tbuckley/cabot-search huggingface dataset:
Evaluation of cancer-targeting, pharmacokinetics and antitumor activity of liposomal methotrexate with transferrin ligand, MBP-Y003.
Authors: Mieko Nagasawa, Chizuko Hashimoto, Kazushi Okada, Mikihiko Naito, Donghyun Kim, Tadashi Fujisawa
Journal: Cancer Research (2007)

5650  Purpose: MBP-Y003 is a novel liposomal methotrexate (MTX) modified with N-glutaryl phosphatidylethanolamine (NGPE) to avoid entrapment in the reticuloendothelial system and to enhance retention in blood. Transferrin (Tf) is adopted as a ligand to introduce an active targeting function to the liposome. For evaluating potency of clinical use, we investigated in vitro cancer-targeting, retention in blood in mice and efficacy of MBP-Y003 in human tumor-bearing mice. Methods: Growth inhibitory activity to six kinds of human tumor cell line was compared using Tf conjugated liposomal MTX with non-Tf conjugated liposomal MTX. The binding of Tf of MBP-Y003 to the Tf receptor (Tf-R), and internalization were observed by Confocal Laser Microscopy using human tumor cells. MBP-Y003 and MTX were administered as a single iv dose of 30 mg/kg to evaluate blood retention in normal mice. MTX concentrations were measured in serum by fluorescence polarization immunoassay. The antitumor efficacy of MBP-Y003 (iv) and MTX (ip) was investigated in a human tumor xenograft model at each maximum tolerated dose (MTD) of 5 mg/kg and 45 mg/kg q4d x 3, respectively. Results: Tf conjugated liposomal MTX MBP-Y003 showed higher growth inhibitory activity than non-Tf conjugated liposomal MTX in all cell lines that were tested. Regarding the binding between Tf of MBP-Y003 and Tf-R, at first, the binding of Tf-R and Tf was observed at the cell surfaces, and then internalized into the cytoplasm in a time dependent fashion. AUC0-24h and Cmax of total plasma MTX concentrations in the MBP-Y003 group were significantly higher than those in MTX group. Plasma terminal half-life of MBP-Y003 was also substantially improved compared to the naked MTX. The MBP-Y003 5 mg/kg group showed 89% tumor growth inhibition against PC-3 tumor in nude mice compared with the control group. The antitumor activity achieved with MBP-Y003 was also better than mice treated with standard MTX at 45 mg/kg. No death or change in clinical signs was observed in any group. It was concluded that retention in blood and anti-tumor effects of MBP-Y003 were significantly greater than those of standard MTX. Conclusion: Present results suggest that MBP-Y003 has cancer-targeting activity via Tf - Tf-R interaction. MBP-Y003 has enhanced systemic exposure and efficacy compared to standard MTX at doses that appear well tolerated.
Abstract 12243: Associations Between Physical Activity and Prognostic Biomarkers in Patients With Stable Coronary Heart Disease in the STABILITY Trial
Authors: Claes Held, Ralph A Stewart, Paul W Armstrong, Christopher P Cannon, Nermin Hadziosmanovic, Emil Hagström, Judith S Hochman, Wolfgang Koenig, Eva Lonn, Jose Nicolau, Agneta Siegbahn, Philippe Gabriel Steg, David Watson, Harvey D White, Lars Wallentin
Journal: Circulation (2015)

Introduction: Physical activity (PA) reduces the risk of events in patients with stable coronary heart disease (CHD). Biomarkers reflecting myocardial dysfunction, renal function and inflammatory activity are associated with outcomes in stable CHD. It is poorly known to what extent the benefits of PA may be linked to biomarker levels. Hypothesis: The association between PA and outcomes may be mediated by processes indicated by changes in the levels of prognostic biomarkers. Methods: At baseline, 15,486 patients with stable CHD participating in the global STABILITY trial, completed a baseline lifestyle questionnaire including self-reporting on hours spent each week on mild, moderate and vigorous exercise, corresponding to approximately 2, 4 and 8 METS, respectively. Plasma levels of high-sensitivity (hs) C-reactive protein (hs-CRP), hs-troponin T (hs-TnT), N-terminal pro-B type natriuretic peptide (NT-proBNP), cystatin-C, growth differentiation factor-15 (GDF-15) and lipoprotein-associated phospholipase A2 (Lp-PLA2) activity were assessed from plasma samples obtained at baseline. Associations between PA and biomarker levels were evaluated after multivariable adjustments (age, gender, traditional clinical cardiovascular risk factors and standard biomarkers including cholesterol levels) with sedentary patients as reference. Results: Associations between levels of PA and hs-CRP, hs-TnT, NT-proBNP, cystatin C, GDF-15 and activity of Lp-PLA2 are shown in the Table, after adjustments for co-variables. PA was independently and inversely associated with all biomarker levels, except for Lp-PLA2. Conclusions: Increasing PA, was independentlyand inversely associated with levels of most clinically important biomarkers, except for Lp-PLA2. The effects of PA on outcomes may partly be explained by disease processes reflected by changes in biomarker levels.
Abstract 10110: Effects of Inorganic Nitrate on Endothelial Dysfunction Induced by Periodontitis
Authors: Daniel Fernandes, Rayomand Khambata, Amrita Ahluwalia
Journal: Circulation (2015)

Introduction: Evidence supports an association between periodontal disease and cardiovascular disease (CVD) risk. Periodontal disease is thought to cause vascular dysfunction contributing to atherogenesis and resulting in an increased risk of stroke and coronary heart disease. Safe therapeutics that might improve vascular function in such patients to reduce risk of CVD is a current unmet need. It is thought that a critical step in the increased CVD risk relates to a periodontitis-induced endothelial dysfunction. Evidence suggests that the intervention of dietary nitrate, to elevate circulating nitrite levels, improves endothelial function. We investigated whether dietary nitrate might provide a method for prevention or reversal of the endothelial dysfunction induced by periodontitis. Methods: Male C57BL6 mice were either untreated or randomly assigned to receive KNO3 or KCl (15 mmol/L; in the drinking water) either 7 days prior or 7 days post ligature placement (periodontitis) or a sham procedure. After 14 days blood samples were collected for assessment of circulating cell types and activation state using flow cytometry. The vasoreactivity of aortic rings were assessed ex vivo. Maxillae were removed for alveolar bone loss measurement. Results: When compared to sham animals, ligature-induced periodontitis resulted in bone loss (~2-fold increase in the distance cement enamel junction and the alveolar crest, p&lt;0.001, n=9). This was associated with neutrophilia (n=9, P&lt;0.05) and endothelial dysfunction, reflected by a reduction of acetylcholine-induced relaxation (~20% suppression of the Max response, p&lt;0.05, n=5). Vascular responses to the endothelium-independent vasorelaxant, spermine NONOate, were unchanged. Dietary nitrate treatment improved endothelial function when given either as prophylaxis (p&lt;0.01, n=5) or reversal therapy (p&lt;0.01, n=5). These improvements were not associated with any changes in ligature-induced bone loss but were associated with reduced numbers and activation of circulating neutrophils. Conclusion: Dietary nitrate improves vascular function in periodontitis in mice and thus may represent an alternative treatment in the cardiovascular complications associated with this condition.
Abstract 15650: Hospital Variation in the Use of Targeted Temperature Management for Out-of-Hospital Cardiac Arrest
Authors: Rohan Khera, Andrew Humbert, Brian Leroux, Graham Nichol, Peter Kudenchuk, Damon C Scales, Andrew Baker, Mike Austin, Craig Newgard, Ryan P Radecki, Gary M Vilke, Kelly N Sawyer, George Sopko, Ahamed H Idris, Henry E Wang, Paul S Chan, Michael C Kurz
Journal: Circulation (2017)

Background: Patients with an out-of-hospital cardiac arrest (OHCA) treated with targeted temperature management (TTM) have improved survival. However, real world use of TTM and hospital deviation f...
Abstract P005: Comparative Effectiveness of Rivaroxaban versus Warfarin for the Treatment of Patients with Non-valvular Atrial Fibrillation
Authors: Faye L Norby, Lindsay G Bengtson, Lin Y Chen, Richard F MacLehose, Pamela L Lutsey, Ian Rapson, Alvaro Alonso
Journal: Circulation (2016)

Background: Rivaroxaban is a novel oral anticoagulant approved in the US in 2011 for prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF). Information on risks and benefits among rivaroxaban users in real-world populations is limited. Methods: We used data from the US MarketScan Commercial and Medicare Supplemental databases between 2010 and 2013. We selected patients with a history of NVAF and initiating rivaroxaban or warfarin. Rivaroxaban users were matched with up to 5 warfarin users by age, sex, database enrollment date and drug initiation date. Ischemic stroke, intracranial bleeding (ICB), myocardial infarction (MI), and gastrointestinal (GI) bleeding outcomes were defined by ICD-9-CM codes in an inpatient claim after drug initiation date. Cox proportional hazards models were used to assess the association between rivaroxaban vs. warfarin use and outcomes adjusting for age, sex, and CHA2DS2-VASc score. Separate models were used to compare a) new rivaroxaban users with new warfarin users, and b) switchers from warfarin to rivaroxaban to continuous warfarin users. Results: Our analysis included 34,998 rivaroxaban users matched to 102,480 warfarin users with NVAF (39% female, mean age 71), in which 487 ischemic strokes, 179 ICB, 647 MI, and 1353 GI bleeds were identified during a mean follow-up of 9 months. Associations of rivaroxaban vs warfarin were similar in new users and switchers; therefore we pooled both analyses. Rivaroxaban users had lower rates of ICB (hazard ratio (HR) (95% confidence interval (CI)) = 0.72 (0.46, 1.12))) and ischemic stroke (HR (95% CI) = 0.88 (0.68, 1.13)), but higher rates of GI bleeding (HR (95% CI) = 1.15 (1.01, 1.33)) when compared to warfarin users (table). Conclusion: In this large population-based study of NVAF patients, rivaroxaban users had a non-significant lower risk of ICB and ischemic stroke than warfarin users, but a higher risk of GI bleeding. These real-world findings are comparable to results reported in published clinical trials.
Abstract 14511: Communication About the Heart Failure Prognosis in the Us and Europe: Oceans Apart?
Authors: Lisa Hjelmfors, Martje van der Wal, Anna Stromberg, Lorraine S Evangelista, Janet Hildebrand, Tiny Jaarsma
Journal: Circulation (2017)

Introduction: International heart failure (HF) guidelines advocate discussing prognosis with patients. However, cultural differences might exist that influence such communication and therefore, we ...
Abstract 20051: Divergent Actions of Circulating Angiopoietin-2 on Vascular Inflammation and Leak in a Mouse Model of Acute Lung Injury
Authors: Kenny Schlosser, Mohamad Taha, Yupu Deng, Shirley H Mei, Duncan J Stewart
Journal: Circulation (2015)

Introduction: Angiopoietin-2 (Angpt2) is a partial agonist/antagonist of the vascular-stabilizing endothelial Tie2 receptor. In both animal models and patients with acute lung injury (ALI), Angpt2 circulating levels are elevated; however, it remains unclear whether these elevated levels contribute to, or protect against, the lung inflammation and vascular leak associated with ALI. Objective: To evaluate the biological consequences of elevated circulating Angpt2 levels in a mouse model of endotoxin-induced ALI. Methods and Results: Transgenic mice (Angpt2OVR) with elevated circulating levels of human (h)Angpt2, via conditional hepatocyte-specific overexpression, were examined at several timepoints (from 3 h to 72 h) following lipopolysaccharide (LPS)-induced ALI (n=7-14 mice/genotype group/timepoint). Bronchoalveolar lavage (BAL) neutrophil and inflammatory cytokine levels were significantly higher (P&lt;0.05) in Angpt2OVR versus littermate controls at 48 h and 6 h post LPS, respectively. In contrast, vascular leak, evidenced by decreased BAL IgM and albumin levels at 24 and 48 h, was attenuated in Angpt2OVR mice. Systemic Angpt2 overexpression showed no net detriment or benefit for survival following LPS-induced injury (n=37-38 mice/group). Tail vein injection of an anti-hAngpt2-neutralizing aptamer (versus non-functional scrambled-sequence control; n=12-13 mice/group), reversed the pro-inflammatory and anti-leak effects observed at 48 h in LPS-injured Angpt2OVR mice. Transcript profiling, via PCR array, was also conducted to probe the effects of Angpt2 neutralization on the lung tissue expression of 84 genes involved in vascular biology. Angpt2 neutralization via aptamer caused alterations in multiple genes linked to angiogenesis, vascular tone, inflammation, apoptosis, cell adhesion, coagulation, and platelet activation (P&lt;0.05 versus scrambled control, n=4/group). Conclusions: Angpt2 exerts differential effects on lung inflammation and permeability under pathological conditions in vivo. These data establish novel context-dependent actions of Angpt2, and suggest elevated circulating levels may help regulate multiple pathways necessary to fine-tune the vascular response to lung injury.
Investigation of a Cluster of <i>Sphingomonas koreensis</i> Infections
Authors: Ryan C. Johnson, Clay Deming, Sean Conlan, Caroline J. Zellmer, Angela V. Michelin, ShihQueen Lee-Lin, Pamela J. Thomas, Morgan Park, Rebecca A. Weingarten, John Less, John P. Dekker, Karen M. Frank, Kimberlee A. Musser, John R. McQuiston, David K. Henderson, Anna F. Lau, Tara N. Palmore, Julia A. Segre
Journal: New England Journal of Medicine (2018)

Plumbing systems are an infrequent but known reservoir for opportunistic microbial pathogens that can infect hospitalized patients. In 2016, a cluster of clinical sphingomonas infections prompted an investigation.We performed whole-genome DNA sequencing on clinical isolates of multidrug-resistant Sphingomonas koreensis identified from 2006 through 2016 at the National Institutes of Health (NIH) Clinical Center. We cultured S. koreensis from the sinks in patient rooms and performed both whole-genome and shotgun metagenomic sequencing to identify a reservoir within the infrastructure of the hospital. These isolates were compared with clinical and environmental S. koreensis isolates obtained from other institutions.The investigation showed that two isolates of S. koreensis obtained from the six patients identified in the 2016 cluster were unrelated, but four isolates shared more than 99.92% genetic similarity and were resistant to multiple antibiotic agents. Retrospective analysis of banked clinical isolates of sphingomonas from the NIH Clinical Center revealed the intermittent recovery of a clonal strain over the past decade. Unique single-nucleotide variants identified in strains of S. koreensis elucidated the existence of a reservoir in the hospital plumbing. Clinical S. koreensis isolates from other facilities were genetically distinct from the NIH isolates. Hospital remediation strategies were guided by results of microbiologic culturing and fine-scale genomic analyses.This genomic and epidemiologic investigation suggests that S. koreensis is an opportunistic human pathogen that both persisted in the NIH Clinical Center infrastructure across time and space and caused health care-associated infections. (Funded by the NIH Intramural Research Programs.).
Amyloid, tau, pathogen infection and antimicrobial protection in Alzheimer’s disease –conformist, nonconformist, and realistic prospects for AD pathogenesis
Authors: Hongmei Li, Chia-Chen Liu, Hui Zheng, Timothy Y. Huang
Journal: Translational Neurodegeneration (2018)

Alzheimer's disease (AD) is a fatal disease that threatens the quality of life of an aging population at a global scale. Various hypotheses on the etiology of AD have been developed over the years to guide efforts in search of therapeutic strategies.
Abstract 17338: Predictors of Fatal Incident Coronary Heart Disease in the Women’s Health Initiative
Authors: Shirin Zarafshar, Jin Li, Elias Salfati, Liana Del Gobbo, Themistocles L Assimes
Journal: Circulation (2016)

Introduction: Identifying predictors of a fatal incident CHD may allow us to better understand the pathophysiology of fatal events and to reduce case-fatality rates through more efficient implement...
ASLAN003, a Novel and Potent Dihydroorotate Dehydrogenase (DHODH) Inhibitor, Induces Differentiation of Acute Myeloid Leukemia
Authors: Jianbiao Zhou, Jessie Yiying Quah, Jing Yuan Chooi, Sabrina Hui-Min Toh, Yvonne Ng, Baohong Lin, Motomi Osato, Qihui Seet, A.G. Lisa Ooi, Bertil Lindmark, Mark McHale, Wee Joo Chng
Journal: Blood (2018)
CD14+CD16+ Monocyte Binding to Myeloma Cells Is Required for Daratumumab Dependent Killing in Multiple Myeloma Patients
Authors: Paola Storti, Rosanna Vescovini, Valentina Marchica, Marina Bolzoni, Federica Costa, Emanuela Vicario, Denise Toscani, Anna Benedetta Dalla Palma, Fabrizio Accardi, Fabio Malavasi, Franco Aversa, Nicola Giuliani
Journal: Blood (2018)
Abstract 15991: Assessing Longitudinal Medication Use in Pragmatic Clinical Trials: Insights From the ARTEMIS Trial
Authors: Tracy Wang, Lisa A Kaltenbach, Gregg C Fonarow, Timothy D Henry, Christopher P Cannon, David J Cohen, Eileen Fonseca, Durgesh D Bhandary, Naeem Khan, Kevin J Anstrom, Eric D Peterson
Journal: Circulation (2017)

Background: Tracking patient adherence to medication is important in clinical practice and research, yet how to do this efficiently and accurately is not clear. Patient self-report is the most economical option, but may be limited by recall bias. Pharmacy fill data denote drug dispensing, but may not reflect patients taking the therapy. Direct blood tests measure ingestion, but only assess recent compliance and are costly to implement in large trials. Agreement between these methodologies is unknown. Methods: ARTEMIS is an ongoing, pragmatic, randomized trial that enrolled patients with acute myocardial infarction (MI) discharged on P2Y12 inhibitor therapy from 287 United States hospitals (NCT# 02406677). All enrolled patients are interviewed every 3 months and asked whether they are taking a P2Y12 inhibitor. Pharmacy fill records were merged in and available for 8,254 (75%) of ARTEMIS patients, and blood P2Y12 inhibitor drug levels were measured in 1,006 (9%) randomly selected ARTEMIS patients. On-treatm...
Abstract 20150: Whole Exome Sequencing, Genomic Triangulation, and Systems Biology Converge to Identify TAB2 as a Novel Susceptibility Gene for Polyvalvular Syndrome
Authors: John A Smestad, Jamie D Kapplinger, David J Tester, Beau A Crabb, Nancy J Mendelsohn, Michael J Ackerman
Journal: Circulation (2014)

Introduction: The genetic basis for polyvalvular syndrome remains elusive. A male child was born with polyvalvular syndrome, aortic root dilatation, and an ASD, VSD, and PDA that were surgically cl...
Abstract 19382: Ablation of the Cardiac-Specific Gene Leucine-Rich Containing 10 (lrrc10) Results in Dilated Cariomyopathy
Authors: Matt Brody, Timothy A Hacker, Junichi Sadoshima, Sergei Tevosian, Youngsook Lee
Journal: Circulation (2012)

Dilated cardiomyopathy is the most common form of cardiomyopathy and is a leading cause of heart failure. Leucine-rich repeat containing 10 (LRRC10) is a cardiac-specific protein containing leucine-rich repeat motifs ideal for protein:protein interactions. We have previously shown that LRRC10 is essential for proper cardiac function in developing zebrafish. However, the role of LRRC10 in mammalian cardiac physiology remains unknown. To determine if LRRC10 is critical for mammalian cardiac function, Lrrc10-null (Lrrc10-/-) mice were evaluated by echocardiography. Lrrc10-/- mice exhibit prenatal systolic dysfunction and progressive dilated cardiomyopathy in postnatal life. Importantly, Lrrc10-/- mice have diminished cardiac performance in utero, prior to ventricular dilation observed in young adults. Gene expression profiling revealed that cardiac muscle contraction and oxidative phosphorylation are the most upregulated pathways in adult Lrrc10-/- hearts. We demonstrate that LRRC10 physically interacts with α-actinin and actin isoforms by coimmunoprecipitation, GST pulldown, and yeast two-hybrid screening, suggesting that LRRC10 may provide a link between the myofilament Z-disc and the actin cytoskeleton. Interaction of LRRC10 with α-actinin and actin positions it in ideal location in the cardiomyocyte to sense or transduce signals in response to biomechanical stress. To test the role of LRRC10 in response to biomechanical stress, transverse aortic constriction (TAC) was performed. Lrrc10-/- mice exhibit exacerbated and accelerated cardiomyopathy in response to 28 days of TAC with markedly greater left ventricular (LV) chamber dilation and severely compromised systolic and diastolic function relative to controls. Moreover, endogenous Lrrc10 expression is downregulated in controls in response to TAC, suggesting an important role for LRRC10 in cardiac adaptation to biomechanical stress. In summary, we identify the cardiac-specific factor Lrrc10 as a novel dilated cardiomyopathy candidate gene. LRRC10 is essential for normal cardiac function and is indispensible for proper adaptation of the mammalian heart to biomechanical stress.
“T2-high” in severe asthma related to blood eosinophil, exhaled nitric oxide and serum periostin
Authors: Stelios Pavlidis, Kentaro Takahashi, Francois Ng Kee Kwong, Jiaxing Xie, Uruj Hoda, Kai Sun, Vahid Elyasigomari, Paul Agapow, Matthew Loza, Fred Baribaud, Pascal Chanez, Steve J. Fowler, Dominic E. Shaw, Louise J. Fleming, Peter H. Howarth, Ana R. Sousa, Julie Corfield, Charles Auffray, Bertrand De Meulder, Richard Knowles, Peter J. Sterk, Yike Guo, Ian M. Adcock, Ratko Djukanovic, Kian Fan Chung
Journal: European Respiratory Journal (2018)

Type-2 (T2) immune responses in airway epithelial cells (AECs) classifies mild–moderate asthma into a T2-high phenotype. We examined whether currently available clinical biomarkers can predict AEC-defined T2-high phenotype within the U-BIOPRED cohort. The transcriptomic profile of AECs obtained from brushings of 103 patients with asthma and 44 healthy controls was obtained and gene set variation analysis used to determine the relative expression score of T2 asthma using a signature from interleukin (IL)-13-exposed AECs. 37% of asthmatics (45% nonsmoking severe asthma, n=49; 33% of smoking or ex-smoking severe asthma, n=18; and 28% mild–moderate asthma, n=36) were T2-high using AEC gene expression. They were more symptomatic with higher exhaled nitric oxide fraction ( F eNO ) and blood and sputum eosinophils, but not serum IgE or periostin. Sputum eosinophilia correlated best with the T2-high signature. F eNO (≥30 ppb) and blood eosinophils (≥300 cells·µL −1 ) gave a moderate prediction of T2-high asthma. Sputum IL-4, IL-5 and IL-13 protein levels did not correlate with gene expression. T2-high severe asthma can be predicted to some extent from raised levels of F eNO , blood and sputum eosinophil counts, but serum IgE or serum periostin were poor predictors. Better bedside biomarkers are needed to detect T2-high.