tbuckley/cabot-search huggingface dataset:
Chronic thromboembolic pulmonary hypertension: advances from bench to patient management
Authors: Joanna Pepke-Zaba, Marius M. Hoeper, Marc Humbert
Journal: European Respiratory Journal (2012)

ur understanding of chronic thromboembolic pulmonary hypertension (CTEPH), in terms of its natural history, pathophysiology and management of patients, has greatly improved since the landmark descriptions given by Kenneth Moser and Nina Braunwald [1] more than 40 yrs ago.At that time, small case series were available depicting the clinical features of patients suffering from ''long-standing thromboembolic pulmonary hypertension'', ''chronic massive thromboembolic obstruction'' or ''chronic obstruction of large pulmonary arteries''.The success of a surgical procedure, namely pulmonary endarterectomy (PEA), has transformed this lethal disorder into a potentially curable form of pulmonary hypertension.As a consequence, the referral of cases suitable for surgery has gradually increased with time.At the University of San Diego (San Diego, CA, USA), more than 2,700 PEA procedures have been performed since 1970, the majority over the past 20 yrs [2][3][4].European centres have subsequently contributed to broaden the knowledge on the disease [5][6][7].
Impaired thymic tolerance to α-myosin directs autoimmunity to the heart in mice and humans
Authors: HuiJuan Lv, Evis Havari, Sheena Pinto, Raju V.S.R.K. Gottumukkala, Lizbeth Cornivelli, Khadir Raddassi, Takashi Matsui, Anthony Rosenzweig, Roderick T. Bronson, Ross Smith, Anne L. Fletcher, Shannon J. Turley, Kai Wucherpfennig, Bruno Kyewski, Myra A. Lipes
Journal: Journal of Clinical Investigation (2011)

Autoimmunity has long been linked to myocarditis and its sequela, dilated cardiomyopathy, the leading causes of heart failure in young patients. However, the underlying mechanisms are poorly defined, with most clinical investigations focused on humoral autoimmunity as the target for intervention. Here, we show that the α-isoform of myosin heavy chain (α-MyHC, which is encoded by the gene Myh6) is the pathogenic autoantigen for CD4+ T cells in a spontaneous mouse model of myocarditis. Further, we found that Myh6 transcripts were absent in mouse medullary thymic epithelial cells (mTECs) and peripheral lymphoid stromal cells, which have been implicated in mediating central and peripheral T cell tolerance, respectively. Transgenic expression of α-MyHC in thymic epithelium conferred tolerance to cardiac myosin and prevented myocarditis, demonstrating that α-MyHC is a primary autoantigen in this disease process. Remarkably, we found that humans also lacked α-MyHC in mTECs and had high frequencies of α-MyHC-specific T cells in peripheral blood, with markedly augmented T cell responses to α-MyHC in patients with myocarditis. Since α-MyHC constitutes a small fraction of MyHC in human heart, these findings challenge the longstanding notion that autoimmune targeting of MyHC is due to its cardiac abundance and instead suggest that it is targeted as a result of impaired T cell tolerance mechanisms. These results thus support a role for T cell-specific therapies for myocarditis.
Precision-cut liver slices: A tool to model the liver ex vivo
Authors: Peter Olinga, Detlef Schuppan
Journal: Journal of Hepatology (2013)

D is ea se Precision-cut liver slices: A tool to model the liver ex vivo Peter Olinga1,2,*, Detlef Schuppan2 1Division of Pharmaceutical Technology and Biopharmacy, Departement of Pharmacy, University of Groningen, The Netherlands; 2Molecular and Translational Medicine, Department of Medicine I, University Medical Center, Johannes Gutenberg University Mainz, Germany *Corresponding author. Address: Division of Pharmaceutical Technology and Biopharmacy, Departement of Pharmacy, University of Groningen, The Netherlands. Tel.: + 31 50 363 8373; fax: +31 50 363 2500. *E-mail address: P.Olinga@rug.nl
Identification of a specific radioligand for the cardiac rapidly activating delayed rectifier K+ channel.
Authors: C C Chadwick, A M Ezrin, B O'Connor, W A Volberg, D I Smith, K J Wedge, R J Hill, G M Briggs, E D Pagani, P J Silver
Journal: Circulation Research (1993)

Class III antiarrhythmic drugs show promise as effective treatments for the suppression of potentially lethal cardiac arrhythmias. Dofetilide (UK-68,798), is a potent class III antiarrhythmic agent that is presently under clinical investigation. The objective of this study was to determine whether [3H]dofetilide could be used as a specific radioligand for the rapidly activating delayed rectifier K+ channel of the heart. We find that [3H]dofetilide binds to high-affinity sites on guinea pig cardiac myocytes. Competition studies using unlabeled dofetilide indicate that binding is characterized by an IC50 of 100 +/- 30 nM (mean +/- SD, n = 13). Scatchard analyses of binding indicate a Kd of 70 +/- 6 nM and a maximal binding capacity of 0.30 +/- 0.02 pmol/mg protein. [3H]Dofetilide is displaced from guinea pig myocytes by dofetilide, clofilium, quinidine, sotalol, and sematilide with a rank order of potency that correlates with functional blockade of the rapidly activating delayed rectifier K+ current (correlation coefficient, 0.951; slope, 0.99 +/- 0.19; p = 0.014). High-affinity [3H]dofetilide binding is not detected in rat myocytes, which are devoid of delayed rectifier K+ current. We conclude that [3H]dofetilide specifically binds to sites associated with the rapidly activating delayed rectifier K+ channel of guinea pig myocardium.
Essential role of the C5a receptor in E coli-induced oxidative burst and phagocytosis revealed by a novel lepirudin-based human whole blood model of inflammation
Authors: Tom Eirik Mollnes, Ole-Lars Brekke, Michael Fung, Hilde Fure, Dorte Christiansen, Grethe Bergseth, Vibeke Videm, Knut Tore Lappegård, Jörg Köhl, John D. Lambris
Journal: Blood (2002)
Cardiac Myosin Binding Protein C Gene Is Specifically Expressed in Heart During Murine and Human Development
Authors: Françoise Fougerousse, Anne-Lise Delezoide, Marc Y. Fiszman, Ketty Schwartz, Jacques S. Beckmann, Lucie Carrier
Journal: Circulation Research (1998)

Abstract —Cardiac myosin binding protein C (MyBP-C) is a substantial component of the sarcomere, with both structural and regulatory roles. The gene encoding cardiac MyBP-C in humans is located on chromosome 11p11.2, and mutations that are most predicted to produce truncated proteins have been identified in this gene in unrelated families with familial hypertrophic cardiomyopathy (FHC). To understand better the pathophysiology of FHC and with a view to the development of animal models for this disease, we have investigated by in situ hybridization the pattern of expression of the cardiac MyBP-C gene during human and mouse development using species-specific oligonucleotide probes. From 4 weeks of human development, a strong labeling of cardiac MyBP-C mRNAs was unambiguously detected in all heart compartments, and no signal could be visualized in somites. In murine embryos, from embryonic day 9.5 until birth, a strong signal was detected exclusively in the heart. Our results showed that during both human and murine development, in contrast to chicken development, the cardiac MyBP-C gene is abundantly and specifically expressed in the heart.
Role of dietary fibres, intestinal hypermotility and leukotrienes in the pathogenesis of NSAID-induced small intestinal ulcers in cats
Authors: H. Satoh, S. Shiotani, N. Otsuka, K. Hatao, S. Nishimura
Journal: Gut (2008)

<h3>Background:</h3> Recent advances in endoscopy have revealed that non-steroidal anti-inflammatory drugs (NSAIDs) often cause ulcers in the human small intestine. However, the mechanism of intestinal ulcer formation is still unclear. <h3>Aims:</h3> The role of dietary fibre (DF), intestinal motility and leukotrienes (LTs) in the formation of small intestinal ulcers induced by indomethacin (IND) was investigated in cats. <h3>Methods:</h3> Several types of diets containing DF at various percentages were given to animals twice daily during the experiment. IND was administered orally once daily after the morning meal for 3 days, and the area of mucosal lesions in the intestine was measured. Gastrointestinal motility was measured using a telemetry system in conscious cats implanted with force transducers. <h3>Results:</h3> In cats fed regular dry food containing 2.8% DF, IND (3 mg/kg, p.o.) significantly increased the motility of the lower half of the small intestine and produced many severe lesions; the total lesion area was 7.7 (SEM 2.0) cm<sup>2</sup> (n = 5). The lesions were markedly decreased with the low-DF diet (0.4%) and increased with the high-DF diet (7.2%). The lesion area was 0.1 (SEM 0.1) cm<sup>2</sup> (p&lt;0.05) and 18.2 (SEM 4.1) cm<sup>2</sup> (p&lt;0.05), respectively. Supplementation with insoluble DF (6% cellulose), but not soluble DF (pectin), in the low-DF diet increased the lesion area significantly. The hypermotility and lesion formation in the small intestine induced by IND were significantly (p&lt;0.05) inhibited by AA-861 (a 5-lipoxygenase inhibitor), pranlukast (a LT receptor antagonist) or atropine. <h3>Conclusions:</h3> Insoluble DF, intestinal hypermotility, leukotrienes and cholinergic pathways are implicated in the pathogenesis of small intestinal ulcers induced by NSAIDs.
Somatostatin Molecular Variants in the Vitreous Fluid
Authors: Cristina Hernández, Esther Carrasco, Roser Casamitjana, Ramon Deulofeu, José García-Arumí, Rafael Simó
Journal: Diabetes Care (2005)

OBJECTIVE—There is growing evidence to indicate that somatostatin could be added to the list of natural antiangiogenic factors that exist in the vitreous fluid. In addition, a deficit of intravitreous somatostatin-like immunoreactivity (SLI) has been found in diabetic patients with proliferative diabetic retinopathy (PDR). In the present study, we have determined the main molecular variants of somatostatin (somatostatin-14 and somatostatin-28) in the vitreous fluid and plasma of nondiabetic control subjects and diabetic patients with PDR. In addition, the contribution of cortistatin, a neuropeptide with strong structural similarities to somatostatin, to SLI and its levels in vitreous and plasma in both nondiabetic and diabetic patients has also been measured. RESERCH DESIGN AND METHODS—Plasma and vitreous fluid from 22 diabetic patients with PDR and 22 nondiabetic control subjects were analyzed. Somatostatin-14, somatostatin-28 and cortistatin were measured by radioimmunoassay but separation by high-performance liquid chromatography was required to measure somatostatin-14. RESULTS—The predominant molecular form of somatostatin within the vitreous fluid was somatostatin-28 (fivefold higher than somatostatin-14 in control subjects and threefold higher in patients with PDR). Cortistatin significantly contributed to SLI and its intravitreous levels were higher than those detected in plasma (nondiabetic control subjects: 147 [102–837] vs. 78 [24–32] pg/ml; patients with PDR: 187 [87–998] vs. 62 [24–472] pg/ml; P = 0.01 for both). Intravitreous somatostatin-14 was similar in both subjects with PDR and the control group (P = 0.87). By contrast, somatostatin-28 concentration was lower in patients with PDR than in nondiabetic control subjects (350 ± 32 vs. 595 ± 66 pg/ml; P = 0.004). CONCLUSIONS—Somatostatin-28 is the main molecular variant in the vitreous fluid. The intravitreous SLI deficit detected in patients with PDR is mainly due to somatostatin-28. Cortistatin is abundant in the vitreous fluid and significantly contributes to SLI. These findings could open up new strategies for PDR treatment.
Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression through paracrine neuregulin 1/HER3 signalling
Authors: Astrid De Boeck, Patrick Pauwels, Karen Hensen, Jean-Luc Rummens, Wendy Westbroek, An Hendrix, Dawn Maynard, Hannelore Denys, Kathleen Lambein, Geert Braems, Christian Gespach, Marc Bracke, Olivier De Wever
Journal: Gut (2012)

<h3>Objective</h3> Bone marrow-derived mesenchymal stem cells (BM-MSC) migrate to primary tumours and drive tumour progression. This study aimed to identify the molecular mechanisms associated with these heterotypic cellular interactions and analyse their relevance in colorectal cancer (CRC). <h3>Design</h3> Paracrine interactions of BM-MSC with CRC cells were studied using collagen invasion assays, cell counts, flow cytometric cell-cycle analysis and tumour xenograft models. The role of neuregulin 1 (NRG1) and the human epidermal growth factor receptor (HER) family pathways were investigated using tyrosine kinase assays, mass spectrometry, pharmacological inhibition, antibody-mediated neutralisation and RNA interference. Transmembrane neuregulin 1 (tNRG1), HER2 and HER3 expression was analysed in primary CRC (n=54), adjacent normal colorectal tissues (n=4), liver metastases (n=3) and adjacent normal liver tissues (n=3) by immunohistochemistry. <h3>Results</h3> BM-MSC stimulate invasion, survival and tumorigenesis of CRC through the release of soluble NRG1, activating the HER2/HER3-dependent PI3K/AKT signalling cascade in CRC cells. Similarly, tumour-associated mesenchymal cells (T-MC) in CRC demonstrate high tNRG1 expression, which is significantly associated with advanced Union for International Cancer Control stage (p=0.005) and invasion depth (p=0.04) and decreased 5-year progression-free survival (p=0.01). HER2 and HER3 show membrane localisation in cancer cells of CRC tissue. <h3>Conclusion</h3> Paracrine NRG1/HER3 signals initiated by BM-MSC and T-MC promote CRC cell progression, and high tNRG1 expression is associated with poor prognosis in CRC.
Evidence for naive T-cell repopulation despite thymus irradiation after autologous transplantation in adults with multiple myeloma: role of ex vivo CD34+ selection and age
Authors: Marion Malphettes, Guislaine Carcelain, Pierre Saint-Mezard, Véronique Leblond, Hester Korthals Altes, Jean-Pierre Marolleau, Patrice Debré, Jean-Claude Brouet, Jean-Paul Fermand, Brigitte Autran
Journal: Blood (2003)
Sporadic adenomatous polyp regression with exisulind is effective but toxic: a randomised, double blind, placebo controlled, dose-response study
Authors: N Arber
Journal: Gut (2005)

A 12 month, multicentre, randomised, double blind, placebo controlled, phase 3, dose-response study was carried out. Exisulind inhibits tumour growth by induction of apoptosis. The aim of our study was to investigate if exisulind induces regression of sporadic colonic adenomas.A 12 month multicentre randomised double blind placebo controlled phase 3 dose response study was carried out. At baseline colonoscopy, left sided polyps (3-10 mm) were tattooed, measured, and left in place. Subjects received exisulind 200 or 400 mg, or placebo daily. Follow up sigmoidoscopy was performed after six months, and removal of any remaining polyps at the 12 month colonoscopy. The primary efficacy variable was change in polyp size from baseline.A total of 281 patients were enrolled and randomised; 155 (55%) fulfilled the criteria for the intention to treat (ITT) analysis and 114 (41%) fulfilled the criteria for the efficacy evaluation analysis (patients who underwent the 12 month colonoscopy). The decrease in median polyp size was significantly greater (p=0.03) in patients who received exisulind 400 mg (-10 mm2) compared with those who received placebo (-4 mm2). Complete or partial response was significantly higher in the exisulind 400 mg group (54.6%) compared with the placebo group (30.2%), and disease progression was significantly lower (6.1% v 27.9%) (p=0.04 and 0.02, respectively). Increased liver enzymes (8.4%) and abdominal pain (14.7%) were also reported at a greater frequency in the exisulind 400 mg group.Exisulind caused significant regression of sporadic adenomatous polyps but was associated with more toxicity. This model of polyp regression, short in its term and involving a comparatively small patient sample size, may be the best available tool to assess a therapeutic regimen before launching into large preventive clinical studies.
Effective Cancer Therapy Through Immunomodulation
Authors: Thomas A. Waldmann
Journal: Annual Review of Medicine (2005)

MAbs directed toward tumor cells, tumor neovasculature, and host negative immunoregulatory elements (checkpoints) have emerged as useful immunotherapeutic agents against cancer. However, effective active modulation of the immune response with anticancer vaccines will require identifying appropriate tumor-rejection antigens; optimizing the interactions of peptides, antigen-presenting cells, and T cells; and blockading negative immunological checkpoints that impede an effective immune response. Checkpoints being targeted include CTLA-4 and PD1 that are negative signaling receptors expressed on activated T cells, CD4 + CD25 + Foxp3-expressing Tregs (suppressor T cells), IL-2-mediated activation-induced cell death (AICD), and the cytokine TGFβ.
Predicting the course of functional limitation among older adults with knee pain: do local signs, symptoms and radiographs add anything to general indicators?
Authors: E Thomas, G Peat, C Mallen, L Wood, R Lacey, R Duncan, P Croft
Journal: Annals of the Rheumatic Diseases (2008)

<h3>Objective:</h3> To determine the additional prognostic value of clinical history, physical examination and <i>x</i>-ray findings to a previously derived simple generic model (age, body mass index, anxiety and pain severity) in a cohort of older adults with knee pain. <h3>Methods:</h3> Prospective cohort study in community-dwelling adults in North Staffordshire. 621 participants (aged ⩾50 years) reporting knee pain who attended a research clinic at recruitment and were followed up by postal questionnaire at 18 months. Poor functional outcome was measured by the Physical Functioning Scale of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at 18-month follow-up defined in 60% of participants. <h3>Results:</h3> Three clinical history variables (bilateral knee pain, duration of morning stiffness and inactivity gelling) were independently associated with poor outcome. The addition of the "clinical history" model to the "generic" model led to a statistical improvement in model fit (likelihood ratio (LR) = 24.84, p = 0.001). Two physical examination variables (knee tender point count and single-leg balance) were independently associated with poor outcome but did not lead to a significant improvement when added to the "clinical history and generic" model (LR = 6.34, p = 0.50). Functional outcome was significantly associated with severity of knee radiographic osteoarthritis (OA), but did not lead to any improvement in fit when added to the "generic, clinical history and physical examination" model (LR = 1.86, p = 0.39). <h3>Conclusions:</h3> Clinical history, physical examination and severity of radiographic knee OA are of limited value over generic factors when trying to predict which older adults with knee pain will experience progressive or persistent functional difficulties.
Mechanisms of risk in preterm low‐birthweight infants
Authors: CATHERINE E. C. S. WILLIAMS, ELIZABETH S. DAVENPORT, JONATHAN A. C. STERNE, VYTHILINGAM SIVAPATHASUNDARAM, JANICE M. FEARNE, MICHAEL A. CURTIS
Journal: Periodontology 2000 (2000)

The periodontal diseases share many common risk factors with preterm low birth weight. Examples are, age, socioeconomic status and smoking (Fig. 5). Studies to date have only shown an association between the two conditions, and this does not indicate a causal relationship. However, since the inflammatory mediators that occur in the periodontal diseases, also play an important part in the initiation of labor, there are plausible biological mechanisms that could link the two conditions. The challenge for the future is to characterize the nature of the factors that predispose a mother to give birth prematurely to infants less than 2500 g and to assign relative probabilities to each. Studies are taking place in many parts of the world to determine the probability of a preterm low-birth-weight outcome, the interdependence of the factors that contribute to a birth event and possible casual relationships between these factors. Further information about the details of the effects of maternal infection will come from intervention studies, animal studies and more detailed examination of the mechanisms.
Hepatitis B viraemia: its heritability and association with common genetic variation in the interferon signalling pathway
Authors: H.-H. Huang, W.-L. Shih, Y.-H. Li, C.-F. Wu, P.-J. Chen, C.-L. Lin, C.-J. Liu, Y.-F. Liaw, S.-M. Lin, S.-D. Lee, M.-W. Yu
Journal: Gut (2010)

High viraemia of hepatitis B virus (HBV) influences all phases in the development of hepatocellular carcinoma (HCC). This study was designed to estimate the overall contribution of host genetics to HBV viraemia, and investigate the influence of common single-nucleotide polymorphisms (SNPs) in the interferon γ (IFNγ) signalling pathway, which is pivotal in the non-cytolytic clearance of HBV.We first determined familial correlations and heritability (ie, proportion of phenotypic variation that is attributable to additive genetic factors) for HBV viraemia using 280 HCC families, including 766 adult HBV carriers. Then family-based association analysis was conducted for viraemia with a panel of 40 SNPs across ten IFNγ-related genes. For replication, seven tagging SNPs in identified candidate regions were also tested in a further 1011 unrelated individuals with longitudinal data on HBV viraemia over 16 years.After adjustment for HBV genotype and sex, significant correlations for viraemia were detected among both siblings and mother-child pairs. Heritability accounted for approximately 30% (p<0.0002) of the variance of viral load, whereas HBV genotype and sex together explained less than 3%. Heritability estimates increased up to 74.0% after further exclusion of subjects with episodes of liver biochemical abnormalities. Our initial family-based association analysis identified two SNPs (rs2284553 (intronic SNP) and rs9808753 (Q64R)) on the IFNγ receptor 2 (IFNGR2) gene that were robustly associated with viraemia after multitest correction (all p<0.02). The SNPs were also associated with the longitudinal levels of viraemia and the persistence of a high viraemia of ≥4.39 log copies/ml (all p<0.0001) in unrelated individuals.HBV viraemia appears to have substantial heritability. Polymorphisms in the IFNGR2 gene appear to be associated with the variability of viraemia.