circadian Expression of Clock Genes In Vitro and In Vivo
Authors: TakeshigeKunieda, TohruMinamino, TaroKatsuno, KaoruTateno, Jun-ichiroNishi, HideyukiMiyauchi, MasayukiOrimo, ShoOkada, IsseiKomuro
Journal: Circulation Research (2006)

Circadian rhythms are regulated by a set of clock genes that form transcriptional feedback loops and generate circadian oscillation with a 24-hour cycle. Aging alters a broad spectrum of physiological, endocrine, and behavioral rhythms. Although recent evidence suggests that cellular aging contributes to various age-associated diseases, its effects on the circadian rhythms have not been examined. We report here that cellular senescence impairs circadian rhythmicity both in vitro and in vivo. Circadian expression of clock genes in serum-stimulated senescent cells was significantly weaker compared with that in young cells. Introduction of telomerase completely prevented this reduction of clock gene expression associated with senescence. Stimulation by serum activated the cAMP response element-binding protein, but the activation of this signaling pathway was significantly weaker in senescent cells. Treatment with activators of this pathway effectively restored the impaired clock gene expression of senescent ...
Moving Beyond Symptom Remission to Optimize Long-term Treatment of Attention-Deficit/Hyperactivity Disorder
Authors: Scott H. Kollins
Journal: JAMA Pediatrics (2018)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Pediatrics HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Pediatrics journal
Abstract 631: Intratumoral activation of STING with a synthetic cyclic dinucleotide elicits antitumor CD8 T-cell immunity that effectively combines with checkpoint inhibitors
Authors: Anthony L. Desbien, Kelsey Sivick Gauthier, Leticia Corrales, Gabrielle Reiner, Laura Hix Glickman, George Katibah, Thomas E. Hudson, Uyen Vu, Natalie H. Surh, Brian Francica, Weiwen Deng, David B. Kanne, Justin J. Leong, Chudi Ndubaku, Ken Metchette, Jeffery M. McKenna, Steven L. Bender, Meredith L. Leong, Thomas W. Dubensky, Andrea van Elsas, Sarah M. McWhirter
Journal: Cancer Research (2018)

Abstract Activation of the STING pathway by intratumoral (IT) injection of synthetic cyclic dinucleotides (CDNs) induces stable tumor regression in preclinical models, yet the underlying immune correlates are not fully understood. ADU-S100, a CDN under clinical evaluation, was administered IT with an optimized dosing regimen to explore the immune requirements for antitumor efficacy in mouse syngeneic tumor models. We show that CD8+ T cells are necessary and sufficient for durable antitumor immunity elicited by ADU-S100 and that activation of STING in hematopoietic cells mediates CD8+ T cell induction. Both type I IFN and TNFα, which are induced by STING pathway activation, influence the antitumor immune response. The combination of ADU-S100 and anti-PD1 treatment enhances CD8+ T cell-dependent, noninjected tumor control that correlates with an enhanced effector profile of CD8+ T cells in the tumor. Combination of ADU-S100 with checkpoint inhibition also enhances durable immunity in a poorly immunogenic tumor model. Together, these results elucidate the immune correlates to STING-mediated antitumor efficacy and highlight the potential of combining STING agonists with checkpoint inhibition in the clinic. Citation Format: Anthony L. Desbien, Kelsey Sivick Gauthier, Leticia Corrales, Gabrielle Reiner, Laura Hix Glickman, George Katibah, Thomas E. Hudson, Uyen Vu, Natalie H. Surh, Brian Francica, Weiwen Deng, David B. Kanne, Justin J. Leong, Chudi Ndubaku, Ken Metchette, Jeffery M. McKenna, Steven L. Bender, Meredith L. Leong, Thomas W. Dubensky Jr., Andrea van Elsas, Sarah M. McWhirter. Intratumoral activation of STING with a synthetic cyclic dinucleotide elicits antitumor CD8 T-cell immunity that effectively combines with checkpoint inhibitors [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 631.