tbuckley/cabot-search huggingface dataset:
C4b-binding protein (C4BP) inhibits development of experimental arthritis in mice
Authors: A M Blom, K S Nandakumar, R Holmdahl
Journal: Annals of the Rheumatic Diseases (2008)

Objectives: To assess the human complement inhibitor C4b-binding protein (C4BP) for treatment of arthritis. Methods: We have used two mouse models of rheumatoid arthritis (RA) to assess the therapeutic effect of C4BP on different phases of arthritis, the collagen antibody-induced arthritis (CAIA), an acute antibody-induced disease and the collagen-induced arthritis (CIA), which carries the full complexity of arthritis. Results: Purified human C4BP injected intraperitoneally alleviated CAIA significantly in a manner similar to cobra venom factor that depletes complement due to massive activation. Furthermore, C4BP was injected before and after the disease development into CIA mice. In the former case, the disease onset was delayed and in the latter, the severity of the disease was reduced in animals treated with C4BP. However, C4BP did not affect the anti-CII antibody synthesis. C4BP present in mouse sera decreased activity of the classical but not the alternative pathway of the complement system when these were assessed in a fluid phase. However, C4BP was efficiently inhibiting the alternative pathway when present on the activating surface. Taken together, the disease ameliorating effect of C4BP appears to be related to inhibition of both pathways of complement. Conclusions: Although human C4BP was cleared relatively fast from the circulation and was only moderately affecting complement activity, its effect on the disease severity was substantial, suggesting that minor alterations in complement activity can have significant therapeutic value in RA.
Runx2 mediates epigenetic silencing of the bone morphogenetic protein-3B (BMP-3B/GDF10) in lung cancer cells
Authors: Manish Tandon, Karthiga Gokul, Syed A Ali, Zujian Chen, Jane Lian, Gary S Stein, Jitesh Pratap
Journal: Molecular Cancer (2012)

The Runt-related transcription factor Runx2 is essential for bone development but is also implicated in progression of several cancers of breast, prostate and bone, where it activates cancer-related genes and promotes invasive properties. The transforming growth factor β (TGF-β) family member bone morphogenetic protein-3B (BMP-3B/GDF10) is regarded as a tumor growth inhibitor and a gene silenced in lung cancers; however the regulatory mechanisms leading to its silencing have not been identified.Here we show that Runx2 is highly expressed in lung cancer cells and downregulates BMP-3B. This inverse relationship between Runx2 and BMP-3B expression is further supported by increased expression of BMP-3B in mesenchymal cells from Runx2 deficient mice. The ectopic expression of Runx2, but not DNA binding mutant Runx2, in normal lung fibroblast cells and lung cancer cells resulted in suppression of BMP-3B levels. The chromatin immunoprecipitation studies identified that the mechanism of Runx2-mediated suppression of BMP-3B is due to the recruitment of Runx2 and histone H3K9-specific methyltransferase Suv39h1 to BMP-3B proximal promoter and a concomitant increase in histone methylation (H3K9) status. The knockdown of Runx2 in H1299 cells resulted in decreased histone H3K9 methylation on BMP-3B promoter and increased BMP-3B expression levels. Furthermore, co-immunoprecipitation studies showed a direct interaction of Runx2 and Suv39h1 proteins. Phenotypically, Runx2 overexpression in H1299 cells increased wound healing response to TGFβ treatment.Our studies identified BMP-3B as a new Runx2 target gene and revealed a novel function of Runx2 in silencing of BMP-3B in lung cancers. Our results suggest that Runx2 is a potential therapeutic target to block tumor suppressor gene silencing in lung cancer cells.
Human infection with porcine ascaris
Authors: F. J. O'Rourke
Journal: BMJ (1967)

Pyloric Stenosis in Turner's Syndrome SIR,-The prevalence of congenital hyper- trophic stenosis in the general population is estimated to be about 2 to 5 per 1,000 live births,'`and Carter was able to demonstrate that the sex ratio for this malformation amounted to 5:1, boys being more affected than girls.'Benson and King have drawn attention to a possibly high prevalence of this condition in patients with Turner's syn- drome.'We have investigated a series of 43 patients with Turner's syndrome and found two patients with congenital pyloric stenosis.'The diagnosis of Turner's syndrome in Case 1 was established at the age of 19 years on the following criteria:(1) Sexual infantilism with primary amenor- rhoea, infantile external and internal genitalia, and absence of breast development.
Exon capture analysis of G protein-coupled receptors identifies activating mutations in GRM3 in melanoma
Authors: Todd D Prickett, Xiaomu Wei, Isabel Cardenas-Navia, Jamie K Teer, Jimmy C Lin, Vijay Walia, Jared Gartner, Jiji Jiang, Praveen F Cherukuri, Alfredo Molinolo, Michael A Davies, Jeffrey E Gershenwald, Katherine Stemke-Hale, Steven A Rosenberg, Elliott H Margulies, Yardena Samuels
Journal: Nature Genetics (2011)
Standard- vs High-Dose Clopidogrel Based on Platelet Function Testing After Percutaneous Coronary Intervention
Authors: Matthew J Price, Peter B Berger, Paul S Teirstein, Jean-François Tanguay, Dominick J Angiolillo, Douglas Spriggs, Sanjeev Puri, Mark Robbins, Kirk N Garratt, Olivier F Bertrand, Michael E Stillabower, Michael E Stillablower, Joseph R Aragon, David E Kandzari, Curtiss T Stinis, Michael S Lee, Steven V Manoukian, Christopher P Cannon, Nicholas J Schork, Eric J Topol
Journal: JAMA (2011)

High platelet reactivity while receiving clopidogrel has been linked to cardiovascular events after percutaneous coronary intervention (PCI), but a treatment strategy for this issue is not well defined.To evaluate the effect of high-dose compared with standard-dose clopidogrel in patients with high on-treatment platelet reactivity after PCI.Randomized, double-blind, active-control trial (Gauging Responsiveness with A VerifyNow assay-Impact on Thrombosis And Safety [GRAVITAS]) of 2214 patients with high on-treatment reactivity 12 to 24 hours after PCI with drug-eluting stents at 83 centers in North America between July 2008 and April 2010.High-dose clopidogrel (600-mg initial dose, 150 mg daily thereafter) or standard-dose clopidogrel (no additional loading dose, 75 mg daily) for 6 months.The primary end point was the 6-month incidence of death from cardiovascular causes, nonfatal myocardial infarction, or stent thrombosis. The key safety end point was severe or moderate bleeding according to the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) definition. A key pharmacodynamic end point was the rate of persistently high on-treatment reactivity at 30 days.At 6 months, the primary end point had occurred in 25 of 1109 patients (2.3%) receiving high-dose clopidogrel compared with 25 of 1105 patients (2.3%) receiving standard-dose clopidogrel (hazard ratio [HR], 1.01; 95% confidence interval [CI], 0.58-1.76; P = .97). Severe or moderate bleeding was not increased with the high-dose regimen (15 [1.4%] vs 25 [2.3%], HR, 0.59; 95% CI, 0.31-1.11; P = .10). Compared with standard-dose clopidogrel, high-dose clopidogrel provided a 22% (95% CI, 18%-26%) absolute reduction in the rate of high on-treatment reactivity at 30 days (62%; 95% CI, 59%-65% vs 40%; 95% CI, 37%-43%; P < .001).Among patients with high on-treatment reactivity after PCI with drug-eluting stents, the use of high-dose clopidogrel compared with standard-dose clopidogrel did not reduce the incidence of death from cardiovascular causes, nonfatal myocardial infarction, or stent thrombosis.clinicaltrials.gov Identifier: NCT00645918.
Meta-analysis: Cardiac Resynchronization Therapy for Patients With Less Symptomatic Heart Failure
Authors: Nawaf S. Al-Majed, Finlay A. McAlister, Jeffrey A. Bakal, Justin A. Ezekowitz
Journal: Annals of Internal Medicine (2011)

Background: Cardiac resynchronization therapy (CRT) reduces morbidity and mortality in patients with advanced symptoms of heart failure. Purpose: To assess the benefits and harms of CRT in patients with advanced heart failure and those with less symptomatic disease. Data Sources: A search of electronic databases (1950 to December 2010), hand-searching of reference lists, and unpublished data from principal investigators. Searches were not limited to the English language. Study Selection: Randomized, controlled trials of CRT compared with usual care and right or left ventricular pacing in adults with heart failure and a left ventricular ejection fraction of 0.40 or less. Data Extraction: Two reviewers performed independent study selection, data abstraction, and quality assessment by using the Cochrane tool for assessing risk for bias. Data Synthesis: There were 9082 patients in 25 trials. In patients with New York Heart Association (NYHA) class I and II symptoms, CRT reduced all-cause mortality (6 trials, 4572 participants; risk ratio [RR], 0.83 [95% CI, 0.72 to 0.96]) and heart failure hospitalizations (4 trials, 4349 participants; RR, 0.71 [CI, 0.57 to 0.87]) without improving functional outcomes or quality of life. In patients with NYHA class III or IV symptoms, CRT improved functional outcomes and reduced both all-cause mortality (19 trials, 4510 participants; RR, 0.78 [CI, 0.67 to 0.91]) and heart failure hospitalizations (11 trials, 2663 participants; RR, 0.65 [CI, 0.50 to 0.86]). The implant success rate was 94.4%; peri-implantation deaths occurred in 0.3% of trial participants, mechanical complications in 3.2%, lead problems in 6.2%, and infections in 1.4%. Limitation: Subgroup analyses were underpowered and lack data for persons with NYHA class I symptoms, atrial fibrillation, chronic kidney disease, or right bundle branch block. Conclusion: Cardiac resynchronization therapy is beneficial for patients with reduced left ventricular ejection fraction, symptoms of heart failure, and prolonged QRS, regardless of NYHA class. Primary Funding Source: None.
Antigen Presentation by Dendritic Cells after Immunization with DNA Encoding a Major Histocompatibility Complex Class II–restricted Viral Epitope
Authors: Sofia Casares, Kayo Inaba, Teodor-Doru Brumeanu, Ralph M. Steinman, Constantin A. Bona
Journal: The Journal of Experimental Medicine (1997)

Intramuscular and intracutaneous immunization with naked DNA can vaccinate animals to the encoded proteins, but the underlying mechanisms of antigen presentation are unclear. We used DNA that encodes an A/PR/8/34 influenza peptide for CD4 T cells and that elicits protective antiviral immunity. DNA-transfected, cultured muscle cells released the influenza polypeptide, which then could be presented on the major histocompatibility complex class II molecules of dendritic cells. When DNA was injected into muscles or skin, and antigen-presenting cells were isolated from either the draining lymph nodes or the skin, dendritic, but not B, cells presented antigen to T cells and carried plasmid DNA. We suggest that the uptake of DNA and/or the protein expressed by dendritic cells triggers immune responses to DNA vaccines.
Relationship between psychological state and level of activity of extrinsic gut innervation in patients with a functional gut disorder
Authors: A V Emmanuel, H J Mason, M A Kamm
Journal: Gut (2001)

Anxiety and depression are known to be associated with alterations in central autonomic activity, and this may manifest as a functional gut disturbance. However, the final expression of motility disturbance is non-specific and non-quantifiable. This study examines the relationship between psychological state and psychosocial functioning with a new direct measure of the level of activity of extrinsic autonomic gut innervation, rectal mucosal Doppler blood flow.Thirty four female patients (mean age 36 years, range 19--45) with constipation for greater than five years and 19 healthy women (mean age 38 years, range 21--60) were studied. They completed the general health questionnaire-28 point scale (GHQ-28; psychosocial functioning) and the Bem sex role inventory (BSRI; an index of women's psychological feelings about their own femininity). On the same day they underwent measurement of rectal mucosal Doppler blood flow, a new validated measure of the activity of gut extrinsic nerve innervation. Measurements were made during the follicular phase and in the fasted state.Women with constipation scored higher on the total GHQ-28 score and the somatisation (p=0.05) and anxiety (p=0.05) subscales of the GHQ-28. There was a negative correlation between mucosal blood flow and GHQ somatisation subscale (r=-0.45, p<0.005), anxiety (r=-0.38, p<0.05), and depression (r=-0.40, p<0.01) scores in women with constipation. Although constipated women scored no higher than controls on the BSRI, there was a significant negative correlation between blood flow and BSRI score (r=-0.49, p<0.005) for constipated women.General psychosocial function, somatisation, anxiety, depression, and feelings about female role are impaired in women with constipation and associated with altered rectal mucosal blood flow, a measure of extrinsic gut innervation. These findings suggest that psychological factors are likely to influence gut function via autonomic efferent neural pathways.
New Strategies for Treatment of <i>ALK</i>-Rearranged Non–Small Cell Lung Cancers
Authors: Takaaki Sasaki, Pasi A. Jänne
Journal: Clinical Cancer Research (2011)

The identification of oncogenic alterations in subsets of patients with non-small cell lung cancer (NSCLC) is transforming clinical care. Genomic rearrangements in anaplastic lymphoma kinase (ALK) are detected in 3% to 7% of patients with NSCLC. The ALK tyrosine kinase inhibitor crizotinib has demonstrated clinical efficacy in ALK-rearranged NSCLC patients and was recently approved by the U.S. Food and Drug Administration. Crizotinib is currently under additional phase III clinical development as both initial and second-line therapy for advanced ALK-rearranged NSCLC. However, new challenges in the diagnosis and treatment of this subset of NSCLC have emerged, including the need to determine the most effective means of diagnosing ALK-rearranged NSCLC and the emergence of acquired drug resistance to crizotinib. In this review, we discuss current strategies for treatment and diagnosis, as well as the current knowledge about mechanisms of acquired resistance to crizotinib. Finally, we discuss the strategies that are underway to clinically overcome acquired drug resistance.
Thymosin Fraction V and Intensive Combination Chemotherapy
Authors: Martin H. Cohen
Journal: JAMA (1979)

Patients with small-cell bronchogenic carcinoma who received intensive remission-induction chemotherapy randomly received either thymosin fraction V, 60 mg /sq m or 20 mg /sq m twice weekly, or no thymosin treatment during the initial six weeks of chemotherapy. Chemotherapy was then continued for two years. Thymosin administration did not increase the complete response rate. Patients receiving thymosin, 60 mg/sq m, had significantly prolonged survival times relative to the other treatment groups. This benefit was due to prolonged relapse-free survival in complete responders to treatment. The mechanism by which thymosin increased survival duration is unclear but may relate to restoration of immune deficits due to disease or treatment. (<i>JAMA</i>241:1813-1815, 1979)
Differential DNA Methylation in Umbilical Cord Blood of Infants Exposed to Low Levels of Arsenic<i>in Utero</i>
Authors: Devin C. Koestler, Michele Avissar-Whiting, E. Andres Houseman, Margaret R. Karagas, Carmen J. Marsit
Journal: Environmental Health Perspectives (2013)

There is increasing epidemiologic evidence that arsenic exposure in utero, even at low levels found throughout much of the world, is associated with adverse reproductive outcomes and may contribute to long-term health effects. Animal models, in vitro studies, and human cancer data suggest that arsenic may induce epigenetic alterations, specifically by altering patterns of DNA methylation. In this study we aimed to identify differences in DNA methylation in cord blood samples of infants with in utero, low-level arsenic exposure. DNA methylation of cord-blood derived DNA from 134 infants involved in a prospective birth cohort in New Hampshire was profiled using the Illumina Infinium Methylation450K array. In utero arsenic exposure was estimated using maternal urine samples collected at 24-28 weeks gestation. We used a novel cell mixture deconvolution methodology for examining the association between inferred white blood cell mixtures in infant cord blood and in utero arsenic exposure; we also examined the association between methylation at individual CpG loci and arsenic exposure levels. We found an association between urinary inorganic arsenic concentration and the estimated proportion of CD8+ T lymphocytes (1.18; 95% CI: 0.12, 2.23). Among the top 100 CpG loci with the lowest p-values based on their association with urinary arsenic levels, there was a statistically significant enrichment of these loci in CpG islands (p = 0.009). Of those in CpG islands (n = 44), most (75%) exhibited higher methylation levels in the highest exposed group compared with the lowest exposed group. Also, several CpG loci exhibited a linear dose-dependent relationship between methylation and arsenic exposure. Our findings suggest that in utero exposure to low levels of arsenic may affect the epigenome. Long-term follow-up is planned to determine whether the observed changes are associated with health outcomes.
Sexual-selection accounts of human characteristics: Just So Stories or scientific hypotheses?
Authors: Nora Newcombe, Mary Ann Baenninger
Journal: Behavioral and Brain Sciences (1996)

Abstract We evaluate three of Geary's claims, finding that (1) there is little evidence for sex differences in object- vs. person-orientation; (2) sex differences in competition, even if biologically caused, lead to sex differences in mathematics only given a certain style of teaching; and (3) sex differences in mental rotation, though real, are not well explained in a sociobiological framework or by the proximate biological variables assumed by Geary.
Effect of dietary intake of omega-3 and omega-6 fatty acids on severity of asthma in children
Authors: L Hodge, CM Salome, JM Hughes, D Liu-Brennan, J Rimmer, M Allman, D Pang, C Armour, AJ Woolcock
Journal: European Respiratory Journal (1998)

We assessed the clinical and biochemical effects in asthmatic children of fish oil supplementation and a diet that increases omega-3 and reduces omega-6 fatty acids. Thirty nine asthmatic children aged 8-12 yrs participated in a double-blind, randomized, controlled trial for 6 months during which they received fish oil capsules plus canola oil and margarine (omega-3 group) or safflower oil capsules plus sunflower oil and margarine (omega-6 group). Plasma fatty acids, stimulated tumour necrosis factor alpha (TNFalpha) production, circulating eosinophil numbers and lung function were measured at baseline and after 3 and 6 months of dietary modification. Day and night symptoms, peak flow rates and medication use were recorded for 1 week prior to laboratory visits. Plasma phospholipid omega-3 fatty acids were significantly greater in the omega-3 group at 3 and 6 months compared to the omega-6 group (p&lt;0.001). In the omega-3 group TNFalpha production fell significantly compared with baseline (p=0.026), but the magnitude of change between groups did not reach significance (p=0.075). There were no significant changes in clinical outcome measures. Dietary enrichment of omega-3 fatty acids over 6 months increased plasma levels of these fatty acids, reduced stimulated tumour necrosis factor alpha production, but had no effect on the clinical severity of asthma in these children.
Efficacy of lower-limb muscle training modalities in severely dyspnoeic individuals with COPD and quadriceps muscle weakness: results from the DICES trial
Authors: Maurice J H Sillen, Frits M E Franssen, Jeannet M L Delbressine, Anouk W Vaes, Emiel F M Wouters, Martijn A Spruit
Journal: Thorax (2014)

<h3>Rationale</h3> Strength training and neuromuscular electrical stimulation (NMES) improve lower-limb muscle function in dyspnoeic individuals with chronic obstructive pulmonary disease (COPD). However, high-frequency NMES (HF-NMES) and strength training have never been compared head-to-head; and effects of low-frequency NMES (LF-NMES) have never been studied in COPD. Therefore, the optimal training modality to improve lower-limb muscle function, exercise performance and other patient-related outcomes in individuals with severe COPD remains unknown. <h3>Objectives</h3> To study prospectively the efficacy of HF-NMES (75 Hz), LF-NMES (15 Hz) or strength training in severely dyspnoeic individuals with COPD with quadriceps muscle weakness at baseline. <h3>Methods</h3> 120 individuals with COPD (FEV<sub>1</sub>: 33±1% predicted, men: 52%, age: 64.8±0.8 years) were randomised to HF-NMES, LF-NMES or strength training as part of a comprehensive inpatient pulmonary rehabilitation programme. No treadmill walking or stationary cycling was provided. <h3>Measurements and main results</h3> Groups were comparable at baseline. Quadriceps muscle strength increased after HF-NMES (+10.8 Newton-metre (Nm)) or strength training (+6.1 Nm; both p&lt;0.01), but not after LF-NMES (+1.4 Nm; p=0.43). Quadriceps muscle endurance, exercise performance, lower-limb fat-free mass, exercise-induced symptoms of dyspnoea and fatigue improved significantly compared with baseline after HF-NMES, LF-NMES or strength training. The increase in quadriceps muscle strength and muscle endurance was greater after HF-NMES than after LF-NMES. <h3>Conclusions</h3> HF-NMES is equally effective as strength training in severely dyspnoeic individuals with COPD and muscle weakness in strengthening the quadriceps muscles and thus may be a good alternative in this particular group of patients. HF-NMES, LF-NMES and strength training were effective in improving exercise performance in severely dyspnoeic individuals with COPD and quadriceps weakness. <h3>Trial registration</h3> NTR2322
Redox signalling in vascular responses to shear and stretch
Authors: S LEHOUX
Journal: Cardiovascular Research (2006)

Blood vessels are permanently exposed to stretch and shear stress due to blood pressure and blood flow. Significant variations in the mechanical environment, of physiological or pathophysiological nature, occur in vivo. These trigger acute changes in vessel diameter that tend to restore basal levels of tensile and shear stress. However, when altered mechanical conditions persist, they lead to compensatory phenotypical modulation of the endothelial and vascular smooth muscle cells, producing structural and functional modifications of the arterial wall. Such vascular remodelling is a fundamental basis of normal vessel growth and adaptation. However, when the vascular environment changes, due to humoral, metabolic or surgical alterations, for example, mechanical factors may actually exacerbate the underlying conditions and contribute significantly to disease progression. Several studies have demonstrated that reactive oxygen species are induced in the vascular response to changes in shear stress or stretch. It appears that the balance between oxidant and antioxidant generation, which is directly determined by the nature of the mechanical stimulus, can greatly influence the process of vascular remodelling, contributing to both transient and more prolonged adaptations.