tbuckley/cabot-search huggingface dataset:
Abstract IA01: Mechanisms of formation and progression of preleukemic stem cells
Authors: Ulrich Steidl
Journal: Clinical Cancer Research (2017)

Abstract Relapse continues to be the most common cause of death in AML and overall cure rates remain low. Recent evidence has shown that the accumulation of stepwise genetic and epigenetic changes in HSC lead to the formation of precancerous/preleukemic stem cells (pre-LSC) that play a pivotal role not only in disease origination but also in leukemia relapse. While the existence and essentiality of such precancerous cell states has been demonstrated in mice and humans, still very little is known about the molecular mechanisms driving pre-LSC formation and progression. We have recently performed molecular studies of pre-leukemic cell states in mouse genetic models as well as primary cells from patients, and discovered new transcription factors and regulatory mechanisms in pre-LSC in MDS and AML. Specifically, we discovered critical roles for several nonclustered homeobox transcription factors in pre-LSC, and identified functionally critical and pharmacologically targetable downstream effectors. We also found that enhancer haplodeficiency and consequent minimal reduction of key transcription factors is sufficient to induce pre-LSC formation and subsequent progression to MDS and AML. Such models provide novel tools for mechanistic study of pre-LSC and their progression to overt MDS and AML, and for the development and testing of pharmacologic approaches to therapeutically interfere with these processes. In summary, recent studies have started to shed light on preleukemic cell states as the earliest origin of MDS and AML, as well as molecular mechanisms driving their formation and progression, which provides a basis for their specific therapeutic targeting for causative treatment of MDS and AML. Citation Format: Ulrich Steidl. Mechanisms of formation and progression of preleukemic stem cells [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr IA01.
Heme Oxygenase-1 and Carbon Monoxide in Vascular Pathobiology
Authors: JozefDulak, JessyDeshane, AlicjaJozkowicz, AnupamAgarwal
Journal: Circulation (2008)

Angiogenesis involves the formation of new blood vessels and is critical for fundamental events such as development and repair after injury. Perturbances in angiogenesis contribute to the pathogenesis of diverse clinical conditions including cancer, complications of diabetes mellitus, ischemia/reperfusion injury of the heart and other organs, and preeclampsia, as well as a number of inflammatory disorders. Recent work has identified heme oxygenase-1 and its gaseous product, carbon monoxide, to possess potent proangiogenic properties in addition to well-recognized antiinflammatory, antioxidant, and antiapoptotic effects. Angiogenic factors, such as vascular endothelial growth factor and stromal cell–derived factor-1, mediate their proangiogenic effects through induction of heme oxygenase-1, making it an attractive target for therapeutic intervention. This review will provide an overview of the role of heme oxygenase-1 and carbon monoxide in angiogenesis.
Abstract 18180: Predictors of Extraction Sheath Assistance for Chronically Indwelling Endovascular Leads
Authors: Sean PSwearingen, RyanKipp, MatthewTattersall, DouglasKopp, MiguelLeal
Journal: Circulation (2016)

Introduction: Recently implanted pace-sense and defibrillator (ICD) leads are typically removable via gentle manual traction. Clinical predictors of the need for dedicated extraction sheaths (ES) (use of laser or mechanical cutting sheaths) during removal of pace-sense or ICD leads have not been well defined. Methods: A retrospective, single-center analysis was performed on all patients referred for lead extraction between 2010 and 2014. Baseline and lead characteristics were included in a multivariate logistic regression model assessing the need for ES during the procedure. Results: A total of 170 patients (255 leads) were included in this analysis. ES was required for 75% of all leads. No lead implanted for less than 6 months required ES. Time since lead implantation and ICD lead type were significantly associated with need for ES (OR 1.03 per 30 days, 95% CI 1.02-1.05, and OR 5.22, 95% CI 2.00-13.93, respectively). When analyzed independently, ICD leads with longer dwell time and younger patient age we...
Abstract 1427: Comprehensive investigation of false mutation discoveries in FFPE samples
Authors: Thomas M. Blomquist, Wenming Xiao
Journal: Cancer Research (2018)

Abstract Next generation sequencing (NGS) has emerged as a primary tool for “precision” medicine, especially in the rapidly evolving field of cancer care. However NGS-based somatic variant calling in a clinical oncology setting is susceptible to numerous sources of technical error impeding optimal patient management. One important source of error in variant reporting is formalin fixation and paraffin embedding (FFPE). Of note, FFPE-derived errors are commonly present at clinically actionable loci and can occur at allelic frequencies (5-65%) that meet treatment criteria. Compounding this problem, degree of FFPE error is highly susceptible to inter-specimen and inter-laboratory variations. In this context, static variant calling thresholds to control for “general FFPE-effect” are likely inadequate; resulting in both False-Negatives (ignoring true somatic variation) and False-Positives (reporting technical error as truth). Despite the importance of fresh tissue for molecular studies, routine tissue histology (derived from FFPE) continues to be the gold standard for cancer staging/grading. And, as emphasis on smaller sample sizes becomes the norm, routine histology will be prioritized in many scenarios. Thus, the need to understand how molecular testing performs in FFPE tissue is a driving imperative for optimal cancer care. In this study, our aim was to develop and evaluate “best” quality control practices that would minimize False-Positive or -Negative somatic variant calling in FFPE specimens. Reference samples (paired breast carcinoma and “normal” lymphoblast cell-lines) from the FDA-led Sequencing Quality Control Phase II (SEQC2) consortium were used. These specimens were subjected to varying FFPE conditions (n=8) mimicking the pathology laboratory setting. For each condition, multiple replicates of whole genome and exome sequencing (WGS/WES) were performed with ~100X coverage across the entire human genome. Observed somatic variation frequencies for each genomic position for each FFPE condition were compared to ground truth and quality control measures derived from matched fresh materials using numerous statistical models. Applying rigorous analytical strategies, we aim to identify genomic regions that serve as markers (internal control regions) for the full range of FFPE-effect, develop QC measures and statistics to define lower limit of detection for variant calling for each genomic position, and provide general guidance for the community on how to accurately report mutations in FFPE processed clinical cancer specimens. Citation Format: Thomas M. Blomquist, Wenming Xiao, Somatic Mutation Working Group of the SEQC2 Consortium. Comprehensive investigation of false mutation discoveries in FFPE samples [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 1427.
Overdiagnosis in primary care: framing the problem and finding solutions
Authors: Minal S Kale, Deborah Korenstein
Journal: BMJ (2018)

Overdiagnosis, is defined as the diagnosis of a condition that, if unrecognized, would not cause symptoms or harm a patient during his or her lifetime, and it is increasingly acknowledged as a consequence of screening for cancer and other conditions. Because preventive care is a crucial component of primary care, which is delivered to the broad population, overdiagnosis in primary care is an important problem from a public health perspective and has far reaching implications. The scope of overdiagnosis as a result of services delivered in primary care is unclear, though overdiagnosis of indolent breast, prostate, thyroid, and lung cancers is well described and overdiagnosis of chronic kidney disease, depression, and attention-deficit/hyperactivity disorder is also recognized. However, overdiagnosis is a known consequence of all screening and can be assumed to occur in many more clinical contexts. Overdiagnosis can harm patients by leading to overtreatment (with associated potential toxicities), diagnosis related anxiety or depression, and labeling, or through financial burden. Many entrenched factors facilitate overdiagnosis, including the growing use of advanced diagnostic technology, financial incentives, a medical culture that encourages greater use of tests and treatments, limitations in the evidence that obscure the understanding of diagnostic utility, use of non-beneficial screening tests, and the broadening of disease definitions. Efforts to reduce overdiagnosis are hindered by physicians' and patients' lack of awareness of the problem and by confusion about terminology, with overdiagnosis often conflated with related concepts. Clarity of terminology would facilitate physicians' understanding of the problem and the growth in evidence regarding its prevalence and downstream consequences in primary care. It is hoped that international coordination regarding diagnostic standards for disease definitions will also help minimize overdiagnosis in the future.
Smoking Cessation, Weight Change, Type 2 Diabetes, and Mortality
Authors: Yang Hu, Geng Zong, Gang Liu, Molin Wang, Bernard Rosner, An Pan, Walter C. Willett, JoAnn E. Manson, Frank B. Hu, Qi Sun
Journal: New England Journal of Medicine (2018)

In three cohort studies involving men and women in the United States, we identified those who had reported quitting smoking and we prospectively assessed changes in smoking status and body weight. We estimated risks of type 2 diabetes, death from cardiovascular disease, and death from any cause among those who had reported quitting smoking, according to weight changes after smoking cessation.
Serotonin Transporter Gene Polymorphism and Myocardial Infarction
Authors: FrédéricFumeron, DinaBetoulle, VivianeNicaud, AlunEvans, FrankKee, Jean-BernardRuidavets, DominiqueArveiler, GéraldLuc, FrançoisCambien
Journal: Circulation (2002)

Background— Depression is a risk factor for myocardial infarction (MI). Selective serotonin reuptake inhibitors reduce this risk. The site of action is the serotonin transporter (SLC6A4), which is expressed in brain and blood cells. A functional polymorphism in the promoter region of the SLC6A4 gene has been described. This polymorphism may be associated with the risk of MI. Methods and Results— The SLC6A4 polymorphism has been investigated by polymerase chain reaction in 671 male patients with MI and in 688 controls from the Etude Cas-Temoins de l’Infarctus du Myocarde (ECTIM) multicentric study. Percentages for LL, LS, and SS genotypes were 35.5%, 45.4%, and 19.1%, respectively, for cases versus 28.1%, 49.1%, and 22.8%, respectively, for controls. S allele frequency was 41.8% and 47.4% for cases and controls, respectively. After adjustment for age and center by using multivariable logistic regression, the odds ratio for MI associated with the LL genotype was 1.40 (95% CI 1.11 to 1.76, P=0.0047). Conclu...
Transvascular Delivery of Hydrophobically Modified siRNAs: Gene Silencing in the Rat Brain upon Disruption of the Blood-Brain Barrier
Authors: Bruno M.D.C. Godinho, Nils Henninger, James Bouley, Julia F. Alterman, Reka A. Haraszti, James W. Gilbert, Ellen Sapp, Andrew H. Coles, Annabelle Biscans, Mehran Nikan, Dimas Echeverria, Marian DiFiglia, Neil Aronin, Anastasia Khvorova
Journal: Molecular Therapy (2018)
PTU-052 Minimising ercp remuneration losses by improving coding accuracy: an eight month quality improvement project
Authors: S Phillpotts, H Hooper, S Jobling, S Tanwar
Journal: Gut (2017)

Introduction  Whipps Cross Hospital is a 730 bed district general hospital in North East London that generates circa £1,000,000 revenue per annum from approximately 250 ERCP procedures. ERCPs are complex endoscopic procedures with remuneration dependent on both patient and procedural factors (from £723 to over £7283). Innacurate coding leads to a decrease in remuneration.  For example, the insertion of a metal stent with sphincterotomy generates one of three tariffs: £948 (if length of stay (LOS) is ≤2 days), £4443 (if LOS≥3 without major comorbidities), and £7283 (if LOS≥3 days with major comorbidities (eg. sepsis, dementia or renal failure)). However not coding the sphincterotomy would lead to a decrease in remuneration to £909, £4453 and £6771 respectively, and coding the metal stent as plastic would also lead to a decrease in remuneration (£848, £3532 and £5532).  Following a fall in annual remuneration despite an increase in procedure volume and complexity, an eight month quality improvement project (QIP) was commenced to evaluate and improve the situation.  Method  Procedures were identified from the unisoft database. For each patient the coding summary, co-morbidities and LOS were retrieved from Cerner Millennium. Using these data a senior gastroenterologist determined the expected remuneration based upon patient and procedural factors. These figures were then compared to the actual ‘coded’ remuneration (%remuneration). In addition the% of procedures with coding discrepancies were recorded.  Following a four month retrospective benchmark audit our QIP identified a number of areas to be improved: using a dedicated and trained ERCP coder, clearer procedural documentation, and protocols to ensure that all procedures were coded.  Results  Our benchmark audit identified a deficit of £35 534 in coded activity, equivalent to a remuneration of 85%.  We have now completed 3 PDSA cycles. The first two show month-on-month improvements with reduced procedures with discrepant coding, and an improvement in remuneration. Cycle 3 was carried out without a dedicated coder to evaluate the significance of this change. The marked fall in both outcome measures highlights the importance of this intervention.  Conclusion  This project has identified a potential £1 50 000 shortfall (15%) in annual income from ERCP. Our interventions have already identified a number of areas that have improved coding accuracy and remuneration. We suspect these problems will be ubiquitous and would recommend similar projects to be carried out at other centres providing ERCP.  Disclosure of Interest  None Declared
Immunoneutralization of Glycoprotein Ibα Attenuates Endotoxin-Induced Interactions of Platelets and Leukocytes With Rat Venular Endothelium In Vivo
Authors: TomihiroKatayama, YasuoIkeda, MakotoHanda, TakuyaTamatani, ShinjiSakamoto, MasaharuIto, YuzuruIshimura, MakotoSuematsu
Journal: Circulation Research (2000)

Abstract—This study aimed to examine molecular mechanisms for endotoxin-induced adhesive changes in platelets in vivo. Platelets labeled with carboxyfluorescein diacetate succinimidyl ester were visualized in rat mesenteric venules through intravital microscopy assisted by a high-speed fluorescence video imager at 1000 frames per second or by a normal-speed intensifier under monitoring of erythrocyte velocity. Leukocyte rolling was examined by normal-speed transmission video images. The velocity of platelets traveling along the centerline of venules followed that of erythrocytes, whereas that measured at the periendothelial space was significantly smaller than the erythrocyte velocity; a majority of these cells exhibited transient but notable rolling with endothelium. Administration of endotoxin increased the density of periendothelial platelets and reduced the rolling velocities of platelets and leukocytes in venules: All events were attenuated by anti–rat P-selectin monoclonal antibody s789G or by anti–...
Abstract 5171: Tfap2b overexpression contributes to tumor growth &amp; progression of thyroid cancer through AKT&amp;VEGF/PEDF signaling pathway
Authors: Xiaoyan Fu, Zhongyuan Yang, Shuwei Chen
Journal: Cancer Research (2018)

Abstract TFAP2 is a family of transcription factors implicated in many aspects of development.TFAP2B is a member of the AP2 transcription factor family, which orchestrates a variety of cell processes. However, the roles of TFAP2B in regulating thyroid carcinogenesis remain largely unknown. Here, we investigated the regulatory effects of TFAP2B on thyroid cancer growth &amp; identified the underlying mechanisms of actions in thyroid cancer cells.We examined the expression of TFAP2B in thyroid cancer cell lines &amp; tumor tissues. We also analyzed the TNM staging of TFAP2B in thyroid cancer. Then we investigated the molecular mechanisms by which TFAP2B knockdown or overexpression regulated thyroid cancer cell growth, angiogenesis &amp; apoptosis, &amp; further confirmed the role of TFAP2B in tumor growth in a thyroid cancerxenograft mouse model.TFAP2B was expressed in thyroid cancer lines &amp;tumortissues,especially in anaplastic thyroid cancer. Strong TFAP2B expression showed a positive correlation with the poor differentiation of patients with thyroid cancer . TFAP2B knockdown by siRNA significantly inhibited cell growth &amp; induced apoptosis in thyroid cancer cells in vitro &amp; in a thyroid cancersubcutaneous xenograft model, whereas TFAP2B overexpression promoted cell growth. The observed regulation of cell growth was accompanied by the TFAP2B-mediated modulation of the VEGF/PEDF-dependent signaling pathways in thyroid cancer cells.These results indicate that TFAP2B plays a critical role in regulating thyroid cancer growth &amp; could serve as a promising therapeutic target or diagonistic biomarker for thyroid cancer . Citation Format: Xiaoyan Fu, Zhongyuan Yang, Shuwei Chen. Tfap2b overexpression contributes to tumor growth &amp; progression of thyroid cancer through AKT&amp;VEGF/PEDF signaling pathway [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 5171.
Bioinstructive Naringin‐Loaded Micelles for Guiding Stem Cell Osteodifferentiation
Authors: Pedro Lavrador, Vítor M. Gaspar, João F. Mano
Journal: Advanced Healthcare Materials (2018)

Abstract Naringin is a naturally occurring flavanone with recognized neuroprotective, cardioprotective, anti‐inflammatory, and antiosteoporotic properties. Herein, the delivery of Naringin‐loaded methoxy‐poly(ethylene glycol)–maleimide–thiol–poly( l ‐lactide) (mPEGMSPLA) diblock polymeric micelles to human adipose‐derived stem cells (hASCs) with the aim to augment its pro‐osteogenic effect in these cells is reported for the first time. The synthesis of the diblock copolymer is performed via Michael‐type addition reaction between hydrophilic methoxy‐poly(ethylene glycol)–maleimide (mPEGMAL) and hydrophobic thiol–poly( l ‐lactide) (PLASH) and confirmed by 1 H NMR and attenuated total reflectance Fourier transformed infrared (ATR‐FTIR) spectroscopy. The resulting mPEGMSPLA copolymer self‐assembles into monodispersed polymeric micelles (≈84.4 ± 2 nm) and presents a high Naringin encapsulation efficiency (87.8 ± 4%), with a sustained release profile at physiological pH. Alongside, in vitro data reveal that upon internalization into hASC 2D cultures, Naringin nanomicellar formulations attain a higher pro‐osteogenic effect than that of free drug. Notably, these bioactive carriers also induce superior osteopontin expression and increase matrix mineralization in these cells over free drug administration. Overall, such findings support for the first time the use of polymeric nanomicelles for Naringin delivery into hASCs as a valid approach for modulating stem cell osteogenic differentiation.
Abstract 13860: The Mitochondria-targeted Antioxidant Therapy Improves Age-related Cardiovascular Dysfunction
Authors: Takashi Owada, Shu-ichi Saitoh, Hiroyuki Yamauchi, Shunsuke Miura, Hirofumi Machii, Yasuchika Takeishi
Journal: Circulation (2015)

Senescence is a major factor to increase oxidant stress in mitochondria, which contributes to the pathogenesis of heart diseases. We postulated that scavenging effect of superoxide targeted in mitochondria would have benefit in the aged heart. Increased levels of superoxide and NADPH oxidase activity were appeared in cardiac myocytes isolated from old mice (70 W) compared to those in young mice (8 W) (superoxide: 2.6±0.4 vs. 1.2±0.2 nmol/mg protein; NADPH oxidase activity: 2654±282 vs. 1124±156 RLU, p&lt;0.01, n=16, respectively). In old mice treated with mitochondria-targeted antioxidant, MitoTEMPO, co-infusion using minipump (180 μg/kg/day, 28 days), levels of superoxide and NADPH oxidase activity decreased (0.2±0.2 nmol/mg protein and 342±45 RLU, p&lt;0.01, respectively). Treatment with MitoTEMPO improved left ventricular ejection fraction from 48±5% to 62±5% (p&lt;0.01) with old mice in echocardiography. Endothelium-dependent coronary artery vasodilation, eNOS and Sirt1 levels were lower in old mice compared to those in young mice, which were improved by MitoTEMPO treatment (n=12 each, Figures). %SOD activity in cardiac mitochondria was lower in old mice compared to that in young mice (38.7±3.7 vs. 65.0±5.2%, p&lt;0.05), which were improved by MitoTEMPO treatment (61.2±4.1%). Treatment with MitoTEMPO in old mice improved decreased oxygen consumption rate in complex I and III of cardiac mitochondria to the level of those in young mice. Resolution of mitochondrial oxidant stress by MitoTEMPO in old mice restored cardiovascular function to the same magnitude observed in young mice. Therefore, antioxidant strategy targeting mitochondria could have therapeutic benefit in heart diseases with senescence.