tbuckley/cabot-search huggingface dataset:
Chemotherapy of Experimental Streptococcal Endocarditis
Authors: David T. Durack, Lawrence L. Pelletier, Robert G. Petersdorf
Journal: Journal of Clinical Investigation (1974)

Bacterial endocarditis was produced by intravenous injection of Streptococcus viridans into rabbits with preexisting sterile endocardial vegetations. After 6 h had elapsed, bacteria in the vegetations could not be eradicated by brief treatment with antimicrobials to which the streptococci were sensitive. However, when treatment with penicillin was continued for 4 days, the animals were cured. The 6-h infection therefore offered a model in which treatments could be conveniently compared over a short period. Synergism was demonstrated between penicillin and streptomycin in endocarditis due to a fully penicillin-sensitive streptococcus, a point which had not been previously proved in vivo. The clinical implications are discussed.
Failure off Inoculation With Polyoma Virus To Influence Chemical Carcinogenesis in Mice
Authors: Richard A. Malmgren, Alan S. Rabson
Journal: JNCI Journal of the National Cancer Institute (1963)

Because inoculation with the polyoma virus will protect adult mice against growth of a relatively small number of cells of transplantable polyoma-induced tumors and because the immunity apparently is not due to the virus per se but to an altered cell antigen, it seemed pertinent to determine whether inoculation with the polyoma virus would also protect against chemical carcinogenesis. C3H/HeN female mice, treated with 3-methylcholanthrene by subcutaneous injection or skin painting, developed the same number of tumors and at the same rate in polyoma-virus infected and uninfected animals. A/LN male mice treated with urethan developed the same number of lung tumors in polyoma-virus infected and uninfected animals. Polyoma virus infection therefore did not interfere with or protect against chemical carcinogenesis.
Genetic and Epigenetic Alterations in the von Hippel-Lindau Gene: the Influence on Renal Cancer Prognosis
Authors: Kim M. Smits, Leo J. Schouten, Boukje A.C. van Dijk, Christina A. Hulsbergen-van de Kaa, Kim A.D. Wouters, Egbert Oosterwijk, Manon van Engeland, Piet A. van den Brandt
Journal: Clinical Cancer Research (2008)

Abstract Background: Inactivation of the von Hippel-Lindau (VHL) gene is considered as an early event in renal cancer tumorigenesis. The prognostic relevance of these changes, however, is not clear and previous results are contradictory. We have evaluated the influence of (epi)genetic alterations in VHL on cause-specific survival in clear-cell renal cell cancer (ccRCC) in a large, population-based group of cases. Methods: One hundred and eighty-five cases of ccRCC, identified in the Netherlands Cohort Study on diet and cancer diagnosed in the period 1986 to 1997, were included in the analyses. Mortality information until December 2005, including causes of death, were obtained for all cases through linkage with the Central Bureau of Statistics. VHL mutations were determined with PCR single-strand conformational polymorphism and direct sequencing. VHL methylation was determined with methylation-specific PCR. Kaplan-Meier analyses and Cox proportional hazards models were used to assess associations between VHL alterations and cause-specific mortality. Results: Median follow-up in our population was 6 years. The frequency of loss of function mutations and methylation, separately or combined, did not differ statistically significant between different cancer stages or between tumors with different sizes. We observed no influence of loss of function mutations or methylation of the VHL gene on cause-specific mortality (hazard ratio, 1.08; 95% confidence interval, 0.69-1.68, P = 0.735) as compared with patients with a wild-type or silent mutation in VHL. Discussion: Our results indicate that (epi)genetic alterations in the VHL gene do not have prognostic value in ccRCC.
Cell migration leads to spatially distinct but clonally related airway cancer precursors
Authors: Christodoulos P Pipinikas, Theodoros S Kiropoulos, Vitor H Teixeira, James M Brown, Aikaterini Varanou, Mary Falzon, Arrigo Capitanio, Steven E Bottoms, Bernadette Carroll, Neal Navani, Frank McCaughan, Jeremy P George, Adam Giangreco, Nicholas A Wright, Stuart A C McDonald, Trevor A Graham, Sam M Janes
Journal: Thorax (2014)

<h3>Background</h3> Squamous cell carcinoma of the lung is a common cancer with 95% mortality at 5 years. These cancers arise from preinvasive lesions, which have a natural history of development progressing through increasing severity of dysplasia to carcinoma in situ (CIS), and in some cases, ending in transformation to invasive carcinoma. Synchronous preinvasive lesions identified at autopsy have been previously shown to be clonally related. <h3>Methods</h3> Using autofluorescence bronchoscopy that allows visual observation of preinvasive lesions within the upper airways, together with molecular profiling of biopsies using gene sequencing and loss-of-heterozygosity analysis from both preinvasive lesions and from intervening normal tissue, we have monitored individual lesions longitudinally and documented their visual, histological and molecular relationship. <h3>Results</h3> We demonstrate that rather than forming a contiguous field of abnormal tissue, clonal CIS lesions can develop at multiple anatomically discrete sites over time. Further, we demonstrate that patients with CIS in the trachea have invariably had previous lesions that have migrated proximally, and in one case, into the other lung over a period of 12 years. <h3>Conclusions</h3> Molecular information from these unique biopsies provides for the first time evidence that field cancerisation of the upper airways can occur through cell migration rather than via local contiguous cellular expansion as previously thought. Our findings urge a clinical strategy of ablating high-grade premalignant airway lesions with subsequent attentive surveillance for recurrence in the bronchial tree.
Prognostic value of lung function and pulmonary haemodynamics in OSA patients treated with CPAP
Authors: A. Chaouat, E. Weitzenblum, J Krieger, E Sforza, H. Hammad, M. Oswald, R. Kessler
Journal: European Respiratory Journal (1999)

The aim of the present study was to determine survival rates of obstructive sleep apnoea patients treated with continuous positive airway pressure (CPAP) and to investigate the prognostic value of pretreatment lung function and pulmonary haemodynamics. Two hundred and ninety-six patients, exhibiting > or = 20 apnoeas plus hypopnoeas per hour of sleep, were included. Patients were treated with nasal CPAP and regularly followed up. The cumulative survival rates were 0.96 (95% confidence interval (CI): 0.94-0.99) at 3 yrs and 0.93 (95% CI: 0.91-0.97) at 5 yrs. Most patients died from cardiovascular disease. Apart from age, covariates associated with a lower survival were the presence of a heavy smoking history, a low vital capacity, a low forced expiratory volume in one second (FEV1) and a high mean pulmonary artery pressure. Only three covariates were included by forward stepwise selection in the multivariate analysis, smoking habit (>30 pack-yrs), age and FEV1. The observed survival rates of the group as a whole were similar to those of the general population matched in terms of age, sex and smoking habit, except for patients between 50 and 60 yrs old who had reduced survival. This difference disappeared when patients of the present study with an associated chronic obstructive pulmonary disease were excluded from the comparison. In conclusion, survival of obstructive sleep apnoea patients treated with nasal continuous positive airway pressure is near to that of the general population. The prognosis is worse in subgroups of patients with a history of heavy smoking and with an associated chronic obstructive pulmonary disease.
Toll-like Receptor 2 Down-regulation in Established Mouse Allergic Lungs Contributes to Decreased Mycoplasma Clearance
Authors: Qun Wu, Richard J. Martin, Spencer LaFasto, Benjamin J. Efaw, John G. Rino, Ronald J. Harbeck, Hong Wei Chu
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Respiratory Mycoplasma pneumoniae (Mp) infection is involved in asthma pathobiology, but whether the established allergic airway inflammation compromises lung innate immunity and subsequently predisposes patients with asthma to Mp infection remains unknown.To test whether the established allergic airway inflammation compromises host innate immunity (e.g., Toll-like receptor 2 [TLR2]) to hinder the elimination of Mp from the lungs.We used mouse models of ovalbumin (OVA)-induced allergic airway inflammation with an ensuing Mp infection, and cultures of mouse primary lung dendritic cells (DCs) and bone marrow-derived DCs.Lung Mp clearance in allergic mice and TLR2 and IL-6 levels in lung cells, including DCs as well as cultured primary lung DCs and bone marrow-derived DCs, were assessed. The established OVA-induced allergic airway inflammation, or the prominent Th2 cytokines IL-4 and IL-13, inhibited TLR2 expression and IL-6 production in lung cells, including lung DCs, and eventually led to impaired host defense against Mp. Studies in IL-6 knockout mice indicated that IL-6 directly promoted Mp clearance from the lungs. IL-4- and IL-13-induced suppression of TLR2 was mediated by inhibiting nuclear factor-kappaB activation through signal transducer and activator of transcription 6 (STAT6) signaling pathway.The established OVA-induced allergic airway inflammation impairs TLR2 expression and host defense cytokine (e.g., IL-6) production, and subsequently delays lung bacterial clearance. This could offer novel therapeutic strategies to reinstate TLR2 activation by using TLR2 ligands and/or blocking IL-4 and IL-13 to ameliorate persisting respiratory bacterial infections in allergic lungs.
Simvastatin inhibits NOR-1 expression induced by hyperlipemia by interfering with CREB activation
Authors: J CRESPO, J MARTINEZGONZALEZ, J RIUS, L BADIMON
Journal: Cardiovascular Research (2005)

Our aim was to investigate whether neuron-derived orphan receptor-1 (NOR-1), an early gene induced by low density lipoproteins (LDL) in vascular smooth muscle cells (VSMC), is regulated by statins.NOR-1 expression was analyzed in human VSMC in culture and in vivo in the aorta of diet-induced hyperlipemic pigs by RT-PCR and real-time PCR. [3H]Thymidine incorporation was used as an index of DNA synthesis. NOR-1 promoter activity was analyzed using a luciferase reporter system. Cyclic AMP response element binding protein (CREB) binding was assessed by EMSA and ELISA and CREB activation (phosphorylation in Ser133) by Western blotting.Simvastatin inhibited NOR-1 expression induced by LDL in VSMC and by hypercholesterolemia in the abdominal aorta of hyperlipemic pigs. The inhibition of the isoprenylation of geranylgeranylated proteins by simvastatin was key in both NOR-1 up-regulation and DNA synthesis induced by LDL. Inhibitors of RhoA (toxin B and exotoxin C3) and ROCK (Y-27632) mimicked the effect of simvastatin on NOR-1. Similarly both simvastatin treatment and cells transfected with a RhoA dominant-negative (RhoAT19N) showed inhibition of LDL-induced NOR-1 promoter activity. These effects were associated to the interference of the activation of CREB, a key transcription factor involved in NOR-1 induction. Finally, simvastatin prevented LDL induction of a reporter construct containing four consensus CRE and inhibited the expression of SMemb (a marker for dedifferentiated VSMC) dependent on CREB.NOR-1 is a target for simvastatin in the vascular wall. We identified NOR-1 and CREB as key transcription factors mediating the effect of statins on VSMC proliferation through a mechanism dependent on RhoA/ROCK.
A good year for European rheumatology
Authors: T K Kvien
Journal: Annals of the Rheumatic Diseases (2006)

I am pleased to be able to summarise 2006 as a year of further advances in European rheumatology.

EULAR was very satisfied with the large number of attendants at the European Congress of Rheumatology in Amsterdam in June. We had more than 11 000 delegates from 107 different countries; 3030 abstracts were submitted; 215 were accepted as oral presentations and 1825 as posters.

An important goal of EULAR is to raise the awareness of rheumatic diseases. Our lobbing campaign in Brussels seems to be successful as rheumatic diseases will have a more prominent mention in the research framework program 7, but we need to continuously influence the allocation of research money in the direction of rheumatic diseases in the forthcoming calls for applications.

EULAR is fostering …
Endothelial protein C receptor polymorphisms and risk of severe sepsis in critically ill patients
Authors: Alice G. Vassiliou, Nikolaos A. Maniatis, Anastasia Kotanidou, Marina Kallergi, Foteini S. Karystinaki, Eleftheria Letsiou, Constantinos Glynos, Petros Kopterides, Dimitra Vassiliadi, Nikitas Nikitas, Ioanna Dimopoulou, Apostolos Armaganidis, Stylianos E. Orfanos
Journal: Intensive Care Medicine (2013)
Non-genotoxic carcinogen exposure induces defined changes in the 5-hydroxymethylome
Authors: John P Thomson, Harri Lempiäinen, Jamie A Hackett, Colm E Nestor, Arne Müller, Federico Bolognani, Edward J Oakeley, Dirk Schübeler, Rémi Terranova, Diana Reinhardt, Jonathan G Moggs, Richard R Meehan
Journal: Genome biology (2012)

Abstract Background Induction and promotion of liver cancer by exposure to non-genotoxic carcinogens coincides with epigenetic perturbations, including specific changes in DNA methylation. Here we investigate the genome-wide dynamics of 5-hydroxymethylcytosine (5hmC) as a likely intermediate of 5-methylcytosine (5mC) demethylation in a DNA methylation reprogramming pathway. We use a rodent model of non-genotoxic carcinogen exposure using the drug phenobarbital. Results Exposure to phenobarbital results in dynamic and reciprocal changes to the 5mC/5hmC patterns over the promoter regions of a cohort of genes that are transcriptionally upregulated. This reprogramming of 5mC/5hmC coincides with characteristic changes in the histone marks H3K4me2, H3K27me3 and H3K36me3. Quantitative analysis of phenobarbital-induced genes that are involved in xenobiotic metabolism reveals that both DNA modifications are lost at the transcription start site, while there is a reciprocal relationship between increasing levels of 5hmC and loss of 5mC at regions immediately adjacent to core promoters. Conclusions Collectively, these experiments support the hypothesis that 5hmC is a potential intermediate in a demethylation pathway and reveal precise perturbations of the mouse liver DNA methylome and hydroxymethylome upon exposure to a rodent hepatocarcinogen.
Dysregulation of Cholesterol Homeostasis in Human Prostate Cancer through Loss of <i>ABCA1</i>
Authors: Byron H. Lee, Margaret G. Taylor, Peggy Robinet, Jonathan D. Smith, Jessica Schweitzer, Ephraim Sehayek, Sara M. Falzarano, Cristina Magi-Galluzzi, Eric A. Klein, Angela H. Ting
Journal: Cancer Research (2012)

Recent epidemiologic data show that low serum cholesterol level as well as statin use is associated with a decreased risk of developing aggressive or advanced prostate cancer, suggesting a role for cholesterol in aggressive prostate cancer development. Intracellular cholesterol promotes prostate cancer progression as a substrate for de novo androgen synthesis and through regulation of AKT signaling. By conducting next-generation sequencing-based DNA methylome analysis, we have discovered marked hypermethylation at the promoter of the major cellular cholesterol efflux transporter, ABCA1, in LNCaP prostate cancer cells. ABCA1 promoter hypermethylation renders the promoter unresponsive to transactivation and leads to elevated cholesterol levels in LNCaP. ABCA1 promoter hypermethylation is enriched in intermediate- to high-grade prostate cancers and not detectable in benign prostate. Remarkably, ABCA1 downregulation is evident in all prostate cancers examined, and expression levels are inversely correlated with Gleason grade. Our results suggest that cancer-specific ABCA1 hypermethylation and loss of protein expression direct high intracellular cholesterol levels and hence contribute to an environment conducive to tumor progression.
Ionic basis of a differential effect of adenosine on refractoriness in rabbit AV nodal and atrial isolated myocytes
Authors: A Workman
Journal: Cardiovascular Research (1999)

Objectives: Firstly, to compare effects of adenosine on membrane potential and refractoriness in AV nodal and atrial cells. Secondly, to assess the contribution of the effects of adenosine on IKAdo and ICaL to its effects on the functional electrophysiological properties in the two cell types. Methods: The whole cell patch clamp technique was used to record action potentials and ion currents in AV nodal and left atrial myocytes isolated enzymatically from rabbit hearts. Results: Adenosine (10 μM) caused similar hyperpolarisation and shortening of the action potential duration (APD) in both cell types: maximum diastolic potential was hyperpolarised from −59±3 to −66±2 and from −70±2 to −76±2 mV (mean±SEM) and APD90 was shortened by 31±4 and 30±7% in AV nodal (n=14) and atrial cells (n=8), respectively. Adenosine shortened the effective refractory period (ERP) in atrial cells, from 124±15 to 98±14 ms (n=8). In contrast, ERP in AV nodal cells was not significantly affected (112±13 vs. 102±12 ms, n=14), and post-repolarisation refractoriness was prolonged. By contrast, current injection, to induce an equal degree of hyperpolarisation to that produced by adenosine, shortened APD and ERP in both cell types, suggesting an additional action of adenosine in AV nodal cells. Adenosine (10 μM) did not affect peak ICaL in AV nodal cells, but significantly altered the biexponential time course of recovery of ICaL from inactivation. The proportion of recovery in the fast phase (time constant, τ=102±10 ms) was reduced from 71±3 to 55±5%, with shift to the slow phase (τ=858±168 ms), without altering τ in either phase. A similar effect of adenosine was seen in left atrial cells. Conclusion: Adenosine caused hyperpolarisation, APD-shortening and slowing of recovery of ICaL from inactivation, in both AV nodal and atrial cells, but prolonged post-repolarisation refractoriness in AV nodal cells only. This differential effect of adenosine on refractoriness in the two cell types could not be explained by effects on IKAdo, but may be due to slowed reactivation of ICaL, which is the predominant inward current in AV nodal but not left atrial cells.
Measles, month of birth, and Crohn's disease
Authors: N Haslam
Journal: Gut (2000)

The rise in the incidence of Crohn's disease (CD) suggests the role of an environmental factor in the development of the disease in susceptible individuals. Perinatal exposure to infection has been proposed as such an environmental factor.To investigate the influence of birth date on the development of CD in later life.Four registers of patients with CD, diagnosed from 1972 to 1989, were combined, and data from 1624 patients were examined. The birth dates of CD patients were compared with national birth figures for three decades (1941-50, 1951-60, and 1961-70) to avoid temporal changes in birth trends, and year of birth was compared with epidemic measles years between 1951 and 1967. Risk ratios with 95% confidence intervals (CI) and chi(2) tests were performed.There were marginal differences between the birth dates of the CD patients and those predicted from the general population. Further analysis of both season of birth and year halves revealed a very weak association with the first half of the year (relative risk 1.14 (95% CI 1.01-1.30)). There was no association between developing CD and birth during measles epidemics between 1951 and 1967.In utero or perinatal exposure to seasonal environmental factors are unlikely potential aetiological agents in the later development of CD.
Pulmonary abnormalities in intermediate alpha-1-antitrypsin deficiency.
Authors: W J Hall, R W Hyde, R H Schwartz, G S Mudholkar, D R Webb, Y P Chaubey, P L Townes
Journal: Journal of Clinical Investigation (1976)

Pulmonary function studies were carried out in a group of asymptomatic nonsmoking adults with intermediate alpha-1-antitrypsin deficiency who were attending an early disease detection unit in Rochester, N. Y. All subjects were identified by specific protease inhibitor (Pi) typing. Fifteen MZ and 14 MS subjects who had never smoked cigarettes were matched by sex and age to MM controls. Spirometry, static lung volumes, and single breath-diffusing capacity were identical in all Pi type groups with no statistically significant differences noted. Maximal expiratory flow volume curves were obtained in all subjects. MZ subjects demonstrated statistically impaired maximal flow rates at 75%, 50%, and 25% of vital capacity compared to their MM controls. Total pulmonary resistance by the oscillometric method was measured at 3, 5, 7, and 9 cycle/s in the same subjects. Increased frequency dependence of resistance (defined as the difference between total pulmonary resistance at 3 cycle/s and 9 cycle/s) was observed in MZ subjects compared to MM controls. No differences were noted by this method in MS-MM pairs. The data suggest that detectable mechanical abnormalities are present in subjects with the MZ phenotype, even in the absence of established risk factors such as cigarette smoking and high air pollution.
Exhaled nitric oxide correlates with airway eosinophils in childhood asthma
Authors: T J Warke
Journal: Thorax (2002)

Background: Exhaled nitric oxide has been proposed as a marker for airway inflammation in asthma. The aim of this study was to compare exhaled nitric oxide levels with inflammatory cells and mediators in bronchoalveolar lavage fluid from asthmatic and normal children. Methods: Children were recruited from elective surgical lists and a non-bronchoscopic bronchoalveolar lavage (BAL) was performed after induction of anaesthesia. Exhaled nitric oxide (parts per billion) was measured by two techniques: tidal breathing and restricted breath. Results: Median (interquartile range) exhaled nitric oxide measured by restricted breath was increased in asthmatics compared with normal children (24.3 (10.5–66.5) <i>v</i> 9.7 (6.5–16.5), difference between medians 14.6 (95% CI 5.1 to 29.9), p=0.001). In asthmatic children exhaled nitric oxide correlated significantly with percentage eosinophils (<i>r</i>=0.78, p&lt;0.001 (tidal breathing) and <i>r</i>=0.78, p&lt;0.001 (restricted breath)) and with eosinophilic cationic protein (<i>r</i>=0.53, p&lt;0.01 (restricted breath)), but not with other inflammatory cells in the BAL fluid. The area under the receiver operator characteristic curves for the prediction of the presence of eosinophilic airways inflammation by exhaled nitric oxide (tidal and restricted) was 0.80 and 0.87, respectively. Conclusions: Exhaled nitric oxide correlates closely with percentage eosinophils in BAL fluid in asthmatic children and is therefore likely to be a useful non-invasive marker of airway inflammation.
Bladder smooth muscle dysfunction in patients with irritable bowel syndrome.
Authors: P J Whorwell, E W Lupton, D Erduran, K Wilson
Journal: Gut (1986)

Urodynamic studies were carried out on 30 patients with irritable bowel syndrome and 30 matched controls. Fifty per cent of the irritable bowel patients compared with only 13% of the control group had evidence of bladder dysfunction (p = 0.006). In the irritable bowel group detrusor instability was observed in 10 patients compared with only one control subject (p = 0.008). A steep cystometrogram occurred in five irritable bowel patients and three controls (NS). Detrusor instability was most common in patients with a bowel habit characterised by alternating constipation and diarrhoea. This is the first study to provide objective evidence that patients with irritable bowel syndrome may have a disorder of smooth muscle or its innervation that is not confined to the gastrointestinal system.