tbuckley/cabot-search huggingface dataset:
Characterization of a Resident Population of Adventitial Macrophage Progenitor Cells in Postnatal Vasculature
Authors: Peter J. Psaltis, Amrutesh S. Puranik, Daniel B. Spoon, Colin D. Chue, Scott J. Hoffman, Tyra A. Witt, Sinny Delacroix, Laurel S. Kleppe, Cheryl S. Mueske, Shuchong Pan, Rajiv Gulati, Robert D. Simari
Journal: Circulation Research (2014)

Macrophages regulate blood vessel structure and function in health and disease. The origins of tissue macrophages are diverse, with evidence for local production and circulatory renewal.We identified a vascular adventitial population containing macrophage progenitor cells and investigated their origins and fate.Single-cell disaggregates from adult C57BL/6 mice were prepared from different tissues and tested for their capacity to form hematopoietic colony-forming units. Aorta showed a unique predilection for generating macrophage colony-forming units. Aortic macrophage colony-forming unit progenitors coexpressed stem cell antigen-1 and CD45 and were adventitially located, where they were the predominant source of proliferating cells in the aortic wall. Aortic Sca-1(+)CD45(+) cells were transcriptionally and phenotypically distinct from neighboring cells lacking stem cell antigen-1 or CD45 and contained a proliferative (Ki67(+)) Lin(-)c-Kit(+)CD135(-)CD115(+)CX3CR1(+)Ly6C(+)CD11b(-) subpopulation, consistent with the immunophenotypic profile of macrophage progenitors. Adoptive transfer studies revealed that Sca-1(+)CD45(+) adventitial macrophage progenitor cells were not replenished via the circulation from bone marrow or spleen, nor was their prevalence diminished by depletion of monocytes or macrophages by liposomal clodronate treatment or genetic deficiency of macrophage colony-stimulating factor. Rather adventitial macrophage progenitor cells were upregulated in hyperlipidemic ApoE(-/-) and LDL-R(-/-) mice, with adventitial transfer experiments demonstrating their durable contribution to macrophage progeny particularly in the adventitia, and to a lesser extent the atheroma, of atherosclerotic carotid arteries.The discovery and characterization of resident vascular adventitial macrophage progenitor cells provides new insight into adventitial biology and its participation in atherosclerosis and provokes consideration of the broader existence of local macrophage progenitors in other tissues.
ASAS modification of the Berlin algorithm for diagnosing axial spondyloarthritis: results from the SPondyloArthritis Caught Early (SPACE)-cohort and from the Assessment of SpondyloArthritis international Society (ASAS)-cohort
Authors: Rosaline van den Berg, Manouk de Hooge, Martin Rudwaleit, Joachim Sieper, Floris van Gaalen, Monique Reijnierse, Robert Landewé, Tom Huizinga, Désirée van der Heijde
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objective</h3> To compare the original Berlin algorithm for diagnosing axial Spondyloarthritis (axSpA) with two modifications in the SPondyloArthritis Caught Early (SPACE)-cohort and the Assessment of SpondyloArthritis international Society (ASAS) axSpA criteria validation (ASAS)-cohort. <h3>Methods</h3> Patients in the SPACE-cohort (back pain ≥3 months, ≤2 years, onset &lt;45 years) and the ASAS-cohort (undiagnosed chronic back pain) were diagnosed according to three algorithms: original (inflammatory back pain (IBP) mandatory), modification 1 (IBP defined by ≥3/5 IBP-features instead of ≥4/5) and modification 2 (IBP deleted as obligatory entry criterion, added as SpA-feature). Diagnosis by rheumatologist, ASAS axSpA criteria and likelihood ratio product were used as external standards to test the performance of the algorithms. <h3>Results</h3> <i>SPACE-cohort</i>: Compared to the diagnosis by rheumatologist (either axSpA or no-axSpA), the original algorithm agreed in 120 patients (76.4%). Agreement decreased using modification 1 (119 patients; 75.8%), increased using modification 2 (125 patients; 79.6%). Sensitivity increased from 66.2% (original) to 72.3% (modification 1) and 78.5% (modification 2). Specificity decreased more using modification 1 (83.7% to 78.3%) than when using modification 2 (83.7% to 79.6%). <i>ASAS-cohort</i>: Compared to the diagnosis by rheumatologist (either axSpA or no-axSpA), the original algorithm agreed in 484 patients (70.7%). Agreement increased using modification 1 (520 patients; 75.9%) and modification 2 (548 patients; 80.0%). Sensitivity increased from 65.3% (original) to 77.9% (modification 1) and 79.6% (modification 2). Specificity decreased more using modification 1 (79.2% to 72.2%) than when using modification 2 (79.2% to 75.6%). <h3>Conclusions</h3> ASAS accepted a modified algorithm for diagnosing axSpA in which IBP is excluded as obligatory entry criterion and added as SpA-feature.
Tissue Doppler Imaging Consistently Detects Myocardial Contraction and Relaxation Abnormalities, Irrespective of Cardiac Hypertrophy, in a Transgenic Rabbit Model of Human Hypertrophic Cardiomyopathy
Authors: Sherif F. Nagueh, Helen A. Kopelen, Do-Sun Lim, William A. Zoghbi, Miguel A. Quiñones, Robert Roberts, Ali J. Marian
Journal: Circulation (2000)

Hypertrophic cardiomyopathy (HCM) is diagnosed clinically by the presence of left ventricular hypertrophy (LVH). However, LVH is absent in a significant number of genotype-positive patients. Because myocyte dysfunction and disarray are the primary abnormalities in HCM, we reasoned that tissue Doppler imaging could identify contraction and relaxation abnormalities, irrespective of hypertrophy, in a transgenic rabbit model of human HCM.M-mode, 2D, Doppler echocardiography and tissue Doppler imaging were performed in nontransgenic (n=24), wild-type beta-myosin heavy chain-arginine(403) (n=14), and mutant beta-myosin heavy chain-glutamic acid(403) (n=24) transgenic rabbits. Mean septal thicknesses were 2.0+/-0.3, 2.0+/-0.25, and 2.75+/-0.3 mm in the 3 groups, respectively (P:=0.001). LVH was absent in 9 of the 24 mutant rabbits. Left ventricular dimensions, systolic function, heart rate, mitral inflow velocities, and time intervals were similar in the groups. However, the difference between atrial reversal and transmitral A wave duration was increased in the mutant rabbits (P:<0.001). More importantly, systolic and early diastolic tissue Doppler velocities were significantly lower in all mutant rabbits (7.45+/-2.2 versus 10.8+/-2.3 cm/s in nontransgenic and 9. 0+/-0.76 cm/s in wild-type; P:<0.001), including the 9 without LVH. A systolic velocity <8.5 cm/s had an 86% sensitivity and 100% specificity in identifying the mutant transgenic rabbits.Myocardial contraction and relaxation were reduced in the mutant beta-myosin heavy chain-glutamic acid(403) transgenic rabbit model of human HCM, irrespective of the presence or absence of LVH. In addition, tissue Doppler imaging is more sensitive than conventional echocardiography for HCM screening.
A New Technic for Complete Correction of Transposition of the Great Vessels
Authors: F. S. IDRISS, I. R. GOLDSTEIN, L. GRANA, D. FRENCH, W. J. POTTS
Journal: Circulation (1961)

A procedure for complete anatomic correction of transposition of the great vessels is described. The technic is based on the concept of isolating an aortic segment containing both coronary ostia and turning the segment over to fit the outflow stump of the left ventricle. Experimental work and two clinical trials are presented and discussed. We believe that this operation provides an anatomic and physiologic correction of the great vessels and coronary arteries in transposition. In spite of two clinical failures, we think this operation is worthy of further trials.
Impact of the U.S. Food and Drug Administration Cardiovascular Assessment Requirements on the Development of Novel Antidiabetes Drugs
Authors: Boaz Hirshberg, Itamar Raz
Journal: Diabetes Care (2011)

Lingering questions related to cardiovascular (CV) safety of type 2 diabetes treatments resulted in new U.S. Food and Drug Administration (FDA) regulations requiring careful assessment of CV risk. These new requirements will provide the medical community with robust data to estimate CV risk associated with new therapeutic agents. To meet these requirements, phase 2 and 3 development programs will need to be larger and more comprehensive and will include high-risk patients. In addition, it is likely that most (if not all) newly approved drugs will be required to conduct post-approval CV safety outcome studies. The purpose of this article is to review the drivers for the new FDA requirements and how these new requirements will affect the development of novel antidiabetes drugs.

The goals of antidiabetes treatment are to forestall the metabolic effects of high glucose levels and to prevent microvascular and macrovascular complications. Compelling data in type 2 diabetic patients support the conclusion that improved long-term glycemic control reduces the risk of microvascular complications (1,2). Based on several large outcome studies (e.g., the Diabetes Control Complications Trial and the UK Prospective Diabetes Study [UKPDS]), glycosylated hemoglobin (HbA1c) was established as a surrogate biomarker of glycemic control and therapeutic goals were set accordingly (3).

Cardiovascular disease is the leading cause of death in patients with type 2 diabetes; more than 60% die of CV disease, and an even greater proportion have serious CV-related complications. Diabetes is associated with a two- to fourfold increase in the risk of coronary heart disease and death (4). Patients with type 2 diabetes who have not had a myocardial infarction (MI) have a risk of infarction similar to that of nondiabetic patients who have had a prior MI (5–7). Pooled data from patients with acute coronary syndrome (ACS) in …
Dynamic PET and Optical Imaging and Compartment Modeling using a Dual-labeled Cyclic RGD Peptide Probe
Authors: Lei Zhu, Ning Guo, Quanzheng Li, Ying Ma, Orit Jacboson, Seulki Lee, Hak Soo Choi, James R. Mansfield, Gang Niu, Xiaoyuan Chen
Journal: Theranostics (2012)

Purpose:The aim of this study is to determine if dynamic optical imaging could provide comparable kinetic parameters to that of dynamic PET imaging by a near-infrared dye/ 64 Cu dual-labeled cyclic RGD peptide.Methods: The integrin α v β 3 binding RGD peptide was conjugated with a macrocyclic chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) for copper labeling and PET imaging and a near-infrared dye ZW-1 for optical imaging.The in vitro biological activity of RGD-C(DOTA)-ZW-1 was characterized by cell staining and receptor binding assay.Sixty-min dynamic PET and optical imaging were acquired on a MDA-MB-435 tumor model.Singular value decomposition (SVD) method was applied to compute the dynamic optical signal from the two-dimensional optical projection images.Compartment models were used to quantitatively analyze and compare the dynamic optical and PET data.Results: The dual-labeled probe 64 Cu-RGD-C(DOTA)-ZW-1 showed integrin specific binding in vitro and in vivo.The binding potential (Bp) derived from dynamic optical imaging (1.762 ± 0.020) is comparable to that from dynamic PET (1.752 ± 0.026). Conclusion:The signal un-mixing process using SVD improved the accuracy of kinetic modeling of 2D dynamic optical data.Our results demonstrate that 2D dynamic optical imaging with SVD analysis could achieve comparable quantitative results as dynamic PET imaging in preclinical xenograft models.
The Human Genome Organisation: towards next-generation ethics
Authors: Bartha Knoppers, Adrian Thorogood, Ruth Chadwick
Journal: Genome Medicine (2013)

Ten years after the completion of the human genome [1], looking back over the policy statements of the Human Genome Organisation's (HUGO) Ethics Committee (EC) and of its Intellectual Property Committee (IPC) is more than just a trip down memory lane; it is the revelation of a seismic shift in the values underlying genomic research (Table 1).Founded in 1992 at the inception of the Human Genome Project, HUGO not only provided prospective scientifi c leadership on approaches to intellectual property, but also on ethical, legal and social issues.Indeed, the Statements constitute a harbinger of policy debates that persist today.In the past two decades, genetic research ethics has expanded rapidly from a domain seemingly 'ungoverned by any explicitly ethical or legal norms' , to a rich and sophisticated fi eld [2].Initially, the concerns of the EC and IPC were to ensure participant autonomy through informed consent, respect for participant privacy and confi dentiality in light of the sensitive nature of genetic information, and an equitable distribution of the burdens and benefi ts of genetic research.Th ese concerns are prevalent throughout the HUGO Statements, even as the focus of genetic ethics has shifted from the protection of individuals, families and communities, to considering the broader interests of society, and international harmonization.
Genetic Polymorphisms of the Human<i>MDR1</i>Drug Transporter
Authors: Matthias Schwab, Michel Eichelbaum, Martin F. Fromm
Journal: The Annual Review of Pharmacology and Toxicology (2003)

P-glycoprotein is an ATP-dependent efflux pump that contributes to the protection of the body from environmental toxins. It transports a huge variety of structurally diverse compounds. P-glycoprotein is involved in limiting absorption of xenobiotics from the gut lumen, in protection of sensitive tissues (brain, fetus, testis), and in biliary and urinary excretion of its substrates. P-glycoprotein can be inhibited or induced by xenobiotics, thereby contributing to variable drug disposition and drug interactions. Recently, several SNPs have been identified in the MDR1 gene, some of which can affect P-glycoprotein expression and function. Potential implications of MDR1 polymorphisms for drug disposition, drug effects, and disease risk are discussed.
Endocrine Therapy With or Without Inhibition of Epidermal Growth Factor Receptor and Human Epidermal Growth Factor Receptor 2: A Randomized, Double-Blind, Placebo-Controlled Phase III Trial of Fulvestrant With or Without Lapatinib for Postmenopausal Women With Hormone Receptor–Positive Advanced Breast Cancer—CALGB 40302 (Alliance)
Authors: Harold J. Burstein, Constance T. Cirrincione, William T. Barry, Helen K. Chew, Sara M. Tolaney, Diana E. Lake, Cynthia Ma, Kimberly L. Blackwell, Eric P. Winer, Clifford A. Hudis
Journal: Journal of Clinical Oncology (2014)

CALGB 40302 sought to determine whether lapatinib would improve progression-free survival (PFS) among women with hormone receptor-positive metastatic breast cancer treated with fulvestrant.Eligible women had estrogen receptor-positive and/or progesterone receptor-positive tumors, regardless of human epidermal growth factor receptor 2 (HER2) status, and prior aromatase inhibitor treatment. Patients received fulvestrant 500 mg intramuscularly on day 1, followed by 250 mg on days 15 and 28 and every 4 weeks thereafter, and either lapatinib 1,500 mg or placebo daily. The study planned to accrue 324 patients and was powered for a 50% improvement in PFS with lapatinib from 5 to 7.5 months.At the third planned interim analysis, the futility boundary was crossed, and the data and safety monitoring board recommend study closure, having accrued 295 patients. At the final analysis, there was no difference in PFS (hazard ratio [HR] of placebo to lapatinib, 1.04; 95% CI, 0.82 to 1.33; P = .37); median PFS was 4.7 months for fulvestrant plus lapatinib versus 3.8 months for fulvestrant plus placebo. There was no difference in overall survival (OS) (HR, 0.91; 95% CI, 0.68 to 1.21; P = .25). For HER2-normal tumors, median PFS did not differ by treatment arm (4.1 v 3.8 months). For HER2-positive tumors, lapatinib was associated with longer median PFS (5.9 v 3.3 months), but the differential treatment effect by HER2 status was not significant (P = .53). The most frequent toxicities were diarrhea, fatigue, and rash associated with lapatinib.Adding lapatinib to fulvestrant does not improve PFS or OS in advanced ER-positive breast cancer and is more toxic.
Effects of Low Phenylalanine-Tyrosine Diets on S91 Mouse Melanomas&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Harry B. Demopoulos
Journal: JNCI Journal of the National Cancer Institute (1966)

Partially synthetic diets low in phenylalanine and tyrosine selectively inhibited pigmented S91 melanomas carried subcutaneously in DBA/2 mice. S37 sarcomas, carried in the same strain mice, served as nonpigmented controls and were not affected by the various diets fed to the hosts. For the 4-week period studied, the somatic growth of the mice was not obviously impaired by the diets low in phenylalanine and tyrosine. The few tumors that did take and grow were smaller, but were grossly as well pigmented as the control S91 tumors. Manometric and tissue culture studies revealed that the in vivo tyrosine-deficient melanomas could consume as much oxygen and grow as well as control S91 melanomas when incubated in medium containing adequate tyrosine. The in vivo inhibition of S91 growth might have been due to substrate limitation of tyrosinase. However, diminished protein synthesis, due to sequestration of tyrosine into melanin, cannot be definitely excluded as the cause of the poor growth of the tyrosine-deficient melanomas.
Novel Modulator for Endothelial Adhesion Molecules
Authors: Noriyuki Ouchi, Shinji Kihara, Yukio Arita, Kazuhisa Maeda, Hiroshi Kuriyama, Yoshihisa Okamoto, Kikuko Hotta, Makoto Nishida, Masahiko Takahashi, Tadashi Nakamura, Shizuya Yamashita, Tohru Funahashi, Yuji Matsuzawa
Journal: Circulation (1999)

Among the many adipocyte-derived endocrine factors, we recently found an adipocyte-specific secretory protein, adiponectin, which was decreased in obesity. Although obesity is associated with increased cardiovascular mortality and morbidity, the molecular basis for the link between obesity and vascular disease has not been fully clarified. The present study investigated whether adiponectin could modulate endothelial function and relate to coronary disease.For the in vitro study, human aortic endothelial cells (HAECs) were preincubated for 18 hours with the indicated amount of adiponectin, then exposed to tumor necrosis factor-alpha (TNF-alpha) (10 U/mL) or vehicle for the times indicated. The adhesion of human monocytic cell line THP-1 cells to HAECs was determined by adhesion assay. The surface expression of vascular cell adhesion molecule-1 (VCAM-1), endothelial-leukocyte adhesion molecule-1 (E-selectin), and intracellular adhesion molecule-1 (ICAM-1) was measured by cell ELISA. Physiological concentrations of adiponectin dose-dependently inhibited TNF-alpha-induced THP-1 adhesion and expression of VCAM-1, E-selectin, and ICAM-1 on HAECs. For the in vivo study, the concentrations of adiponectin in human plasma were determined by a sandwich ELISA system that we recently developed. Plasma adiponectin concentrations were significantly lower in patients with coronary artery disease than those in age- and body mass index-adjusted control subjects.These observations suggest that adiponectin modulates endothelial inflammatory response and that the measurement of plasma adiponectin levels may be helpful in assessment of CAD risk.
Proteomic-Based Prognosis of Brain Tumor Patients Using Direct-Tissue Matrix-Assisted Laser Desorption Ionization Mass Spectrometry
Authors: Sarah A. Schwartz, Robert J. Weil, Reid C. Thompson, Yu Shyr, Jason H. Moore, Steven A. Toms, Mahlon D. Johnson, Richard M. Caprioli
Journal: Cancer Research (2005)

Abstract Clinical diagnosis and treatment decisions for a subset of primary human brain tumors, gliomas, are based almost exclusively on tissue histology. Approaches for glioma diagnosis can be highly subjective due to the heterogeneity and infiltrative nature of these tumors and depend on the skill of the neuropathologist. There is therefore a critical need to develop more precise, nonsubjective, and systematic methods to classify human gliomas. To this end, mass spectrometric analysis has been applied to these tumors to determine glioma-specific protein patterns. Protein profiles have been obtained from human gliomas of various grades through direct analysis of tissue samples using matrix-assisted laser desorption ionization mass spectrometry (MS). Statistical algorithms applied to the MS profiles from tissue sections identified protein patterns that correlated with tumor histology and patient survival. Using a data set of 108 glioma patients, two patient populations, a short-term and a long-term survival group, were identified based on the tissue protein profiles. In addition, a subset of 57 patients diagnosed with high-grade, grade IV, malignant gliomas were analyzed and a novel classification scheme that segregated short-term and long-term survival patients based on the proteomic profiles was developed. The protein patterns described served as an independent indicator of patient survival. These results show that this new molecular approach to monitoring gliomas can provide clinically relevant information on tumor malignancy and is suitable for high-throughput clinical screening.
Time loss injuries compromise team success in Elite Rugby Union: a 7-year prospective study
Authors: Sean Williams, Grant Trewartha, Simon P T Kemp, John H M Brooks, Colin W Fuller, Aileen E Taylor, Matthew J Cross, Keith A Stokes
Journal: British Journal of Sports Medicine (2015)

A negative association between injuries and team success has been demonstrated in professional football, but the nature of this association in elite Rugby Union teams is currently unclear.To assess the association between injury burden measures and team success outcomes within professional Rugby Union teams.A seven-season prospective cohort design was used to record all time-loss injuries incurred by English Premiership players. Associations between team success measures (league points tally and Eurorugby Club Ranking (ECR)) and injury measures (injury burden and injury days per team-match) were modelled, both within (changes from season to season) and between (differences averaged over all seasons) teams. Thresholds for the smallest worthwhile change in league points tally and ECR were 3 points and 2.6%, respectively.Data from a total of 1462 players within 15 Premiership teams were included in the analysis. We found clear negative associations between injury measures and team success (70-100% likelihood), with the exception of between-team differences for injury days per team-match and ECR, which was unclear. A reduction in injury burden of 42 days (90% CI 30 to 70) per 1000 player hours (22% of mean injury burden) was associated with the smallest worthwhile change in league points tally.Clear negative associations were found between injury measures and team success, and moderate reductions in injury burden may have worthwhile effects on competition outcomes for professional Rugby Union teams. These findings may be useful when communicating the value of injury prevention initiatives within this elite sport setting.