tbuckley/cabot-search huggingface dataset:
Variants in <i>TGFB1,</i> Dust Mite Exposure, and Disease Severity in Children with Asthma
Authors: Sunita Sharma, Benjamin A. Raby, Gary M. Hunninghake, Manuel Soto-Quirós, Lydiana Avila, Amy J. Murphy, Jessica Lasky-Su, Barbara J. Klanderman, Jody S. Sylvia, Scott T. Weiss, Juan C. Celedón
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Rationale: Polymorphisms in the gene for transforming growth factor-β1 (TGFB1) have been associated with asthma, but not with airway responsiveness or disease exacerbations in subjects with asthma.Objectives: To test for association between single nucleotide polymorphisms (SNPs) in TGFB1 and markers of asthma severity in childhood.Methods: We tested for the association between nine SNPs in TGFB1 and indicators of asthma severity (lung function, airway responsiveness, and disease exacerbations) in two cohorts: 416 Costa Rican parent-child trios and 465 families of non-Hispanic white children in the Childhood Asthma Management Program (CAMP). We also tested for the interaction between these polymorphisms and exposure to dust mite allergen on asthma severity.Measurements and Main Results: The A allele of promoter SNP rs2241712 was associated with increased airway responsiveness in Costa Rica (P = 0.0006) and CAMP (P = 0.005), and the C allele of an SNP in the promoter region (rs1800469) was associated with increased airway responsiveness in both cohorts (P ≤ 0.01). Dust mite exposure modified the effect of the C allele of exonic SNP rs1800471 on airway responsiveness (P = 0.03 for interactions in both cohorts). The T allele of a coding SNP (rs1982073) was associated with a reduced risk of asthma exacerbations in Costa Rica (P = 0.009) and CAMP (P = 0.005). Dust mite exposure also significantly modified the effect of the A allele of the promoter SNP rs2241712 on asthma exacerbations in both cohorts.Conclusions: SNPs in TGFB1 are associated with airway responsiveness and disease exacerbations in children with asthma. Moreover, dust mite exposure may modify the effect of TGFB1 SNPs on airway responsiveness and asthma exacerbations.
Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings 1PII of original article: S0169-409X(96)00423-1. The article was originally published in Advanced Drug Delivery Reviews 23 (1997) 3–25. 1
Authors: Christopher A Lipinski, Franco Lombardo, Beryl W Dominy, Paul J Feeney
Journal: Advanced Drug Delivery Reviews (2001)
Exploration of Tumor-Suppressive MicroRNAs Silenced by DNA Hypermethylation in Oral Cancer
Authors: Ken-ichi Kozaki, Issei Imoto, Seiki Mogi, Ken Omura, Johji Inazawa
Journal: Cancer Research (2008)

Abstract In the last few years, microRNAs (miRNA) have started a revolution in molecular biology and emerged as key players in the carcinogenesis. They have been identified in various tumor types, showing that different sets of miRNAs are usually deregulated in different cancers. To identify the miRNA signature that was specific for oral squamous cell carcinoma (OSCC), we first examined expression profiles of 148 miRNAs in a panel of 18 OSCC cell lines and the immortalized oral keratinocyte line RT7 as a control. Compared with RT7, the expression of 54 miRNAs (36.5%) was frequently down-regulated in OSCC lines (&amp;lt;0.5-fold expression, ≥66.7% of 18 lines). Among these 54 miRNAs, we further analyzed four of these miRNAs (i.e., miR-34b, miR-137, miR-193a, and miR-203), located around CpG islands, to identify tumor-suppressive miRNAs silenced through aberrant DNA methylation. The expression of those four genes was restored by treatment with 5-aza-2′-deoxycytidine in OSCC cells lacking their expression. In addition, expression levels of the four miRNAs were inversely correlated with their DNA methylation status in the OSCC lines. In primary tumors of OSCC with paired normal oral mucosa, down-regulation of miRNA expression through tumor-specific hypermethylation was more frequently observed for miR-137 and miR-193a than for miR-34b and miR-203. Moreover, the ectopic transfection of miR-137 or miR-193a into OSCC lines lacking their expressions significantly reduced cell growth, with down-regulation of the translation of cyclin-dependent kinase 6 or E2F transcription factor 6, respectively. Taken together, our results clearly show that miR-137 and miR-193a are tumor suppressor miRNAs epigenetically silenced during oral carcinogenesis. [Cancer Res 2008;68(7):2094–105]
Heterodimerization of G Protein-Coupled Receptors: Specificity and Functional Significance
Authors: Steven C. Prinster, Chris Hague, Randy A. Hall
Journal: Pharmacological Reviews (2005)

G protein-coupled receptors (GPCRs) are cell surface receptors that mediate physiological responses to a diverse array of stimuli. GPCRs have traditionally been thought to act as monomers, but recent evidence suggests that GPCRs may form dimers (or higher-order oligomers) as part of their normal trafficking and function. In fact, certain GPCRs seem to have a strict requirement for heterodimerization to attain proper surface expression and functional activity. Even those GPCRs that do not absolutely require heterodimerization may still specifically associate with other GPCR subtypes, sometimes resulting in dramatic effects on receptor pharmacology, signaling, and/or internalization. Understanding the specificity and functional significance of GPCR heterodimerization is of tremendous clinical importance since GPCRs are the molecular targets for numerous therapeutic drugs.
The inter-locus recombinant HLA-B*4601 has high selectivity in peptide binding and functions characteristic of HLA-C.
Authors: L D Barber, L Percival, N M Valiante, L Chen, C Lee, J E Gumperz, J H Phillips, L L Lanier, J C Bigge, R B Parekh, P Parham
Journal: The Journal of Experimental Medicine (1996)

The vast majority of new human HLA class I alleles are formed by conversions between existing alleles of the same locus. A notable exception to this rule is HLA-B*4601 formed by replacement of residues 66-76 of the alpha 1 helix of B*1501 by the homologous segment of Cw*0102. This inter-locus recombination, which brings together characteristic elements of HLA-B and HLA-C structure, is shown here to influence function dramatically. Naturally processed peptides bound by B*4601 are distinct from those of its parental allotypes B*1501 and Cw*0102 and dominated by three high abundance peptides. Such increased peptide selectivity by B*4601 is unique among HLA-A,B,C allotypes. For other aspects of function, presence of the small segment of HLA-C-derived sequence in an otherwise HLA-B framework converts B*4601 to an HLA-C-like molecule. Alloreactive cytotoxic T lymphocytes (CTL), natural killer (NK) cells, and cellular glycosidases all recognize B*4601 as though it were an HLA-C allotype. These unusual properties are those of an allotype which has frequencies as high as 20% in south east Asian populations and is associated with predisposition to autoimmune diseases and nasopharyngeal carcinoma.
Incidence and mechanisms of cardiorespiratory arrests in epilepsy monitoring units (MORTEMUS): a retrospective study
Authors: Philippe Ryvlin, Lina Nashef, Samden D Lhatoo, Lisa M Bateman, Jonathan Bird, Andrew Bleasel, Paul Boon, Arielle Crespel, Barbara A Dworetzky, Hans Høgenhaven, Holger Lerche, Louis Maillard, Michael P Malter, Cecile Marchal, Jagarlapudi MK Murthy, Michael Nitsche, Ekaterina Pataraia, Terje Rabben, Sylvain Rheims, Bernard Sadzot, Andreas Schulze-Bonhage, Masud Seyal, Elson L So, Mark Spitz, Anna Szucs, Meng Tan, James X Tao, Torbjörn Tomson
Journal: The Lancet Neurology (2013)
Type 2 Diabetic Nephropathy
Authors: Karl F. Hilgers, Roland Veelken
Journal: Journal of the American Society of Nephrology (2005)

Type 2 diabetes mellitus is now the leading cause of end-stage renal disease in the United States and other developed countries ([1][1]). The pathogenesis of renal failure in type 2 diabetes is complex ([1][1],[2][2]), but a role of the renin-angiotensin system (RAS) has been recognized for more
Potentiation by 1-α,25-0ihydroxyvitamin D3 of Cytotoxicity to HL-60 Cells Produced by Cytarabine and Hydroxyurea
Authors: George P. Studzinski, Amarjit K. Bhandal, Zamir S. Breivi
Journal: JNCI Journal of the National Cancer Institute (1986)

A short (4-hr) exposure to 1-4 X 10(-7) M 1,25-dihydroxyvitamin D3 [(1,25(OH)2D3); 1-alpha,25-dihydroxycholecalciferol] induced transient differentiation in a clone (R2AB2) of human promyelocytic leukemia cells (HL-60) but caused no permanent growth impairment and no detectable cytotoxicity. This treatment with 1,25(OH)2D3 also produced an inhibition of DNA synthesis that was promptly reversed when 1,25(OH)2D3 was removed. When such treatment with 1,25(OH)2D3 immediately followed a sublethal exposure to drugs that inhibit DNA synthesis, including the cancer chemotherapeutic agents cytarabine and hydroxyurea, the proportion of HL-60 cells lethally damaged was increased. This finding was demonstrated by morphologic evidence of cell damage and disintegration, an increased permeability to trypan blue, loss of cells from culture, and a reduced clonogenic potential of the treated cells. Exposure to 1,25(OH)2D3 before treatment with a cytotoxic agent had a slightly protective rather than a damaging effect. These observations suggest that the presence of 1,25(OH)2D3 markedly reduces the capacity of HL-60 cells to repair DNA damage or to reduce the intracellular concentration of cytotoxic agents.
Sensitivity and specificity of eicosanoid radioimmunoassays: new strategy
Authors: F. DRAY
Journal: British Journal of Dermatology (2006)

In radioimmunoassays (RIAs) the limit of detection of the unknown (ligand, competitor) depends first on the affinity of antibody populations engaged in the immunological reaction at a given dilution of the antiserum, second on the specific radioactivity of the tracer or inhibitor, and third on the degree of structural homology of both components (unknown and tracer) of the competition. The commercially available tritiated eicosanoids have up to eight atoms of tritiu incorporated into their molecules, allowing RIAs with convenient sensitivities to be developed. Often, however, a higher sensitivity is needed in several studies. First attempts (Dray et al. 1972) using PGF2x covalently bound to bacteriophage T4 as a tracer yielded a highly sensitive viroimmunoassay (limit of detection, less than i pg per tube), but its wider application requires further studies, particularly to reduce the non‐specific binding (Andrieu, Mamas & Dray, 1974; Mamas & Dray, 1979). On the other hand, we succeeded in developing very sensitive and reliable RIAs using iodinated derivatives, which could be applied to any eicosanoid.
Efficient phagocytosis and laccase activity affect the outcome of HIV-associated cryptococcosis
Authors: Wilber Sabiiti, Emma Robertson, Mathew A. Beale, Simon A. Johnston, Annemarie E. Brouwer, Angela Loyse, Joseph N. Jarvis, Andrew S. Gilbert, Matthew C. Fisher, Thomas S. Harrison, Robin C. May, Tihana Bicanic
Journal: Journal of Clinical Investigation (2014)

Cryptococcal meningitis (CM) is a leading cause of HIV-associated mortality globally. High fungal burden in cerebrospinal fluid (CSF) at diagnosis and poor fungal clearance during treatment are recognized adverse prognostic markers; however, the underlying pathogenic factors that drive these clinical manifestations are incompletely understood. We profiled a large set of clinical isolates for established cryptococcal virulence traits to evaluate the contribution of C. neoformans phenotypic diversity to clinical presentation and outcome in human cryptococcosis.Sixty-five C. neoformans isolates from clinical trial patients with matched clinical data were assayed in vitro to determine murine macrophage uptake, intracellular proliferation rate (IPR), capsule induction, and laccase activity. Analysis of the correlation between prognostic clinical and host immune parameters and fungal phenotypes was performed using Spearman's r, while the fungal-dependent impact on long-term survival was determined by Cox regression analysis.High levels of fungal uptake by macrophages in vitro, but not the IPR, were associated with CSF fungal burden (r = 0.38, P = 0.002) and long-term patient survival (hazard ratio [HR] 2.6, 95% CI 1.2-5.5, P = 0.012). High-uptake strains were hypocapsular (r = -0.28, P = 0.05) and exhibited enhanced laccase activity (r = 0.36, P = 0.003). Fungal isolates with greater laccase activity exhibited heightened survival ex vivo in purified CSF (r = 0.49, P < 0.0001) and resistance to clearance following patient antifungal treatment (r = 0.39, P = 0.003).These findings underscore the contribution of cryptococcal-phagocyte interactions and laccase-dependent melanin pathways to human clinical presentation and outcome. Furthermore, characterization of fungal-specific pathways that drive clinical manifestation provide potential targets for the development of therapeutics and the management of CM.This work was made possible by funding from the Wellcome Trust (WT088148MF), the Medical Research Council (MR/J008176/1), the NIHR Surgical Reconstruction and Microbiology Research Centre and the Lister Institute for Preventive Medicine (to R.C. May), and a Wellcome Trust Intermediate fellowship (089966, to T. Bicanic). The C. neoformans isolates were collected within clinical trials funded by the British Infection Society (fellowship to T. Bicanic), the Wellcome Trust (research training fellowships WT069991, to A.E. Brouwer and WT081794, to J.N. Jarvis), and the Medical Research Council, United Kingdom (76201). The funding sources had no role in the design or conduct of this study, nor in preparation of the manuscript.
IL-10 inhibits transcription elongation of the human <i>TNF</i> gene in primary macrophages
Authors: Tim Smallie, Giuseppe Ricchetti, Nicole J. Horwood, Marc Feldmann, Andrew R. Clark, Lynn M. Williams
Journal: The Journal of Experimental Medicine (2010)

IL-10 plays a central nonredundant role in limiting inflammation in vivo. However, the mechanisms involved remain to be resolved. Using primary human macrophages, we found that IL-10 inhibits selected inflammatory genes, primarily at a level of transcription. At the TNF gene, this occurs not through an inhibition of RNA polymerase II (Pol II) recruitment and transcription initiation but through a mechanism targeting the stimulation of transcription elongation by cyclin-dependent kinase (CDK) 9. We demonstrated an unanticipated requirement for a region downstream of the TNF 3′ untranslated region (UTR) that contains the nuclear factor κB (NF-κB) binding motif (κB4) both for induction of transcription by lipopolysaccharide (LPS) and its inhibition by IL-10. IL-10 not only inhibits the recruitment of RelA to regions containing κB sites at the TNF gene but also to those found at other LPS-induced genes. We show that although IL-10 elicits a general block in RelA recruitment to its genomic targets, the gene-specific nature of IL-10’s actions are defined through the differential recruitment of CDK9 and the control of transcription elongation. At TNF, but not NFKBIA, the consequence of RelA recruitment inhibition is a loss of CDK9 recruitment, preventing the stimulation of transcription elongation.
Immunodiagnosis of acute leukemia displaying ectopic antigens: Proposal for a classification of promiscuous phenotypes
Authors: Luigi Del Vecchio, Ettore Mariano Schiavone, Felicetto Ferrara, Emilio Pace, Catia Lo Pardo, Maurizio Pacetti, Maria Russo, Dora Cirillo, Clemente Vacca
Journal: American Journal of Hematology (1989)

Abstract The nature of the blast cells in 163 cases of acute leukemia was investigated by immunophenotyping, with particular emphasis on the expression of “ectopic” surface membrane structures. Although no antigen included in our panel except CD3 revealed absolute lineage restriction, immunological typing allowed a definite characterization of blast cells in more than 90% of cases. Four groups of patients were identified (A, B, C, D) with different degrees of antigen ectopic expression. We classified as group A leukemias (74%) those expressing conventional antigenic patterns, in absence of cross‐lineage markers. Samples classified as group B (18%) showed a single ectopic membrane specificity, apparently discordant with the overall composite phenotype; such a “low‐grade deviation” did not prevent a definite immunodiagnosis. Pattern C specimens (5%) revealed a promiscuous coexpression of markers related to different lineages (biphenotypic leukemias), whereas group D included unclassifiable phenotypes, characterized by no antigen or DR‐only expression. Our findings suggest the possibility of interpreting complex phenotypic constellations of membrane markers in a consistent and logical manner.
Update on the profile of the EUSTAR cohort: an analysis of the EULAR Scleroderma Trials and Research group database
Authors: Florian M P Meier, Klaus W Frommer, Robert Dinser, Ulrich A Walker, Laszlo Czirjak, Christopher P Denton, Yannick Allanore, Oliver Distler, Gabriela Riemekasten, Gabriele Valentini, Ulf Müller-Ladner
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objectives</h3> Systemic sclerosis (SSc) is a rare disease requiring multicentre collaboration to reveal comprehensive details of disease-related causes for morbidity and mortality. <h3>Methods</h3> The European League Against Rheumatism (EULAR) Scleroderma Trials and Research (EUSTAR) group initiated a database to prospectively gather key data of patients with SSc using a minimal essential dataset that was reorganised in 2008 introducing new items. Baseline visit data of patients who were registered between 2004 and 2011 were analysed using descriptive statistics. <h3>Results</h3> In June 2011, 7655 patients (2838 with diffuse cutaneous (dc) and 4481 with limited cutaneous (lc) SSc who fulfilled the American College of Rheumatology diagnostic criteria had been registered in 174 centres, mainly European. The most prominent hallmarks of disease were Raynaud9s phenomenon (96.3%), antinuclear antibodies (93.4%) and a typical capillaroscopic pattern (90.9%). Scleroderma was more common on fingers and hands than on any other part of the skin. Proton pump inhibitors (65.2%), calcium channel blockers (52.7%), and corticosteroids (45.3%) were most often prescribed. Among the immunosuppressant agents, cyclophosphamide was used more often in dcSSc than in lcSSc. <h3>Conclusions</h3> The EUSTAR database provides an abundance of information on the true clinical face of SSc that will be helpful in improving the classification of SSc and its subsets and for developing more specific therapeutic recommendations.
The dependence of the cardiac effects of nifedipine on the responses of the peripheral vascular system.
Authors: P B Kurnik, A J Tiefenbrunn, P A Ludbrook
Journal: Circulation (1984)

To elucidate the mechanisms of reduction of left ventricular end-diastolic pressure by nifedipine in certain individuals, we evaluated cardiac and peripheral hemodynamic responses in 32 patients after they were randomly assigned to nifedipine (20 mg sublingually) or to placebo treatment. Forearm plethysmography was performed during cardiac catheterization with micromanometers. No hemodynamic parameters were changed after placebo. Left ventricular end-diastolic pressure declined by 14% (p less than .02) after nifedipine in patients with impaired left ventricular function, but was unchanged in those with normal function; indexes of peripheral venous hemodynamics (forearm venous tone, forearm volume change) were not affected. In those patients with abnormal left ventricular function, forearm vascular resistance decreased 36% and forearm blood flow increased 31% (p less than .0005 for both), while neither changed in those with normal function. Cardiac output increased by 10% in patients with impaired left ventricular function but was unchanged in the remainder, while calculated total systemic resistance fell by 24% in those with abnormal left ventricular function (p less than .002 for both). Thus, reduction of left ventricular preload by nifedipine is not attributable to venous pooling, but rather this beneficial effect appears to be attributable to improved left ventricular systolic function in response to afterload reduction, particularly in patients with impaired left ventricular function.
DNAzyme Targeting c- <i>jun</i> Suppresses Skin Cancer Growth
Authors: Hong Cai, Fernando S. Santiago, Leonel Prado-Lourenco, Bo Wang, Margaret Patrikakis, Miles P. Davenport, Ghassan J. Maghzal, Roland Stocker, Christopher R. Parish, Beng H. Chong, Graham J. Lieschke, Tak-Wah Wong, Colin N. Chesterman, Douglas J. Francis, Fergal J. Moloney, Ross St.C. Barnetson, Gary M. Halliday, Levon M. Khachigian
Journal: Science Translational Medicine (2012)

Catalytic DNA molecules that target the transcription factor c- jun inhibit skin cancer growth in mice.
Electron Microscopy of Induced Secretion in Mammary Epithelial Cells of Hypophysectomized-Ovariectomized-Adrenalectomized BALB/cCrgl Mice&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: S. R. Wellings, S. Nandi
Journal: JNCI Journal of the National Cancer Institute (1968)

Intact virgin female mice of the BALB/cCrgl strain, 115 days old, were treated for 14 days with a hormonal combination of estradiol 17β (1 μg/day) plus progesterone (1 mg/day), to artificially induce lobuloalveolar development of the mammary glands. The mice were then hypophysectomized-ovariectomized-adrenalectomized on the 15th day and subsequently treated with estradiol 17β (1 μs/day) plus progesterone (1 mg/day) plus ovine mammotropin (1 mg/day) plus bovine somatotropin (0.1 mg/day) from days 16–20. The mice were then divided into 3 groups, each group treated 5 additional days with one of the following lactogenic combinations: ovine mammotropin (1 mg/day) plus bovine somatotropin (0.1 mg/day) plus cortisol (250 μg/day); or ovine mammotropin (1 mg/day) plus bovine somatotropin (0.1 mg/day) plus corticosterone (1 mg/day); or ovine mammotropin (1 mg/day) plus bovine somatotropin (0.1 mg/day) plus corticosterone (1 mg/day) plus aldosterone (5 μg/day). On the 26th day, all animals were killed by neck fracture, and the mammary glands were observed to contain many distended, white alveoli. The mammary tissues were prepared for light and electron microscopy. All experimental groups showed light and electron microscopic mammary secretory morphology identical to that in intact, suckled, female control mice, 5 days after parturition. By electron microscopy, these changes, correlating with lactogenesis, included: abundant membranous ergastoplasm, enlarged Golgi apparatus containing milk-protein droplets, increased numbers of apical microvilli in the alveolar cells, and numerous milk-fat and protein droplets in the alveolar lumens. The alveolar epithelial cells of intact female control mice at 18–19 days of pregnancy (late prelactation) exhibited no, or minimal, development of the same ultrastructural features. These results indicate that the sequential procedure used can induce lobuloalveolar development and lactogenesis in the BALB/cCrgl mouse, and that the ultra-structural features induced by the treatment are essentially identical to those in the normal lactating gland of intact mice.