tbuckley/cabot-search huggingface dataset:
Graft-versus-leukemia activity may overcome therapeutic resistance of chronic lymphocytic leukemia with unmutated immunoglobulin variable heavy-chain gene status: implications of minimal residual disease measurement with quantitative PCR
Authors: Matthias Ritgen, Stephan Stilgenbauer, Nils von Neuhoff, Andreas Humpe, Monika Brüggemann, Christiane Pott, Thorsten Raff, Alexander Kröber, Donald Bunjes, Richard Schlenk, Norbert Schmitz, Hartmut Döhner, Michael Kneba, Peter Dreger
Journal: Blood (2004)
Persisting Illness and Fatigue in Adults with Evidence of Epstein-Barr Virus Infection
Authors: STEPHEN E. STRAUS
Journal: Annals of Internal Medicine (1985)

Clinical, serologic, virologic, and immunologic evaluations for 31 adults with chronic illness and fatigue suggested that 23 had persisting Epstein-Barr virus infection. Among these 23 patients, cellular immune mechanisms were generally normal, but 4 had mild immunoglobulin deficiencies. However, 20 patients had abnormal serologic profiles specific for Epstein-Barr virus shown by significantly elevated titers of antibodies to the viral capsid antigen or early antigen, or by a deficiency of late-appearing antibodies. In 11 of 15 patients tested, circulating immune complexes were found. Circulating interferon was not found in 18 patients tested, but the activity of 2-5 oligoadenylate synthetase, an interferon-induced enzyme, was increased in 5 patients studied. Of 19 patients, 18 had persisting suppressor T-cell activity typically found in patients recovering from acute infectious mononucleosis. We believe that the Epstein-Barr virus may be associated with chronic illness in adults.
Community-based recruitment of patients with COPD into clinical research
Authors: Simon E Brill, Ethaar El-Emir, James P Allinson, Gavin C Donaldson, Irwin Nazareth, Jadwiga A Wedzicha
Journal: Thorax (2014)

Identifying subjects for clinical trials is difficult and the evidence base for recruitment strategies is limited, particularly in the field of COPD. We compared the efficiency and patient characteristics of different community-based recruitment strategies during a non-commercial COPD trial in the UK. Recruiting from general practice COPD registers was less efficient and identified patients with significantly milder disease than recruiting through pulmonary rehabilitation and patient groups. We report our experience and propose that pulmonary rehabilitation and patient groups may represent an enriched pool of COPD patients to recruit into clinical trials.EudraCT 2011-001063-43.
Deficiency of G-Protein-Coupled Bile Acid Receptor Gpbar1 (TGR5) Enhances Chemically Induced Liver Carcinogenesis
Authors: Wei-Dong Chen, Donna Yu, Barry M. Forman, Wendong Huang, Yan-Dong Wang
Journal: Hepatology (2012)

Gpbar1 (TGR5), a membrane-bound bile acid receptor, is well known for its roles in regulation of energy homeostasis and glucose metabolism. TGR5 activation also inhibits nuclear factor κB (NF-κB)-mediated inflammation. Here we show that TGR5 deficiency enhances chemically induced liver carcinogenesis, and that TGR5 is a negative regulator of signal transducer and activator of transcription 3 (STAT3) signaling. Mice lacking TGR5 were much more susceptible to diethylnitrosamine (DEN)-induced acute liver injury and liver carcinogenesis than wildtype (WT) mice. Consistent with the increasing incidence of liver cancer in TGR5−/− mice, hepatocyte death, compensatory proliferation, and gene expression of certain inflammatory cytokines and matrix metalloproteinases were more sensitive to DEN induction in the absence of TGR5 signaling. In vitro , TGR5 activation greatly inhibited proliferation and migration of human liver cancer cells. We then found that TGR5 activation strongly suppressed STAT3 signaling in vitro and in vivo . Furthermore, we observed that TGR5 antagonizes the STAT3 pathway through suppressing STAT3 phosphorylation, its transcription activity, and DNA binding activity, which suggests that TGR5 antagonizes liver tumorigenesis at least in part by inhibiting STAT3 signaling. Conclusion: These findings identify TGR5 as a novel liver tumor suppressor that may serve as an attractive therapeutic tool for human liver cancer.
Overexpression of the Oncoprotein Prothymosin α Triggers a p53 Response that Involves p53 Acetylation
Authors: Takahiko Kobayashi, Ting Wang, Masaji Maezawa, Masanobu Kobayashi, Shunsuke Ohnishi, Kazuteru Hatanaka, Shuhei Hige, Yuichi Shimizu, Mototsugu Kato, Masahiro Asaka, Junji Tanaka, Masahiro Imamura, Kiminori Hasegawa, Yoshiyuki Tanaka, Rainer K. Brachmann
Journal: Cancer Research (2006)

Abstract Activation of the tumor suppressor protein p53 is a critical cellular response to various stress stimuli and to inappropriate activity of growth-promoting proteins, such as Myc, Ras, E2F, and β-catenin. Protein stability and transcriptional activity of p53 are modulated by protein-protein interactions and post-translational modifications, including acetylation. Here, we show that inappropriate activity of prothymosin α (PTMA), an oncoprotein overexpressed in human cancers, triggers a p53 response. Overexpression of PTMA enhanced p53 transcriptional activity in reporter gene assays for p53 target gene promoters hdm2, p21, and cyclin G. Overexpressed PTMA resulted in increased mRNA and protein levels for endogenous p53 target genes, hdm2 and p21, and in growth suppression. In contrast, reduction of endogenous PTMA through RNA interference decreased p53 transcriptional activity. Histone acetyltransferases (HATs) act as p53 coactivators and acetylate p53. PTMA, known to interact with HATs, led to increased levels of acetylated p53. PTMA did not increase the transcriptional activity of an acetylation-deficient p53 mutant, suggesting that p53 acetylation is an indispensable part of the p53 response to PTMA. Chromatin immunoprecipitation assays showed that excess PTMA associates with the p21 promoter and results in increased levels of acetylated p53 at the p21 promoter. Our findings indicate that overexpressed PTMA elicits a p53 response that involves p53 acetylation. (Cancer Res 2006; 66(6): 3137-44)
Determination of triiodothyronine concentration in human serum
Authors: Kenneth Sterling, Diego Bellabarba, Edward S. Newman, Milton A. Brenner
Journal: Journal of Clinical Investigation (1969)

A simplified method has been described for the measurement of triiodothyronine (T3) in human serum. The sensitivity was sufficient for determinations on hypothyroid as well as normal and thyrotoxic sera. The values obtained have been in reasonable agreement with a double isotope derivative assay.
Effect of cationized antibodies in performed immune complexes on deposition and persistence in renal glomeruli.
Authors: V J Gauthier, M Mannik, G E Striker
Journal: The Journal of Experimental Medicine (1982)

To study the interaction of positively charged antibodies in immune complexes with the fixed negative charge on the glomerular capillary wall, chemical cationization of antibody was accomplished with the maintenance of antigen-binding activity. These cationized antibodies bound rapidly to glomeruli but did not persist. Large-latticed immune complexes formed with these cationic antibodies showed rapid deposition and persistence in renal glomeruli, even when administered in small doses. Electron-dense deposits were present at the anionic sites in the glomerular basement membrane at 1 min and 1 h, with extensive subendothelial deposits present from 12 to 72 h. By 14 d, the deposits were seen in the subepithelial region and the glomerular mesangium. The administration of small-latticed immune complexes prepared with cationized antibody revealed initial deposition without persistence in glomeruli in a manner similar to cationized antibodies alone. Thus, the positive charges on antibodies in immune complexes contribute to the deposition and persistence of the complexes in glomeruli, particularly in the subendothelial area.
The Telomerase Antagonist, Imetelstat, Efficiently Targets Glioblastoma Tumor-Initiating Cells Leading to Decreased Proliferation and Tumor Growth
Authors: Calin O. Marian, Steve K. Cho, Brian M. Mcellin, Elizabeth A. Maher, Kimmo J. Hatanpaa, Christopher J. Madden, Bruce E. Mickey, Woodring E. Wright, Jerry W. Shay, Robert M. Bachoo
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Telomerase activity is one of the hallmarks of cancer and is a highly relevant therapeutic target. The effects of a novel human telomerase antagonist, imetelstat, on primary human glioblastoma (GBM) tumor-initiating cells were investigated in vitro and in vivo. Experimental Design: Tumor-initiating cells were isolated from primary GBM tumors and expanded as neurospheres in vitro. The GBM tumor-initiating cells were treated with imetelstat and examined for the effects on telomerase activity levels, telomere length, proliferation, clonogenicity, and differentiation. Subsequently, mouse orthotopic and subcutaneous xenografts were used to assess the in vivo efficacy of imetelstat. Results: Imetelstat treatment produced a dose-dependent inhibition of telomerase (IC50 0.45 μmol/L). Long-term imetelstat treatment led to progressive telomere shortening, reduced rates of proliferation, and eventually cell death in GBM tumor-initiating cells. Imetelstat in combination with radiation and temozolomide had a dramatic effect on cell survival and activated the DNA damage response pathway. Imetelstat is able to cross the blood-brain barrier in orthotopic GBM xenograft tumors. Fluorescently labeled GBM tumor cells isolated from orthotopic tumors, following systemic administration of imetelstat (30 mg/kg every day for three days), showed ∼70% inhibition of telomerase activity. Chronic systemic treatment produced a marked decrease in the rate of xenograft subcutaneous tumor growth. Conclusion: This preclinical study supports the feasibility of testing imetelstat in the treatment of GBM patients, alone or in combination with standard therapies. Clin Cancer Res; 16(1); 154–63
Grade and Stage at Presentation Do Not Predict Mortality in Patients With Bladder Cancer Who Survive Their Disease
Authors: Edward M. Messing, Ralph Madeb, Changyong Feng, Laura Stephenson, Kennedy W. Gilchrist, Terry Young, Jason Gee
Journal: Journal of Clinical Oncology (2009)

Purpose Our goal was to determine whether presenting grade and stage of bladder cancer (BC), which directly affect disease-specific survival, also influence time to and cause of non-BC deaths. Methods Histology slides of all men who lived in Wisconsin age ≥ 50 years diagnosed with BC in 1988 were reviewed centrally, and time and cause of death as reported to the state's tumor registry were recorded. Competing risks analyses based on grade, tumor stage, and age at diagnosis were generated to correlate time and causes of death (BC or non-BC) with tumor histology and age at presentation. Results Grade-stage categories were assigned to 509 patients with BC as follows: LGN = low grade (grade 1 or 2), nonmuscle invading (stage Ta or T1); HGN = high grade (grade 3 or carcinoma in situ), nonmucle invading (stage Ta, T1, or TIS); and INV = any grade, muscle invasive (≥ stage T2). Three hundred nine patients (60.7%) were LGN, 80 (15.7%) were HGN, and 120 (23.6%) were INV. Grade-stage category predicted overall (P = .0001) and BC-specific (P &lt; .0001) mortality but not non-BC mortality (P = .72), with hazard ratios of 1.095 (95% CI, 0.783 to 1.531) for HGN versus LGN, 1.137 (95% CI, 0.799 to 1.617) for INV versus LGN, and 1.038 (95% CI, 0.670 to 1.607) for INV versus HGN. Age had a highly significant effect on overall and non-BC deaths (P &lt; .0001) but only marginally predicted BC deaths (P = .054). Time to non-BC death did not differ significantly between grade-stage category (P = .12) or cause of death (P = .81). Conclusion Grade-stage category at diagnosis predicts overall and BC mortality but not mortality from other causes. Thus, particularly for INV disease, because BC represents the major threat to life, aggressive therapies that have been shown to be effective are justified.
Plugging (publicising) to prevent mucous plugging
Authors: P.-R. Burgel, J. A. Nadel
Journal: European Respiratory Journal (2010)

Mucus has long been known to exist in airways, but it is only relatively recently that mucous hypersecretion has been widely recognised to play major roles in the pathogenesis of chronic obstructive lung diseases, including asthma, chronic obstructive pulmonary disease and cystic fibrosis. Airway mucus is a complex mixture of liquids and proteins. Important components are gel-forming mucins, which are high-molecular-weight glycoproteins whose unusual viscoelastic properties permit the gel to interact with epithelial cilia, thus promoting clearance of deposited foreign materials. Airway mucins are reviewed in detail elsewhere 1. Owing to its clinical importance and the limited effectiveness of current therapies 2, 3, mucous hypersecretion is an appealing target for novel therapies.

How has mucus evolved as an important source of host defence in the airways, and what are the roles of mucous secretion in chronic obstructive airway diseases? When fish migrated from water to land, lungs replaced gills for respiratory gas exchange. Placement of the lungs adjacent to the heart, deep within the thoracic cavity, added the requirement of an air tube to transport inspired air to the lungs. However, inspired air also contains microbes and other irritants, which are deposited on the airway epithelial surface, causing inflammation and invading the host. In response, the host has developed defensive actions, which normally destroy and clear the invading organisms. Among the defensive host responses to inhaled invaders, secreted airway mucins normally play major protective roles. The recruited mucins entrap the invaders, which are then cleared by cough and mucociliary clearance 4. In healthy individuals, mucins in the airways are sparse but sufficient to accomplish entrapment and clearance of invaders efficiently and with minimal symptoms. However, in chronic inflammatory airway diseases, such as asthma, exaggerated mucin production occurs, leading to symptoms and airway obstruction. In the major …
Reflex Venoconstriction and Capacity Vessel Pressure-Volume Relationships in Dogs
Authors: JOHN A. DREES, CARL F. ROTHE
Journal: Circulation Research (1974)

Reflexogenic control of vascular capacity was studied by measuring the mean circulatory pressure (P MC ) at various blood volumes. P MC was obtained by fibrillating the heart for 10 seconds and rapidly transferring blood from the aorta to the vena cava until the pressures equilibrated. It was measured 0.5, 2, and 5 minutes after randomized changes in blood volume of 0 to ± 30% of the control volume in chloralose-urethane anesthetized dogs. Active venoconstriction was suppressed by administering hexamethonium and enhanced by administering norepinephrine. The effective total vascular compliance, expressed as the reciprocal of the slopes of P MC vs . blood volume curves in the controls, was linear. Compliance values differed significantly from each other and increased between 0.5, 2, and 5 minutes after a change in blood volume (2.60, 3.47, and 4.17 ml/kg body weight mm Hg -1 , respectively). With ganglionic blockade, only an 8-ml/ kg hemorrhage was required to bring P MC from the control level of 7.8 mm Hg to 4 mm Hg within 0.5 minutes. With reflexes intact, a 17-ml/kg hemorrhage reduced P MC from a control of 10.7 mm Hg to 4 mm Hg. To maintain this pressure for 5 minutes, an additional 8.2 and 9.1 ml/kg, respectively, had to be hemorrhaged, suggesting that the compensation after about 30 seconds was mostly from passive viscoelastic creep and fluid shifts. Less than half of the compensation for hemorrhage during the first 5 minutes came from the reflex venoconstriction.
Immunization With Mutant<i>p53</i>- and<i>K-ras</i>–Derived Peptides in Cancer Patients: Immune Response and Clinical Outcome
Authors: David P. Carbone, I. Frank Ciernik, Michael J. Kelley, M. Charles Smith, Sorena Nadaf, Denise Kavanaugh, V. Ellen Maher, Michael Stipanov, David Contois, Bruce E. Johnson, C. David Pendleton, Burkhardt Seifert, Charley Carter, Elizabeth J. Read, Jay Greenblatt, Lois E. Top, Morris I. Kelsey, John D. Minna, Jay A. Berzofsky
Journal: Journal of Clinical Oncology (2005)

To determine the ability to induce tumor-specific immunity with individual mutant K-ras-or p53-derived peptides and to monitor clinical outcome.Patients in varying stages of disease underwent genetic analysis for mutations in K-ras and p53. Thirty-nine patients were enrolled. Seventeen-mer peptides were custom synthesized to the corresponding mutation. Baseline immunity was assessed for cytotoxic T-lymphocyte (CTL) response and interferon gamma (IFN-gamma) release from mutant peptide-primed lymphocytes. Patients' peripheral-blood mononuclear cells were pulsed with the corresponding peptide, irradiated, and applied intravenously. Patients were observed for CTL, IFN-gamma, interleukin (IL) -2, IL-5, and granulocyte-macrophage colony-stimulating factor responses, for treatment-related toxicity, and for tumor response.No toxicity was observed. Ten (26%) of 38 patients had detectable CTL against mutant p53 or K-ras, and two patients were positive for CTL at baseline. Positive IFN-gamma responses occurred in 16 patients (42%) after vaccination, whereas four patients had positive IFN-gamma reaction before vaccination. Of 29 patients with evident disease, five experienced a period of stable disease. Favorable prognostic markers were detectable CTL activity and a positive IFN-gamma reaction but not IL-5 release. Median survival times of 393 v 98 days for a positive versus negative CTL response (P = .04), respectively, and of 470 v 88 days for a positive versus negative IFN-gamma response (P = .02), respectively, were detected.Custom-made peptide vaccination is feasible without any toxicity. CTL and cytokine responses specific to a given mutation can be induced or enhanced with peptide vaccines. Cellular immunity to mutant p53 and K-ras oncopeptides is associated with longer survival.
Genetic studies on components of the Wnt signalling pathway and the severity of joint destruction in rheumatoid arthritis
Authors: Diederik P C de Rooy, Nataliya G Yeremenko, Anthony Gerard Wilson, Rachel Knevel, Elisabet Lindqvist, Tore Saxne, Annemarie Krabben, Martha K Leijsma, Nina A Daha, S Tsonaka, A Zhernakova, J J Houwing-Duistermaat, Tom W J Huizinga, René E M Toes, Dominique L P Baeten, E Brouwer, Annette H M van der Helm-van Mil
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background</h3> Progression of joint destruction in rheumatoid arthritis (RA) is partly heritable; knowledge of genetic factors may increase our understanding of the mechanisms underlying joint destruction. The activity of the Wnt/β-catenin pathway influences osteoblast differentiation. Dickkopf-1 (Dkk-1) and sclerostin (Sost) are negative regulators and lipoprotein receptor-related protein-5 (LRP-5) and Kremen-1 are transmembrane receptors involved in this pathway. <h3>Objective</h3> To study variants in the genes encoding these proteins in relation to progression of joint destruction. <h3>Methods</h3> 1418 patients with RA of four cohorts with 4885 sets of hands and feet x-rays were studied. Explorative analyses were performed on 600 patients with RA from Leiden on single nucleotide polymorphisms (SNPs) tagging <i>Dkk-1</i>, <i>Sost</i>, <i>Kremen-1</i> and <i>LRP-5</i>. SNPs significantly associating with joint damage progression were subsequently genotyped in cohorts from Groningen (NL), Sheffield (UK) and Lund (Sweden). Data were summarised in meta-analyses. Serum levels of functional Dkk-1 and sclerostin were measured and studied in relation to genotypes. <h3>Results</h3> In the first cohort, six <i>Dkk-1</i>, three <i>Sost</i>, one <i>Kremen-1</i> and 10 <i>LRP-5</i> SNPs were significantly associated with radiological progression of joint destruction. Three <i>Dkk-1</i> SNPs were associated significantly with progression of joint damage in the meta-analysis, also after correction for multiple testing (rs1896368, rs1896367 and rs1528873). Two <i>Sost</i> SNPs tended to significance (rs4792909 and rs6503475, p=0.07 after false discovery rate correction). Gene–gene interactions between SNPs on <i>Dkk-1</i> and <i>Sost</i> were seen. Serum levels of Dkk-1 were significantly correlated with the genotypes in rs1896368 (p=0.02). <h3>Conclusions</h3> Patients with RA carrying risk alleles of genetic variants in <i>Dkk-1</i> have higher serum levels of functional Dkk-1 and more progressive joint destruction over time.
Doxorubicin-eluting bead-enhanced radiofrequency ablation of hepatocellular carcinoma: A pilot clinical study
Authors: Riccardo Lencioni, Laura Crocetti, Pasquale Petruzzi, Claudio Vignali, Elena Bozzi, Clotilde Della Pina, Irene Bargellini, Dania Cioni, Filippo Oliveri, Paolo De Simone, Carlo Bartolozzi, Maurizia Brunetto, Franco Filipponi
Journal: Journal of Hepatology (2008)
Low intensity pulsed ultrasonography for fractures: systematic review of randomised controlled trials
Authors: J. W Busse, J. Kaur, B. Mollon, M. Bhandari, P. Tornetta, H. J Schunemann, G. H Guyatt
Journal: BMJ (2009)

<b>Objective</b> To determine the efficacy of low intensity pulsed ultrasonography for healing of fractures. <b>Design</b> Systematic review of randomised controlled trials. <b>Data sources</b> Electronic literature search without language restrictions of CINAHL, Embase, Medline, HealthSTAR, and the Cochrane Central Registry of Controlled Trials, from inception of the database to 10 September 2008. <b>Review methods</b> Eligible studies were randomised controlled trials that enrolled patients with any kind of fracture and randomly assigned them to low intensity pulsed ultrasonography or to a control group. Two reviewers independently agreed on eligibility; three reviewers independently assessed methodological quality and extracted outcome data. All outcomes were included and meta-analyses done when possible. <b>Results</b> 13 randomised trials, of which five assessed outcomes of importance to patients, were included. Moderate quality evidence from one trial found no effect of low intensity pulsed ultrasonography on functional recovery from conservatively managed fresh clavicle fractures; whereas low quality evidence from three trials suggests benefit in non-operatively managed fresh fractures (faster radiographic healing time mean 36.9%, 95% confidence interval 25.6% to 46.0%). A single trial provided moderate quality evidence suggesting no effect of low intensity pulsed ultrasonography on return to function among non-operatively treated stress fractures. Three trials provided very low quality evidence for accelerated functional improvement after distraction osteogenesis. One trial provided low quality evidence for a benefit of low intensity pulsed ultrasonography in accelerating healing of established non-unions managed with bone graft. Four trials provided low quality evidence for acceleration of healing of operatively managed fresh fractures. <b>Conclusion</b> Evidence for the effect of low intensity pulsed ultrasonography on healing of fractures is moderate to very low in quality and provides conflicting results. Although overall results are promising, establishing the role of low intensity pulsed ultrasonography in the management of fractures requires large, blinded trials, directly addressing patient important outcomes such as return to function.