tbuckley/cabot-search huggingface dataset:
Preclinical Evaluation of Telomerase-Specific Oncolytic Virotherapy for Human Bone and Soft Tissue Sarcomas
Authors: Tsuyoshi Sasaki, Hiroshi Tazawa, Jo Hasei, Toshiyuki Kunisada, Aki Yoshida, Yuuri Hashimoto, Shuya Yano, Ryosuke Yoshida, Futoshi Uno, Shunsuke Kagawa, Yuki Morimoto, Yasuo Urata, Toshifumi Ozaki, Toshiyoshi Fujiwara
Journal: Clinical Cancer Research (2011)

Tumor-specific replication-selective oncolytic virotherapy is a promising antitumor therapy for induction of cell death in tumor cells but not of normal cells. We previously developed an oncolytic adenovirus, OBP-301, that kills human epithelial malignant cells in a telomerase-dependent manner. Recent evidence suggests that nonepithelial malignant cells, which have low telomerase activity, maintain telomere length through alternative lengthening of telomeres (ALT). However, it remains unclear whether OBP-301 is cytopathic for nonepithelial malignant cells. Here, we evaluated the antitumor effect of OBP-301 on human bone and soft tissue sarcoma cells.The cytopathic activity of OBP-301, coxsackie and adenovirus receptor (CAR) expression, and telomerase activity were examined in 10 bone (OST, U2OS, HOS, HuO9, MNNG/HOS, SaOS-2, NOS-2, NOS-10, NDCS-1, and OUMS-27) and in 4 soft tissue (CCS, NMS-2, SYO-1, and NMFH-1) sarcoma cell lines. OBP-301 antitumor effects were assessed using orthotopic tumor xenograft models. The fiber-modified OBP-301 (termed OBP-405) was used to confirm an antitumor effect on OBP-301-resistant sarcomas.OBP-301 was cytopathic for 12 sarcoma cell lines but not for the non-CAR-expressing OUMS-27 and NMFH-1 cells. Sensitivity to OBP-301 was dependent on CAR expression and not on telomerase activity. ALT-type sarcomas were also sensitive to OBP-301 because of upregulation of human telomerase reverse transcriptase (hTERT) mRNA following virus infection. Intratumoral injection of OBP-301 significantly suppressed the growth of OST and SYO-1 tumors. Furthermore, fiber-modified OBP-405 showed antitumor effects on OBP-301-resistant OUMS-27 and NMFH-1 cells.A telomerase-specific oncolytic adenovirus is a promising antitumor reagent for the treatment of bone and soft tissue sarcomas.
Cardiac dysfunction in juvenile dermatomyositis: a case-control study
Authors: T. Schwartz, H. Sanner, T. Husebye, B. Flato, I. Sjaastad
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Objective</h3> To compare cardiac function in patients with juvenile dermatomyositis (JDM) with matched controls, and examine associations between pathological electrocardiography (ECG), echocardiographic abnormalities and disease variables in patients with JDM. <h3>Methods</h3> A total of 59 patients with JDM, examined a median 16.8 years (range 2–38 years) after disease onset, were compared with 59 age-matched and sex-matched controls. Echocardiography, including early diastolic transmitral flow/early diastolic tissue velocity (E/E9) as a marker for diastolic dysfunction, and 12-channel ECG were performed and analysed blinded to patient information. Disease activity and damage were assessed by clinical examination at follow-up and chart review. <h3>Results</h3> E/E9 was elevated (&gt;9.5) in 13 (22%) patients versus 0 controls (p&lt;0.001). In all, 10 patients presented with pathological ECG compared to 4 controls (p=0.054). Previous or current hypertension was found in 12 patients versus 0 controls (p&lt;0.001). Among the patients, pathological ECG was found in 6/13 patients with versus 4/44 without elevated E/E9 (p=0.002); and systolic blood pressure was correspondingly 132±24 mm Hg versus 112±18 mm Hg in the groups (p=0.012). E/E9 correlated with cumulative organ damage assessed at follow-up (r<sub>sp</sub> 0.41, p=0.001) and disease activity at 1 year (r<sub>sp</sub> 0.56, p&lt;0.001), which also predicted pathological E/E9 after controlling for age and gender. During disease course, 12% of patients with JDM developed pericarditis. <h3>Conclusion</h3> Only patients with JDM and no controls had subclinical left ventricular diastolic dysfunction; the patients with elevated E/E9 also had high prevalence of pathological ECG and hypertension. High disease activity 1-year post diagnosis predicted high E/E9 at follow-up. The findings suggest that subclinical heart disease is related to the systemic nature of JDM.
Dietary ω3 fatty acids modulate the substrate for post-operative atrial fibrillation in a canine cardiac surgery model
Authors: Fadia Mayyas, Seiichiro Sakurai, Rashmi Ram, Julie H. Rennison, Eui-Seock Hwang, Laurie Castel, Beth Lovano, Marie-Luise Brennan, Douglas Bibus, Bill Lands, John Barnard, Mina K. Chung, David R. Van Wagoner
Journal: Cardiovascular Research (2010)

Pre-treatment with dietary ω3 polyunsaturated fatty acids (ω3-PUFA) has been reported to reduce the incidence of new-onset atrial fibrillation (AF) following cardiac surgery. In a canine cardiac surgery model, we evaluated the impact of dietary ω3-PUFA on atrial electrophysiological properties, inflammatory markers, the atrial endothelin-1 (ET-1) system, and the expression and distribution of connexin 43. Adult mongrel dogs received either normal chow (NC, n = 11) or chow supplemented with fish oil (FO, 0.6 g ω3-PUFA/kg/day, n = 9) for 3 weeks before surgery. A left thoracotomy was performed, and the left atrial appendage (LAA) was excised. Atrial pacing/recording wires were placed, and the pericardium/chest was closed. The atrial ratio of ω6/ω3 lipids decreased from 15–20 in NC to 2–3 in FO. FO treatment lowered pre-surgical and stabilized post-surgical arachidonate levels. Peak neutrophil to lymphocyte ratio was lower and decayed faster in FO-treated animals. Extensive inflammatory cell infiltration was present in NC atria, but was reduced in FO-treated dogs. FO-treated animals had lower post-surgical atrial expression of inducible nitric oxide synthase (iNOS) and reduced plasma ET-1. Expression of ET-1 and inositol trisphosphate receptor type-2 proteins in the LAA was also reduced. FO treatment prolonged post-operative atrial effective refractory period, slowed heart rate, and enhanced heart rate variability. Importantly, AF (>30 s) was inducible in four of six NC dogs, but no FO dogs. Dietary FO attenuated AF inducibility following cardiac surgery by modulating autonomic tone and heart rate. FO also reduced atrial inflammation, iNOS, and ET-1 expression.
Impact of a hypomorphic Artemis disease allele on lymphocyte development, DNA end processing, and genome stability
Authors: Ying Huang, William Giblin, Martina Kubec, Gerwin Westfield, Jordan St. Charles, Laurel Chadde, Stephanie Kraftson, JoAnn Sekiguchi
Journal: The Journal of Experimental Medicine (2009)

Artemis was initially discovered as the gene inactivated in human radiosensitive T−B− severe combined immunodeficiency, a syndrome characterized by the absence of B and T lymphocytes and cellular hypersensitivity to ionizing radiation. Hypomorphic Artemis alleles have also been identified in patients and are associated with combined immunodeficiencies of varying severity. We examine the molecular mechanisms underlying a syndrome of partial immunodeficiency caused by a hypomorphic Artemis allele using the mouse as a model system. This mutation, P70, leads to premature translation termination that deletes a large portion of a nonconserved C terminus. We find that homozygous Artemis-P70 mice exhibit reduced numbers of B and T lymphocytes, thereby recapitulating the patient phenotypes. The hypomorphic mutation results in impaired end processing during the lymphoid-specific DNA rearrangement known as V(D)J recombination, defective double-strand break repair, and increased chromosomal instability. Biochemical analyses reveal that the Artemis-P70 mutant protein interacts with the DNA-dependent protein kinase catalytic subunit and retains significant, albeit reduced, exo- and endonuclease activities but does not undergo phosphorylation. Together, our findings indicate that the Artemis C terminus has critical in vivo functions in ensuring efficient V(D)J rearrangements and maintaining genome integrity.
Elimination of interleukin 6 attenuates coagulation activation in experimental endotoxemia in chimpanzees.
Authors: T van der Poll, M Levi, C E Hack, H ten Cate, S J van Deventer, A J Eerenberg, E R de Groot, J Jansen, H Gallati, H R Büller
Journal: The Journal of Experimental Medicine (1994)

The role of interleukin 6 (IL-6) in the toxic sequelae of sepsis is controversial. To assess the part of IL-6 in inflammatory responses to endotoxin, we investigated eight chimpanzees after either a bolus intravenous injection of Escherichia coli endotoxin (n = 4; 4 ng/kg) or after the same dose of endotoxin with a simultaneous bolus intravenous injection of an anti-IL-6 mAb (30 mg; n = 4). Anti-IL-6 did not affect the induction of the cytokine network (tumor necrosis factor [TNF], soluble TNF receptors types I and II, and IL-8) by endotoxin, nor did it influence the occurrence of a neutrophilic leukocytosis and neutrophil degranulation, as monitored by the measurement of elastase-alpha 1-antitrypsin complexes. In contrast, anti-IL-6 markedly attenuated endotoxin-induced activation of coagulation, monitored with the plasma levels of the prothrombin fragment F1+2 and thrombin-antithrombin III complexes, whereas activation of fibrinolysis, determined with the plasma concentrations of plasmin-alpha 2-antiplasmin complexes, remained unaltered. We conclude that IL-6 does not have a feedback effect on the release of other cytokines after injection of endotoxin, and that it is not involved in endotoxin-induced neutrophilia or neutrophil degranulation. IL-6 is, however, an important intermediate factor in activation of coagulation in low grade endotoxemia in chimpanzees.
Resolution of psoriasis upon blockade of IL-15 biological activity in a xenograft mouse model
Authors: Louise S. Villadsen, Janine Schuurman, Frank Beurskens, Tomas N. Dam, Frederik Dagnæs-Hansen, Lone Skov, Jørgen Rygaard, Marleen M. Voorhorst-Ogink, Arnout F. Gerritsen, Marc A. van Dijk, Paul W.H.I. Parren, Ole Baadsgaard, Jan G.J. van de Winkel
Journal: Journal of Clinical Investigation (2003)

Psoriasis is a chronic inflammatory disease of the skin characterized by epidermal hyperplasia, dermal angiogenesis, infiltration of activated T cells, and increased cytokine levels. One of these cytokines, IL-15, triggers inflammatory cell recruitment, angiogenesis, and production of other inflammatory cytokines, including IFN-γ, TNF-α, and IL-17, which are all upregulated in psoriatic lesions. To investigate the role of IL-15 in psoriasis, we generated mAb’s using human immunoglobulin-transgenic mice. One of the IL-15–specific antibodies we generated, 146B7, did not compete with IL-15 for binding to its receptor but potently interfered with the assembly of the IL-15 receptor α, β, γ complex. This antibody effectively blocked IL-15–induced T cell proliferation and monocyte TNF-α release in vitro. In a human psoriasis xenograft model, antibody 146B7 reduced the severity of psoriasis, as measured by epidermal thickness, grade of parakeratosis, and numbers of inflammatory cells and cycling keratinocytes. These results obtained with this IL-15–specific mAb support an important role for IL-15 in the pathogenesis of psoriasis.
Type 2 Diabetes in Older Well-Functioning People: Who Is Undiagnosed?
Authors: Lonneke V. Franse, Mauro Di Bari, Ron I. Shorr, Helaine E. Resnick, Jacques T. M. van Eijk, Doug C. Bauer, Anne B. Newman, Marco Pahor
Journal: Diabetes Care (2001)

OBJECTIVE—To assess, in an older population, the prevalence of diagnosed and undiagnosed diabetes, the number needed to screen (NNTS) to identify one individual with undiagnosed diabetes, and factors associated with undiagnosed diabetes. RESEARCH DESIGN AND METHODS—Socioeconomic and health-related factors were assessed at the baseline examination of the Health, Aging, and Body Composition (Health ABC) Study, a cohort of 3,075 well-functioning people aged 70–79 years living in Memphis, Tennessee and Pittsburgh, Pennsylvania (42% blacks and 48% men). Diabetes was defined according to the 1985 World Health Organization criteria (fasting glucose ≥7.8 mmol/l or 2-h glucose ≥11.1 mmol/l) and the 1997 American Diabetes Association criteria (fasting glucose ≥7.0 mmol/l). RESULTS—The prevalence of diagnosed and undiagnosed diabetes was 15.6 and 8.0%, respectively, among all participants (NNTS 10.6), 13.9 and 9.1% among white men (NNTS 9.5), 7.8 and 7.4% among white women (NNTS 12.4), 22.7 and 9.1% among black men (NNTS 8.5), and 21.6 and 6.2% among black women (NNTS 12.6). In multivariate analyses, compared with individuals without diabetes, individuals with undiagnosed diabetes were more likely to be men and were more likely to have a history of hypertension, higher BMI, and larger waist circumference. NNTS was lowest in men (9.1), individuals with hypertension (8.7), individuals in the highest BMI quartile (6.9), and individuals in the largest waist circumference quartile (6.8). CONCLUSIONS—In approximately one-third of all older people with diabetes, the condition remains undiagnosed. Screening for diabetes may be more efficient among men and individuals with hypertension, high BMI, and large waist circumference.
Characterization of antigen-specific, Ia-restricted, L3T4+ cytolytic T lymphocytes and assessment of thymic influence on their self specificity.
Authors: H Golding, T I Munitz, A Singer
Journal: The Journal of Experimental Medicine (1985)

The goals of the present study were: (a) to generate antigen-specific L3T4+ cytolytic T lymphocytes (CTL), (b) to determine their major histocompatibility complex (MHC) restriction specificity, and (c) to assess the influence of thymic MHC determinants on their self specificity. We found that L3T4+ CTL specific for either trinitrophenyl (TNP)-modified self determinants or minor histocompatibility antigens could be generated from Lyt-2- responder T cells provided that the response cultures were supplemented with supernatants rich in helper factors. Such antigen-specific L3T4+ CTL were Ia-restricted by the criteria that they lysed only Ia+ target cells and that their lysis of Ia+ target cells was specifically inhibited by anti-Ia monoclonal antibodies. The relative frequency of L3T4+ pCTL was found to be only 5-10% of the total anti-TNP pCTL present in the spleens of normal mice. Finally, we utilized radiation bone marrow chimeras to assess the influence of the thymic haplotype on the self-Ia specificity of L3T4+ CTL. Both bulk culture and limiting dilution experiments revealed that the self-Ia specificity of L3T4+ anti-TNP CTL from F1----parent and A----B allogeneic chimeras was not markedly skewed toward the haplotype of the chimeric thymus. These results contrast with those obtained previously for L3T4+ anti-TNP Th cells and demonstrate that in the radiation bone marrow chimera model of T cell differentiation, the self specificity of Th cells but not pCTL is markedly influenced by the haplotype of the chimeric thymus.
Chromosome 13 abnormalities identified by FISH analysis and serum β2-microglobulin produce a powerful myeloma staging system for patients receiving high-dose therapy
Authors: Thierry Facon, Hervé Avet-Loiseau, Gaëlle Guillerm, Philippe Moreau, Franck Geneviève, Marc Zandecki, Jean-Luc Laı̈, Xavier Leleu, Jean-Pierre Jouet, Francis Bauters, Jean-Luc Harousseau, Régis Bataille, Jean-Yves Mary
Journal: Blood (2001)
BTS guidelines for the management of malignant pleural effusions
Authors: G Antunes, E Neville, J Duffy, N Ali
Journal: Thorax (2003)

These guidelines have been replaced by BTS Pleural Disease Guideline 2010  Superseded By BTS Pleural Disease Guideline 2010: BTS Guidelines for the Management of Pleural Disease. Thorax 2003 May; 58(Suppl 2): 1–59.
Lichen planus is associated with human herpesvirus type 7 replication and infiltration of plasmacytoid dendritic cells
Authors: H.J.C. De Vries, J. Van Marle, M.B.M. Teunissen, D. Picavet, F. Zorgdrager, J.D. Bos, J. Weel, M. Cornelissen
Journal: British Journal of Dermatology (2005)

Lichen planus (LP) is a common inflammatory skin disease of unknown aetiology. Viral causes have been suggested.To find candidate viruses associated with LP.Lesional and nonlesional skin samples, peripheral blood mononuclear cells and serum were obtained from patients with LP. Ultrastructural, viral DNA, immunohistochemical and serological analyses were performed, and comparisons were made with psoriatic and normal skin.Electron microscopy revealed typical 120-200-nm enveloped particles with a 100-nm nucleus resembling human herpesvirus (HHV) virions both in dermis and in epidermis of lesional LP tissue. HHV-7 DNA was found in 11 of 18 lesional LP samples, as opposed to only one of 11 nonlesional LP samples (P =0.06), two of 11 lesional psoriasis samples (P = 0.05) and none of four normal skin samples. No relation was found between LP skin and DNA of other known HHVs (HHV-1-6 and 8). With immunohistochemistry, significantly more HHV-7+ cells were found in lesional LP epidermis than in normal epidermis. Lesional LP dermis contained significantly more HHV-7+ cells than nonlesional LP, psoriatic or normal dermis. Moreover, LP skin contained overwhelmingly and consistently more plasmacytoid dendritic cells (upregulated in virally induced conditions) than nonlesional LP samples.We conclude that HHV-7 replicates in LP lesions, but not in psoriasis, another inflammatory skin condition. HHV-7 is possibly involved in the pathogenesis of LP. These preliminary data make further research on this topic of interest.
The Compatible Solute Ectoine Protects against Nanoparticle-induced Neutrophilic Lung Inflammation
Authors: Ulrich Sydlik, Inka Gallitz, Catrin Albrecht, Josef Abel, Jean Krutmann, Klaus Unfried
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Rationale: Inflammatory reactions of the airways induced by nanoparticles of occupational and environmental origin contribute to organ-specific and systemic human diseases. Because this kind of exposure in modern societies is often unavoidable, a strategy of molecular prevention on an individual level could help to prevent inflammation-derived secondary diseases.Objectives: To test whether the compatible solute ectoine [(S)-2-methyl-1,4,5,6-tetrahydropyrimidine-4-carboxylic acid], which is known to reduce cell stress effects on a molecular level, prevents nanoparticle-induced lung inflammation.Methods: Inflammatory parameters were studied in Fischer 344 rats treated with model carbon nanoparticles. The molecular effects of ectoin on proinflammatory signal transduction were demonstrated in the rat and in the human system using cultured lung epithelial cells.Measurements and Main Results: Ectoine, given with or before the nanoparticles, dose-dependently reduced neutrophil inflammation in the lung. This preventive effect was not observed when lung inflammation was induced by bacterial lipopolysaccharide. Analyses of the underlying mode of action revealed that ectoine acted on lung epithelial cells. Ectoine administration inhibited nanoparticle-induced signaling, which is known to be responsible for proinflammatory reactions in rat lung epithelial cells in vitro as well as in vivo. These findings were corroborated and extended in experiments with cultured human bronchial epithelial cells in which ectoine inhibited nanoparticle-triggered cell signaling and IL-8 induction.Conclusions: Because compatible solutes are compliant natural products without known toxic potential, we propose that this group of substances may be used for the prevention of particle-induced airway inflammation in humans.
Essential role of the T cell–specific adapter protein in the activation of LCK in peripheral T cells
Authors: Francesc Marti, Gonzalo G. Garcia, Philip E. Lapinski, Jennifer N. MacGregor, Philip D. King
Journal: The Journal of Experimental Medicine (2006)

T cell–specific adapter protein (TSAd) is a SRC-homology-2 (SH2) domain–containing intracellular signaling molecule that is required for T cell antigen receptor (TCR)–induced cytokine synthesis in T cells. How TSAd functions in TCR signal transduction is not clear. Previous work has suggested a nuclear role for this adapter. However, other evidence suggests that TSAd also functions in the cytoplasm. Using T cells from TSAd-deficient mice, we now show that the major role of TSAd in the cytoplasm is in activation of the LCK protein tyrosine kinase at the outset of TCR signal transduction. Consequently, TSAd regulates several downstream signaling events, including intracellular calcium mobilization and activation of the Ras–extracellular signal–regulated kinase signaling pathway. TSAd regulates LCK activity directly through physical interaction with LCK SH3 and SH2 domains. These studies reveal TSAd as a positive regulator of proximal TCR signal transduction and provide important new information on the mechanism of TCR-induced LCK activation.
Elastic Environment of the Capillary Bed
Authors: Y. C. FUNG, BENJAMIN W. ZWEIFACH, MARCOS INTAGLIETTA
Journal: Circulation Research (1966)

To determine the degree to which the capillary blood vessels in vivo are supported by the elasticity of the surrounding tissue, a study was made of the elastic properties of the mesentery of the rabbit. A torsion test was made on a circular membrane of the avascular region of the mesentery, by applying a graded static torque and measuring the resulting deformation. The mesentery was found to have a modulus of rigidity in the same category as that of larger arteries and veins. It has a nonlinear stress-strain relationship with a tendency to harden at larger strains. In torsion experiments, the shear modulus G can be reduced to the following form G = µ+c 2 |τ| Where c 2 is a constant and |τ| is the absolute value of the shear stress. The constant µ depends on the initial tension in the membrane. For the mesentery specimens, µ ranges from 215 to 1900 gm/cm 2 , whereas the nondimensional constant c 2 has an average value of 8.23 with a standard deviation of 2.1. The hypothesis is advanced that the medium in which the capillaries of the mesentery are embedded is a gel and the capillary in effect is a tunnel in this gel. Such a hypothesis could explain the apparent rigidity of the blood capillaries.
Declining incidence of episodes of asthma: a study of trends in new episodes presenting to general practitioners in the period 1989-98
Authors: D M Fleming
Journal: Thorax (2000)

A study was undertaken to determine trends in the incidence of new episodes of asthma presented to general practitioners participating in the Weekly Returns Service of the Royal College of General Practitioners, comprising 92 practices with a registered population of approximately 680 000 persons well distributed throughout England and Wales. These practices monitor the morbidity presented at every consultation, distinguishing between new episodes of illness and ongoing consultations.Age specific weekly rates of new episodes of asthma (and of acute bronchitis) presenting to the general practitioners over the years 1989-98 were examined in four week blocks and analysed by multiple regression, separating secular from seasonal trends.Quadratic trends in episodes of asthma were evident in each of the age groups with peaks in 1993/4. Corresponding analyses for acute bronchitis disclosed similar trends generally peaking in the winter of 1993/4. Mean weekly incidence data (all ages combined) decreased in all quarters since 1993. Regional analysis (North/Central/South) showed similar decreases.There has been a gradual decrease in the incidence of asthma episodes and of acute bronchitis presenting to general practitioners since 1993. The trend of an increase before 1993 followed by a decrease cannot be explained by changes in the patterns of health care usage or diagnostic preference of doctors.