tbuckley/cabot-search huggingface dataset:
Accelerated Cardiomyopathy in Mice With Overexpression of Cardiac G <sub>s</sub> α and a Missense Mutation in the α-Myosin Heavy Chain
Authors: Stefan E. Hardt, Yong-Jian Geng, Olivier Montagne, Kuniya Asai, Chull Hong, Gui Ping Yang, Sanford P. Bishop, Song-Jung Kim, Dorothy E. Vatner, Christine E. Seidman, J.G. Seidman, Charles J. Homcy, Stephen F. Vatner
Journal: Circulation (2002)

To understand further the pathogenesis of familial hypertrophic cardiomyopathy, we determined how the cardiomyopathy induced by an Arg403-->Gln missense mutation in the alpha-myosin heavy chain (403) is affected by chronically enhancing sympathetic drive by mating the mice with those overexpressing G(s)alpha (G(s)alpha x403).Heart rate in 3-month-old conscious mice was elevated similarly (P<0.05) in mice overexpressing G(s)alpha (G(s)alpha mice; 746 +/- 14 bpm) and G(s)alpha x403 mice (718+/- 19 bpm) compared with littermate wild-type mice (WT; 623+/- 18 bpm) and 403 mice (594+/- 16 bpm). Left ventricular ejection fraction (LVEF), as determined by echocardiography, was enhanced in G(s)alpha x403 mice (88+/- 1%, P<0.001) compared with WT (69+/- 1%), 403 (75+/- 1%), and G(s)alpha (69 +/- 2%) mice. Isolated cardiomyocytes from G(s)alpha x403 mice also exhibited higher (P<0.001) baseline percent contraction (11.9+/- 0.5%) than WT (7.0+/- 0.5%), 403 (5.5+/- 0.5%), and G(s)alpha (7.8+/- 0.3%) cardiomyocytes. Relaxation of myocytes was impaired in 403 mice compared with WT but enhanced in G(s)alpha and normalized in G(s)alpha x403 mice. This was also observed in vivo. In vivo isoproterenol (0.1 microgram . kg(-1) . min(-1)) increased LVEF to maximal levels in G(s)alpha x403 and G(s)alpha, whereas in 403, the response was attenuated compared with WT. At 10 months of age, G(s)alpha x403 had significantly depressed LVEF (57 +/- 4%). Histopathological examination demonstrated that myocyte hypertrophy and fibrosis were already present in young G(s)alpha x403 mice and that old animals had severe cardiomyopathy. By 15 months of age, the survival of G(s)alpha x403 was 0% compared with 100% for WT, 71% for G(s)alpha, and 100% for 403 mice (P<0.05).These results show that the cardiomyopathy developed by G(s)alpha x403 mice is synergistic rather than additive, most likely owing to the elevated baseline function combined with enhanced responsiveness to sympathetic stimulation.
Oral Cancer and Precancerous Lesions
Authors: B. W. Neville, T. A. Day
Journal: CA A Cancer Journal for Clinicians (2002)

In the United States, cancers of the oral cavity and oropharynx represent approximately three percent of all malignancies in men and two percent of all malignancies in women. The American Cancer Society estimates that 28,900 new cases of oral cancer will be diagnosed in 2002, and nearly 7,400 people will die from this disease. Over 90 percent of these tumors are squamous cell carcinomas, which arise from the oral mucosal lining. In spite of the ready accessibility of the oral cavity to direct examination, these malignancies still are often not detected until a late stage, and the survival rate for oral cancer has remained essentially unchanged over the past three decades. The purpose of this article is to review the clinical features of oral cancer and premalignant oral lesions, with an emphasis on early detection.
DEVELOPMENT AND REGULATION OF CELL-MEDIATED IMMUNE RESPONSES TO THE BLOOD STAGES OF MALARIA: Implications for Vaccine Research
Authors: Michael F. Good, Huji Xu, Michelle Wykes, Christian R. Engwerda
Journal: Annual Review of Immunology (2004)

▪ Abstract The immune response to the malaria parasite is complex and poorly understood. Although antibodies and T cells can control parasite growth in model systems, natural immunity to malaria in regions of high endemicity takes several years to develop. Variation and polymorphism of antibody target antigens are known to impede immune responses, but these factors alone cannot account for the slow acquisition of immunity. In human and animal model systems, cell-mediated responses can control parasite growth effectively, but such responses are regulated by parasite load via direct effects on dendritic cells and possibly on T and B cells as well. Furthermore, high parasite load is associated with pathology, and cell-mediated responses may also harm the host. Inflammatory cytokines have been implicated in the pathogenesis of cerebral malaria, anemia, weight loss, and respiratory distress in malaria. Immunity without pathology requires rapid parasite clearance, effective regulation of the inflammatory antiparasite effects of cellular responses, and the eventual development of a repertoire of antibodies effective against multiple strains. Data suggest that this may be hastened by exposure to malaria antigens in low dose, leading to augmented cellular immunity and rapid parasite clearance.
P142 A Comparison of the Simplified Pulmonary Embolism Severity Index with the European Society of Cardiology Severity Score For Acute PE
Authors: MT Harrison, JE Latham, JD Chalmers, S Schembri
Journal: Thorax (2012)

<h3>Introduction</h3> Risk stratification in acute pulmonary embolism (PE) is useful in identifying low risk patients suitable for ambulatory care and those at high risk in need of intensive monitoring. In this study we compared two of the most well used scoring systems, the European Society of Cardiology (ESC) criteria and the simplified pulmonary embolism severity index (sPESI). <h3>Methods</h3> We retrospectively identified patients admitted to NHS Tayside over a 4 year period with radiologically confirmed PE and calculated their ESC and sPESI scores. RV dysfunction was defined by RV/LV ratio &gt;1 on CTPA or by echocardiography. As per the ECS criteria, patients with shock (defined as SBP&lt;90mmHg) and RV dysfunction or myocardial injury (defined as troponin I &gt;0.045) were classified as high risk, RV dysfunction or myocardial injury without shock as intermediate risk and patients with none of the above criteria classified as low risk. <h3>Patients</h3> with any one of the six sPESI risk factors (age&gt;80, cancer, chronic lung disease, SpO<sub>2</sub> &lt;90%, SBP&lt;90mmHg, HR&gt;110) were classified as high risk. The primary outcome was 30-day mortality or requirement for thrombolysis. <h3>Results</h3> 291 patients (45.8% male) were identified with a median age of 67 years (interquartile range 54–78 years). Low risk sPESI patients had a 2.2% risk of mortality or requirement for thrombolysis, in high risk patients (1 or more risk factors) the rate was 15.2%. Using ESC criteria, low risk patients had a 7.0% risk or mortality or thrombolysis with high risk patients having a risk of 21.2%. The positive likelihood ratio for ESC was 2.2 vs 1.6 for sPESI. The negative likelihood ratio was 0.18 for sPESI compared to 0.7 for ESC. The area under the receiver operator characteristic curves for both scores is shown in Figure 1. Both had moderate overall predictive value (AUC 0.68, 95% CI 0.63–0.73) for both scores, p&lt;0.0001. <h3>Conclusion</h3> The sPESI score is superior to the ESC score in identifying patients with acute PE who are at low risk of poor outcome, while ESC is superior to sPESI at identifying high risk patients.
Boosting Bioavailability of Topotecan: What Do We Gain?
Authors: Gary Hudes
Journal: Journal of Clinical Oncology (2002)

Article Tools EDITORIALS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.20.13.2918 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 12089219 Boosting Bioavailability of Topotecan: What Do We Gain? Gary HudesxGary HudesSearch for articles by this author Show More Fox Chase Cancer Center, Philadelphia, PA https://doi.org/10.1200/JCO.2002.20.13.2918 Full Text PDF Figures and Tables "Boosting Bioavailability of Topotecan: What Do We Gain?." Journal of Clinical Oncology, 20(13), pp. 2918–2919© 2002 by American Society of Clinical Oncology
Differences in atrial versus ventricular remodeling in dogs with ventricular tachypacing-induced congestive heart failure
Authors: N HANNA
Journal: Cardiovascular Research (2004)

Background: Congestive heart failure (CHF) causes arrhythmogenic remodeling in both atria and ventricles, but differences between atrial and ventricular remodeling in CHF have not been well characterized. Methods and results: We examined atrial and ventricular tissues from dogs with CHF induced by ventricular tachypacing (220–240/min) for 0 (control) or 24 h, or 1, 2 or 5 weeks. Histopathology was used to assess apoptosis, fibrosis, white blood cell infiltration and cell death, ELISA to measure angiotensin-II concentration and Western blot to evaluate protein expression. Ventricular tachypacing-induced CHF was associated with substantially more fibrosis in left atrium (maximum 10±1% at 5 weeks) than in left ventricle (0.4±0.1% at 5 weeks, P<0.01 versus left atrium). Tissue angiotensin-II concentration increased to steady state in atrial tissue at 24 h but increased more slowly in left ventricle, with a maximum that was significantly higher in atrium than ventricle. Ventricular tachypacing caused tissue apoptosis, inflammatory cell infiltration and cell death, with maximum changes in left atrium being faster, transient and larger than in left ventricle. Mitogen activated protein kinase activation was rapid (within 24 h) in left atrium, but smaller and slower (p38, c-Jun N-terminal kinase) or non-significant (extracellular signal-related kinase) in left ventricle. The 25-kDa activated form of transforming growth factor-β1, a particularly important profibrotic mediator in atrium, increased significantly in left atrium, from 2.6±0.6 (control) to 9.2±1.7 (24 h) and 8.1±1.8 optical density units (1 week), but was not significantly changed in ventricle. Conclusions: There are qualitative and quantitative differences in atrial versus ventricular remodeling in experimental ventricular tachypacing-induced CHF, with potentially important consequences for understanding underlying mechanisms and developing new therapeutic approaches.
Role of urokinase and its receptor in basal and stimulated colonic epithelial cell migration in vitro
Authors: A J Wilson
Journal: Gut (2000)

<h3>BACKGROUND</h3> Migration of colonic epithelial cells is important for mucosal repair following injury. The urokinase (u-PA) system regulates migration in other cell types. <h3>AIM</h3> To examine the role of u-PA and its receptor (u-PAR) in colonic epithelial cell migration. <h3>METHODS</h3> Migration was assessed over 24 hours in circular wounds made in confluent monolayers of LIM1215 and Caco-2 human colon cancer cells. The function of u-PA and u-PAR was ablated with antisense oligonucleotides to block expression, with synthetic u-PA peptides to block interaction, and with aprotinin to block u-PA mediated proteolysis. <h3>RESULTS</h3> Migration was stimulated two to threefold by exogenous u-PA, an effect dependent on u-PAR binding but independent of u-PA mediated mitogenesis and proteolysis. Expression of u-PA and u-PAR was inhibited by 80% by the appropriate antisense oligonucleotide. Basal migration and the motogenic effects of butyrate, epidermal growth factor, and phorbol-12-myristate-13-acetate were suppressed by the u-PAR antisense oligonucleotide (40–60%) but were at best minimally affected following inhibition of u-PA expression and binding. <h3>CONCLUSIONS</h3> In an in vitro model of wounded colonic epithelium, u-PAR promotes cell migration through mechanisms that are not exclusively dependent on u-PA binding. Therefore, u-PA and u-PAR may contribute to colonic mucosal repair in vivo.
Minimally modified low-density lipoprotein induces monocyte adhesion to endothelial connecting segment-1 by activating β1 integrin
Authors: Peggy T. Shih, Mariano J. Elices, Zhuang T. Fang, Tatiana P. Ugarova, Dana Strahl, Mary C. Territo, Joy S. Frank, Nicholas L. Kovach, Carlos Cabanas, Judith A. Berliner, Devendra K. Vora
Journal: Journal of Clinical Investigation (1999)

We have shown previously that treatment of human aortic endothelial cells (HAECs) with minimally modified low-density lipoprotein (MM-LDL) induces monocyte but not neutrophil binding. This monocyte binding was not mediated by endothelial E-selectin, P-selectin, vascular cell adhesion molecule-I, or intercellular adhesion molecule-I, suggesting an alternative monocyte-specific adhesion molecule. We now show that moncytic α4β1 integrins mediate binding to MM-LDL-treated endothelial cells. We present data suggesting that the expression of the connecting segment-1 (CS-1) domain of fibronectin (FN) is induced on the apical surface of HAEC by MM-LDL and is the endothelial α4β1 ligand in MM-LDL-treated cells. Although the levels of CS-1 mRNA and protein were not increased, we show that MM-LDL treatment causes deposition of FN on the apical surface by activation of β1integrins, particularly those associated with α5 integrins.Activation of β1 by antibody 8A2 also induced CS-1-mediated monocyte binding. Confocal microscopy demonstrated the activated β1 and CS-1colocalize in concentrated filamentous patches on the apical surface of HAEC. Both anti-CS-1 and an antibody to activated β1 showed increased staining on the luminal endothelium of human coronary lesions with active monocyte entry. These results suggest the importance of these integrin ligand interactions in human atherosclerosis.
High-fat diet impairs the effects of a single bout of endurance exercise on glucose transport and insulin sensitivity in rat skeletal muscle
Authors: Satsuki Tanaka, Tatsuya Hayashi, Taro Toyoda, Taku Hamada, Yohei Shimizu, Masakazu Hirata, Ken Ebihara, Hiroaki Masuzaki, Kiminori Hosoda, Tohru Fushiki, Kazuwa Nakao
Journal: Metabolism (2007)
Mice Deficient in Nuclear Factor (NF)-κB/p52 Present with Defects in Humoral Responses, Germinal Center Reactions, and Splenic Microarchitecture
Authors: Guido Franzoso, Louise Carlson, Ljiljana Poljak, Elizabeth W. Shores, Suzanne Epstein, Antonio Leonardi, Alex Grinberg, Tom Tran, Tanya Scharton-Kersten, Miriam Anver, Paul Love, Keith Brown, Ulrich Siebenlist
Journal: The Journal of Experimental Medicine (1998)

p52 is a subunit of nuclear factor (NF)-kappa B transcription factors, most closely related to p50. Previously, we have shown that p52, but not p50 homodimers can form transactivating complexes when associated with Bcl-3, an unusual member of the I kappa B family. To determine nonredundant physiologic roles of p52, we generated mice deficient in p52. Null mutant mice were impaired in their ability to generate antibodies to T-dependent antigens, consistent with an absence of B cell follicles and follicular dendritic cell networks in secondary lymphoid organs, and an inability to form germinal centers. Furthermore, the splenic marginal zone was disrupted. These phenotypes are largely overlapping with those observed in Bcl-3 knockout animals, but distinct from those of p50 knockouts, supporting the notion of a physiologically relevant complex of p52 homodimers and Bcl-3. Adoptive transfer experiments further suggest that such a complex may be critical in accessory cell functions during antigen-specific immune reactions. Possible roles of p52 and Bcl-3 are discussed that may underlie the oncogenic potential of these proteins, as evidenced by recurrent chromosomal translocations of their genes in lymphoid tumors.
Anti-TNF treatment blocks the induction of T cell-dependent humoral responses
Authors: Gabriela Franco Salinas, Leen De Rycke, Barbara Barendregt, Jacqueline E Paramarta, Hulda Hreggvidstdottir, Tineke Cantaert, Mirjam van der Burg, Paul P Tak, Dominique Baeten
Journal: Annals of the Rheumatic Diseases (2012)

Experimental and human data suggest that tumour necrosis factor (TNF) blockade may affect B cell responses, in particular the induction of T cell-dependent (TD) humoral immunity. This study aimed to assess this hypothesis directly in patients with arthritis by analysing longitudinally the effect of TNF blockade on B cell activation and the maturation of humoral responses against TD and T cell-independent vaccines.Peripheral blood samples were obtained from 56 spondyloarthritis patients before and after treatment with either non-steroidal anti-inflammatory drug (NSAID) alone or TNF blockers and analysed for B cell activation, plasma cell differentiation, germinal centre versus extra-follicular B cell maturation, and somatic hypermutation. Vaccine responses to hepatitis B and Streptococcus pneumoniae were measured by ELISA.TNF blockade augmented B cell activation as reflected by the expression of early activation markers, CD40, and costimulatory molecules, without affecting differentiation towards plasmablasts. This was associated with a specific increase of the unswitched fraction of circulating memory B cells and a decreased level of somatic hypermutation in anti-TNF treated patients, indicating an impairment of the germinal centre-dependent B cell maturation. In agreement with these findings, TNF blockade profoundly suppressed the response to the TD vaccination against hepatitis B, whereas the T cell-independent response against pneumococcal polysaccharides was only modestly affected.These data indicate that TNF blockade severely impedes the induction of primary TD humoral responses, probably by interfering with the germinal centre reaction.
Role of NAD(P)H Oxidase in Angiotensin II–Induced JAK/STAT Signaling and Cytokine Induction
Authors: Bernhard Schieffer, Maren Luchtefeld, Sabine Braun, Andres Hilfiker, Denise Hilfiker-Kleiner, Helmut Drexler
Journal: Circulation Research (2000)

Abstract —Inflammatory processes involve both synthesis of inflammatory cytokines, such as interleukin-6 (IL-6), and the activation of their distinct signaling pathways, eg, the janus kinases (JAKs) and signal transducers and activators of transcription (STAT). Superoxide (O 2 − ) anions activate this signaling cascade, and the vasoconstrictor angiotensin II (Ang II) enhances the formation of O 2 − anions via the NAD(P)H oxidase system in rat aortic smooth muscle cells. Ang II activates the JAK/STAT cascade via its type 1 (AT 1 ) receptor and induces synthesis and release of IL-6. Therefore, we investigated the role of O 2 − anions generated by the NAD(P)H oxidase system on the Ang II activation of the JAK/STAT cascade and its impact on IL-6 synthesis. Ang II stimulation of rat aortic smooth muscle cells induced a rapid increase in O 2 − anions determined by laser fluoroscopy, which can be abolished by DPI, a flavoprotein inhibitor. Ang II–induced phosphorylation of JAK2, STAT1α/β, STAT3, and IL-6-synthesis can be abolished by DPI, as determined by immunoprecipitations and Northern blot analysis. Electroporation of neutralizing antisera targeted against p47 phox , a NAD(P)H oxidase subunit, abolished Ang II–induced JAK/STAT activation and IL-6 synthesis. Inhibition of JAK2 by its inhibitor AG490 (10 μmol/L) blocked not only JAK2 activation but also IL-6 synthesis. These results suggest that stimulation of the JAK/STAT cascade by Ang II requires O 2 − anions generated by the NAD(P)H oxidase system, and O 2 − anion–dependent activation of the JAK/STAT cascade seems to be additionally involved in Ang II–induced IL-6 synthesis. Thus, Ang II–induced inflammatory effects seem to require O 2 − anions generated by the NAD(P)H oxidase system.
Role of bone morphogenetic proteins in cardiac differentiation
Authors: B VANWIJK, A MOORMAN, M VANDENHOFF
Journal: Cardiovascular Research (2006)

Bone morphogenetic proteins (BMP) are involved in the regulation of a plethora of processes underlying cardiovascular development. This review summarizes the effects of BMP and the signaling pathways that regulate the differentiation of cardiomyocytes from mesoderm in the heart-forming region and at the distal borders of the heart tube from the second heart field. Subsequently, the role of BMPs in the formation of the ventricular chambers and septovalvulogenesis in the atrioventricular canal and outflow tract is described. Finally, the effects of BMPs in stem cell biology and cardiac regeneration are discussed.
Genome-level analysis of genetic regulation of liver gene expression networks
Authors: Daniel Gatti, Akira Maki, Elissa J. Chesler, Roumyana Kirova, Oksana Kosyk, Lu Lu, Kenneth F. Manly, Robert W. Williams, Andy Perkins, Michael A. Langston, David W. Threadgill, Ivan Rusyn
Journal: Hepatology (2007)

The liver is the primary site for the metabolism of nutrients, drugs, and chemical agents. Although metabolic pathways are complex and tightly regulated, genetic variation among individuals, reflected in variations in gene expression levels, introduces complexity into research on liver disease. This study dissected genetic networks that control liver gene expression through the combination of large-scale quantitative mRNA expression analysis with genetic mapping in a reference population of BXD recombinant inbred mouse strains for which extensive single-nucleotide polymorphism, haplotype, and phenotypic data are publicly available. We profiled gene expression in livers of naive mice of both sexes from C57BL/6J, DBA/2J, B6D2F1, and 37 BXD strains using Agilent oligonucleotide microarrays. These data were used to map quantitative trait loci (QTLs) responsible for variations in the expression of about 19,000 transcripts. We identified polymorphic local and distant QTLs, including several loci that control the expression of large numbers of genes in liver, by comparing the physical transcript position with the location of the controlling QTL. Conclusion: The data are available through a public web-based resource (www.genenetwork.org) that allows custom data mining, identification of coregulated transcripts and correlated phenotypes, cross-tissue, and cross-species comparisons, as well as testing of a broad array of hypotheses. (HEPATOLOGY 2007.)
Diagnostic and Therapeutic Approach to Nonsleepy Apnea
Authors: Josep M Montserrat, Francisco Garcia-Rio, Ferran Barbe
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Epidemiological and observational studies suggest that sleep-disordered breathing is associated with the subsequent development of hypertension and ultimately with cardiovascular consequences. It may therefore be assumed that continuous positive airway pressure (CPAP) not only avoids sleep-related symptoms but could also mitigate cardiovascular consequences. Short-term studies have revealed a drop in blood pressure, especially in more severe, symptomatic cases of obstructive sleep apnea. Two recent studies have reported that nonsleepy obstructive sleep apnea is associated with an absence of reduced blood pressure after CPAP treatment. This suggests that this group of patients is less susceptible to the consequences of apneas, even those with mild-moderate hypertension or other cardiovascular disorders. However, in patients with severe cardiovascular disease or a higher number of obstructive events, CPAP treatment should be seriously considered.
Social Anxiety and Social Anxiety Disorder
Authors: Amanda S. Morrison, Richard G. Heimberg
Journal: Annual Review of Clinical Psychology (2013)

Research on social anxiety and social anxiety disorder has proliferated over the years since the explication of the disorder through cognitive-behavioral models. This review highlights a recently updated model from our group and details recent research stemming from the (a) information processing perspective, including attention bias, interpretation bias, implicit associations, imagery and visual memories, and (b) emotion regulation perspective, including positive emotionality and anger. In addition, we review recent studies exploring the roles of self-focused attention, safety behaviors, and post-event processing in the maintenance of social anxiety. Within each area, we detail the ways in which these topics have implications for the treatment of social anxiety and for future research. Finally, we conclude with a discussion of how several of the areas reviewed contribute to our model of social anxiety disorder.