tbuckley/cabot-search huggingface dataset:
Noninvasive In Vivo Magnetic Resonance Imaging of Experimental Coronary Artery Lesions in a Porcine Model
Authors: Stephen G. Worthley, Gérard Helft, Valentin Fuster, Zahi A. Fayad, Oswaldo J. Rodriguez, Azfar G. Zaman, John T. Fallon, Juan J. Badimon
Journal: Circulation (2000)

Background —The ability to characterize and quantify coronary artery atherosclerotic lesions accurately, reproducibly, and noninvasively may allow the stratification of risk for future acute coronary syndromes and help direct therapeutic management. MRI has been shown to accurately characterize and quantify atherosclerosis; however, because of the combination of cardiac and respiratory motion artifacts, nonlinear course, and relatively small size of the coronary arteries, these techniques have not been able to be translated to the coronary system in vivo. Methods and Results —Coronary lesions were induced in Yorkshire albino swine (n=6) with balloon angioplasty, and 4 weeks later MRI of the coronary artery lesions was performed. High-resolution in vivo images of the coronary artery wall and lesions were obtained with a double-inversion-recovery fast-spin-echo sequence in a 1.5-T MR system. There was good agreement between measurements of vessel wall thickness and area from MR images of the coronary arteries and the matched histopathology sections (n=43). The mean difference (MRI minus histopathology ± SD) for mean wall thickness was 0.26±0.18 mm, and for vessel wall area, 5.65±3.51 mm 2 . MRI was also able to visualize intralesion hematoma (sensitivity 82%, specificity 84%). Conclusions —Using a clinical MR system, we were able to image coronary artery lesions in vivo in an experimental porcine model. Further studies are needed to assess the ability of MRI to characterize coronary atherosclerotic lesions in vivo.
Immunobiology and the Future of Myoblast Transfer Therapy
Authors: Gayle M. Smythe, Stuart I. Hodgetts, Miranda D. Grounds
Journal: Molecular Therapy (2000)

In conclusion, striking advances are now being made in defining the mechanisms responsible for donor myoblast death in clinical MTT. As should be clear from this brief survey, this is not a simple problem that will be easily solved: there are many complex and interacting factors at play here. Available evidence identifies key areas to address as follows: •The role of acute host immunological components that can act within minutes of challenge by "foreign" donor cells (such as the complement-activating system);•Expression of MHC class I and II and other antigens by donor myoblasts and the specific receptor/ligand pairs that mediate direct interaction between donor myoblasts and host immune cells;•Direct and indirect involvement of several host immune cell types, particularly T cells, NK cells, macrophages, and mast cells; and•The strong possibility that the tissue culture process per se adversely influences the subsequent in vivo survival of donor myoblasts, probably by altering various cell-surface components.
The Effect of Local Application of Glyceryl Trinitrate (Nitroglycerine) on Raynaud's Disease and Raynaud's Phenomenon
Authors: MARTIN S. KLECKNER, EDGAR V. ALLEN, KHALIL G. WAKIM
Journal: Circulation (1951)

The authors investigated the effect of repeated inunction with 2 per cent glyceryl trinitrate in lanolin on the blood flow and skin temperature of the extremities in 14 cases of Raynaud's disease and in 8 cases in which Raynaud's phenomenon was associated with such vascular diseases as acrosclerosis (3 cases), chronic occlusive disease of the arteries (3 cases), occupational disease of the arteries (1 case) and livedo reticularis (1 case). The inunction almost invariably caused an increase in the blood flow and in the skin temperature of the digits in the 14 cases of Raynaud's disease.
Antagonism of SET Using OP449 Enhances the Efficacy of Tyrosine Kinase Inhibitors and Overcomes Drug Resistance in Myeloid Leukemia
Authors: Anupriya Agarwal, Ryan J. MacKenzie, Raffaella Pippa, Christopher A. Eide, Jessica Oddo, Jeffrey W. Tyner, Rosalie Sears, Michael P. Vitek, María D. Odero, Dale J. Christensen, Brian J. Druker
Journal: Clinical Cancer Research (2014)

The SET oncoprotein, a potent inhibitor of the protein phosphatase 2A (PP2A), is overexpressed in leukemia. We evaluated the efficacy of SET antagonism in chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) cell lines, a murine leukemia model, and primary patient samples using OP449, a specific, cell-penetrating peptide that antagonizes SET's inhibition of PP2A.In vitro cytotoxicity and specificity of OP449 in CML and AML cell lines and primary samples were measured using proliferation, apoptosis, and clonogenic assays. Efficacy of target inhibition by OP449 was evaluated by immunoblotting and PP2A assay. In vivo antitumor efficacy of OP449 was measured in human HL-60 xenografted murine model.We observed that OP449 inhibited growth of CML cells including those from patients with blastic phase disease and patients harboring highly drug-resistant BCR-ABL1 mutations. Combined treatment with OP449 and ABL1 tyrosine kinase inhibitors was significantly more cytotoxic to K562 cells and primary CD34(+) CML cells. SET protein levels remained unchanged with OP449 treatment, but BCR-ABL1-mediated downstream signaling was significantly inhibited with the degradation of key signaling molecules such as BCR-ABL1, STAT5, and AKT. Similarly, AML cell lines and primary patient samples with various genetic lesions showed inhibition of cell growth after treatment with OP449 alone or in combination with respective kinase inhibitors. Finally, OP449 reduced the tumor burden of mice xenografted with human leukemia cells.We demonstrate a novel therapeutic paradigm of SET antagonism using OP449 in combination with tyrosine kinase inhibitors for the treatment of CML and AML.
Homologs of Mitochondrial Transcription Factor B, Sparsely Distributed Within the Eukaryotic Radiation, Are Likely Derived from the Dimethyladenosine Methyltransferase of the Mitochondrial Endosymbiont
Authors: Timothy E. Shutt, Michael W. Gray
Journal: Molecular Biology and Evolution (2006)

Mitochondrial transcription factor B (mtTFB), an essential component in regulating the expression of mitochondrial DNA-encoded genes in both yeast and humans, is a dimethyladenosine methyltransferase (DMT) that has acquired a secondary role in mitochondrial transcription. So far, mtTFB has only been well studied in Opisthokonta (metazoan animals and fungi). Here we investigate the phylogenetic distribution of mtTFB homologs throughout the domain Eucarya, documenting the first examples of this protein outside of the opisthokonts. Surprisingly, we identified putative mtTFB homologs only in amoebozoan protists and trypanosomatids. Phylogenetic analysis together with conservation of intron positions in amoebozoan and human genes supports the grouping of the putative mtTFB homologs as a distinct clade. Phylogenetic analysis further demonstrates that the mtTFB is most likely derived from the DMT of the mitochondrial endosymbiont.
Pramlintide Improved Glycemic Control and Reduced Weight in Patients With Type 2 Diabetes Using Basal Insulin
Authors: Matthew Riddle, Juan Frias, Bei Zhang, Holly Maier, Carl Brown, Karen Lutz, Orville Kolterman
Journal: Diabetes Care (2007)

To assess the efficacy and safety of pramlintide in patients with type 2 diabetes suboptimally controlled with basal insulin.In a 16-week, double-blind, placebo-controlled study, 212 patients using insulin glargine with or without oral antidiabetes agents (OAs) were randomized to addition of pramlintide (60 or 120 microg b.i.d./t.i.d.) or placebo. Insulin glargine was adjusted to target a fasting plasma glucose concentration of 70-100 mg/dl. One coprimary end point was the change in A1C at week 16. The other coprimary end point was a composite measure of overall diabetes control comprising A1C < or = 7.0% or reduction > or = 0.5%, mean daily postprandial glucose (PPG) increments < or = 40 mg/dl, no increase in body weight, and no severe hypoglycemia. Patients meeting all four conditions at week 16 achieved this end point.More pramlintide- than placebo-treated patients achieved the composite end point (25 vs. 7%; P < 0.001). Reductions (means +/- SE) in A1C (-0.70 +/- 0.11% vs. -0.36 +/- 0.08%; P < 0.05) and PPG increments (-24.4 +/- 3.6 mg/dl vs. -0.4 +/- 3.0 mg/dl; P < 0.0001) were greater in pramlintide- versus placebo-treated patients, respectively. Glycemic improvements were accompanied by progressive weight loss with pramlintide and weight gain with placebo (-1.6 +/- 0.3 kg vs. +0.7 +/- 0.3 kg; P < 0.0001). No treatment-related severe hypoglycemia occurred.Pramlintide improved multiple glycemic parameters and reduced weight with no increase in hypoglycemia in patients with type 2 diabetes who were not achieving glycemic targets with basal insulin with or without OAs.
Inhibitory Effect of Vitamin A on Carcinogenesis
Authors: Raymond J. Shamberger
Journal: JNCI Journal of the National Cancer Institute (1971)

In two experiments, β-carotene applied to mice initiated with 7,12-dimethylbenz[β]anthracene (DMBA), concomitantly with croton resin and croton oil, increased tumor incidence by 58 and 29%. In the same experiments, retinyl acetate reduced tumor incidence by 76 and 29%. Retinol in one experiment reduced the number of papillomas by 75%. β-Ionone, squalene, and isoprene had little or no effect on the incidence of tumors. In the mice treated with DMBA and phenol, retinol also reduced the number of tumors. The polyene antibiotic, filipin, dramatically reduced the number of animals with croton oil-induced tumors and also the total number of tumors. After the lysosomal labilizers, filipin and vitamin A, were applied for 3 weeks to DMBA-initiated mice, only a few tumors developed after use of croton oil. The lysosomal stabilizers, chloroquine and hydrocortisone, increased the number of the tumors. In the same experiments, acid phosphatase and aryl sulfatase activities were decreased by chloroquine and hydrocortisone and increased by filipin and vitamin A.
Credentialing a Preclinical Mouse Model of Alveolar Rhabdomyosarcoma
Authors: Koichi Nishijo, Qing-Rong Chen, Lei Zhang, Amanda T. McCleish, Andrea Rodriguez, Min Jung Cho, Suresh I. Prajapati, Jonathan A.L. Gelfond, Gary B. Chisholm, Joel E. Michalek, Bruce J. Aronow, Frederic G. Barr, R. Lor Randall, Marc Ladanyi, Stephen J. Qualman, Brian P. Rubin, Robin D. LeGallo, Chiayeng Wang, Javed Khan, Charles Keller
Journal: Cancer Research (2009)

Abstract The highly aggressive muscle cancer alveolar rhabdomyosarcoma (ARMS) is one of the most common soft tissue sarcoma of childhood, yet the outcome for the unresectable and metastatic disease is dismal and unchanged for nearly three decades. To better understand the pathogenesis of this disease and to facilitate novel preclinical approaches, we previously developed a conditional mouse model of ARMS by faithfully recapitulating the genetic mutations observed in the human disease, i.e., activation of Pax3:Fkhr fusion gene with either p53 or Cdkn2a inactivation. In this report, we show that this model recapitulates the immunohistochemical profile and the rapid progression of the human disease. We show that Pax3:Fkhr expression increases during late preneoplasia but tumor cells undergoing metastasis are under apparent selection for Pax3:Fkhr expression. At a whole-genome level, a cross-species gene set enrichment analysis and metagene projection study showed that our mouse model is most similar to human ARMS when compared with other pediatric cancers. We have defined an expression profile conserved between mouse and human ARMS, as well as a Pax3:Fkhr signature, including the target gene, SKP2. We further identified 7 “druggable” kinases overexpressed across species. The data affirm the accuracy of this genetically engineered mouse model. [Cancer Res 2009;69(7):2902–11]
PKC and PKC differentially regulate Legionella pneumophila-induced GM-CSF
Authors: K. Vardarova, S. Scharf, F. Lang, B. Schmeck, B. Opitz, J. Eitel, A. C. Hocke, H. Slevogt, A. Flieger, S. Hippenstiel, N. Suttorp, P. D. N'Guessan
Journal: European Respiratory Journal (2009)

Legionella pneumophila is an important causative agent of severe pneumonia in humans. The human alveolar epithelium is an effective barrier for inhaled microorganisms and actively participates in the initiation of innate host defense. Although secretion of granulocyte-macrophage colony-stimulating factor (GM-CSF) is essential for the elimination of invading Legionella spp., mechanisms of Legionella pneumophila-induced release of this cytokine are widely unknown. In this study, we have demonstrated a toll-like receptor (TLR)2- and TLR5-dependent release of GM-CSF in L. pneumophila-infected human alveolar epithelial cells. GM-CSF secretion was not dependent on the bacteria type II or type IV secretion system. Furthermore, an increase in protein kinase C (PKC) activity, particularly PKC(alpha) and PKC(epsilon), was noted. Blocking of PKC(alpha) and PKC(epsilon) activity or expression, but not of PKC(beta), PKC(delta), PKC(eta), PKC(theta), and PKC(zeta), significantly reduced the synthesis of GM-CSF in infected cells. While PKC(alpha) was critical for the initiation of a nuclear factor-kappaB-mediated GM-CSF expression, PKC(epsilon) regulated GM-CSF production via activator protein 1. Thus, differential regulation of GM-CSF, production by PKC isoforms, contributes to the host response in Legionnaires' disease.
The Jervell and Lange-Nielsen Syndrome
Authors: Peter J. Schwartz, Carla Spazzolini, Lia Crotti, Jørn Bathen, Jan P. Amlie, Katherine Timothy, Maria Shkolnikova, Charles I. Berul, Maria Bitner-Glindzicz, Lauri Toivonen, Minoru Horie, Eric Schulze-Bahr, Isabelle Denjoy
Journal: Circulation (2006)

Data on the Jervell and Lange-Nielsen syndrome (J-LN), the long-QT syndrome (LQTS) variant associated with deafness and caused by homozygous or compound heterozygous mutations on the KCNQ1 or on the KCNE1 genes encoding the I(Ks) current, are still based largely on case reports.We analyzed data from 186 J-LN patients obtained from the literature (31%) and from individual physicians (69%). Most patients (86%) had cardiac events, and 50% were already symptomatic by age 3. Their QTc was markedly prolonged (557+/-65 ms). Most of the arrhythmic events (95%) were triggered by emotions or exercise. Females are at lower risk for cardiac arrest and sudden death (CA/SD) (hazard ratio, 0.54; 95% CI, 0.34 to 0.88; P=0.01). A QTc >550 ms and history of syncope during the first year of life are independent predictors of subsequent CA/SD. Most mutations (90.5%) are on the KCNQ1 gene; mutations on the KCNE1 gene are associated with a more benign course. beta-Blockers have only partial efficacy; 51% of the patients had events despite therapy and 27% had CA/SD.J-LN syndrome is a most severe variant of LQTS, with a very early onset and major QTc prolongation, and in which beta-blockers have limited efficacy. Subgroups at relatively lower risk for CA/SD are identifiable and include females, patients with a QTc < or =550 ms, those without events in the first year of life, and those with mutations on KCNE1. Early therapy with implanted cardioverter/defibrillators must be considered.
Influence of Comorbidity on Racial Differences in Receipt of Surgery Among US Veterans With Early-Stage Non–Small-Cell Lung Cancer
Authors: Christina D. Williams, Karen M. Stechuchak, Leah L. Zullig, Dawn Provenzale, Michael J. Kelley
Journal: Journal of Clinical Oncology (2012)

It is unclear why racial differences exist in the frequency of surgery for lung cancer treatment. Comorbidity is an important consideration in selection of patients for lung cancer treatment, including surgery. To assess whether comorbidity contributes to the observed racial differences, we evaluated racial differences in the prevalence of comorbidity and their impact on receipt of surgery.A total of 1,314 patients (1,135 white, 179 black) in the Veterans Health Administration diagnosed with early-stage non-small-cell lung cancer in 2007 were included. The effect of comorbidity on surgery was determined by using generalized linear models with a logit link accounting for patient clustering within Veterans Administration Medical Centers.Compared with whites, blacks had greater prevalence of hypertension, liver disease, renal disease, illicit drug abuse, and poor performance status, but lower prevalence of respiratory disease. The impact of most individual comorbidities on receipt of surgery was similar between blacks and whites, and comorbidity did not influence the race-surgery association in a multivariable analysis. The proportion of blacks not receiving surgery as well as refusing surgery was greater than that among whites.Blacks had a greater prevalence of several comorbid conditions and poor performance status; however, the overall comorbidity score did not differ by race. In general, the effect of comorbidity on receipt of surgery was similar in blacks and whites. Racial differences in comorbidity do not fully explain why blacks undergo lung cancer surgery less often than whites.
Risk Factors for Growth and Decline of Lung Function in Asthmatic Individuals up to Age 42 years
Authors: MARION H. GROL, JORRIT GERRITSEN, JUDITH M. VONK, JAN P. SCHOUTEN, GERARD H. KOËTER, BERT RIJCKEN, DIRKJE S. POSTMA
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

Little is known about factors determining the outcome of childhood asthma. The purpose of this longitudinal study was to assess the factors in childhood that determine the level of FEV1 in early adulthood in asthmatic individuals, and to examine factors associated with decline in FEV1 during adulthood. Between 1966 and 1969, 119 allergic asthmatic subjects aged 5 to 14 yr were studied (Visit 1). Of these subjects, 101 (85%) were reinvestigated at ages 22 to 32 yr (Visit 2) and 32 to 42 yr (Visit 3). At the first survey and during follow-up, a standardized questionnaire was used, serum total IgE and peripheral blood eosinophils were measured, and physical examination, skin tests, lung function tests, and histamine challenge (provocative concentration causing a 10% decline in FEV1; PC10) tests were performed according to the same protocol. Multiple linear regression analyses were performed with FEV1 at Visit 2 and with the change of FEV1 from Visit 2 to Visit 3 as outcome variables. A low FEV1% predicted at Visit 1 and PC10 ⩽ 16 mg/ml at Visit 1 were significantly associated with a lower level of FEV1 at Visit 2. Subjects who quit smoking and subjects who continued to use inhaled corticosteroids had a significantly smaller annual decline in FEV1 from Visit 2 to Visit 3, adjusted for attained level of FEV1 at Visit 2. In conclusion, bronchial hyperresponsiveness and a low level of lung function in childhood are independent risk factors for a low level of FEV1 in early adulthood. A smaller decline in FEV1 after ages 22 to 32 yr occurs in asthmatics who quit smoking and who continue to use inhaled corticosteroids. Our data stress the importance of studying intervention strategies for asthma in young childhood and early adulthood in order to prevent or postpone further lung function deficits. Grol MH, Gerritsen J, Vonk JM, Schouten JP, Koëter GH, Rijcken B, Postma DS. Risk factors for growth and decline of lung function in asthmatic individuals up to age 42 years: a 30-year follow-up study.
Altered Bone and Mineral Metabolism in Patients Receiving Imatinib Mesylate
Authors: Ellin Berman, Maria Nicolaides, Robert G. Maki, Martin Fleisher, Suzanne Chanel, Kelly Scheu, Bri-Anne Wilson, Glenn Heller, Nicholas P. Sauter
Journal: New England Journal of Medicine (2006)

Imatinib mesylate inhibits several tyrosine kinases, including BCR-ABL, the C-KIT receptor, and the platelet-derived growth factor receptors alpha and beta, all of which are associated with disease. We observed that hypophosphatemia developed in some patients with either chronic myelogenous leukemia or gastrointestinal stromal tumors who were receiving imatinib.We identified 16 patients who had low serum phosphate levels and 8 patients who had normal serum phosphate levels, all of whom were receiving imatinib. We performed the following biochemical measurements: whole-blood levels of ionized calcium, plasma levels of intact parathyroid hormone, and serum levels of total calcium, phosphate, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, magnesium, and markers of bone formation (bone alkaline phosphatase and osteocalcin) and bone resorption (N-telopeptide of collagen cross-links); urinalysis; and phosphate, calcium, and creatinine levels in "spot" urine specimens.Patients in the low-phosphate group (median serum phosphate level, 2.0 mg per deciliter [0.6 mmol per liter]; normal level, >2.5 mg per deciliter [0.8 mmol per liter]) had elevated parathyroid hormone levels and low-to-normal serum calcium levels, were younger, and were receiving a higher dose of imatinib than patients in the normal-phosphate group (median level, 3.2 mg per deciliter [1.0 mmol per liter]). Both groups had high levels of phosphate excreted in the urine and markedly decreased serum levels of osteocalcin and N-telopeptide of collagen cross-links.Hypophosphatemia, with associated changes in bone and mineral metabolism, develops in a proportion of patients taking imatinib for either chronic myelogenous leukemia or gastrointestinal stromal tumors. The drug may inhibit bone remodeling (formation and resorption), even in patients with normal serum phosphate levels.
Increased augmentation index in patients with cystic fibrosis
Authors: J. H. Hull, R. Garrod, T. B. Ho, R. K. Knight, J. R. Cockcroft, D. J. Shale, C. E. Bolton
Journal: European Respiratory Journal (2009)

Increased large artery stiffness occurs in a range of inflammatory conditions indicating an ageing of the vasculature and additionally being an independent risk factor for cardiovascular events. We determined large artery parameters in adults with cystic fibrosis (CF). 50 clinically stable adult patients with CF (mean+/-sd age 28.0+/-8.2 yrs) and 26 controls matched for age, sex and body mass index were studied. Central aortic blood pressure, augmentation index (AIx) and aortic pulse wave velocity (PWV) were determined using applanation tonometry. Lung function, diabetic status and C-reactive protein (CRP) were also determined. Mean+/-sd AIx was greater in patients than controls, 8.5+/-11.1% and -1.8+/-13.1%, respectively (p<0.001), while PWV was similar. Although AIx was greatest in the sub-group with CF-related diabetes (CFRD), it was also increased in the non-CFRD sub-group when compared with controls. In patients, AIx was related to log(10) CRP (r = 0.33) and forced vital capacity (r = -0.34; both p<0.05), and CRP remained predictive in multiple regression. AIx is increased in adults with CF, in the presence of a normal blood pressure and independent of diabetic status. AIx was related to the systemic inflammatory status. These findings have implications for management and require further exploration so that cardiovascular health can be maintained.