tbuckley/cabot-search huggingface dataset:
Combined deficiency of ABCA1 and ABCG1 promotes foam cell accumulation and accelerates atherosclerosis in mice
Authors: Laurent Yvan-Charvet, Mollie Ranalletta, Nan Wang, Seongah Han, Naoki Terasaka, Rong Li, Carrie Welch, Alan R. Tall
Journal: Journal of Clinical Investigation (2007)

HDLs protect against the development of atherosclerosis, but the underlying mechanisms are poorly understood. HDL and its apolipoproteins can promote cholesterol efflux from macrophage foam cells via the ATP-binding cassette transporters ABCA1 and ABCG1. Experiments addressing the individual roles of ABCA1 and ABCG1 in the development of atherosclerosis have produced mixed results, perhaps because of compensatory upregulation in the individual KO models. To clarify the role of transporter-mediated sterol efflux in this disease process, we transplanted BM from Abca1–/–Abcg1–/– mice into LDL receptor–deficient mice and administered a high-cholesterol diet. Compared with control and single-KO BM recipients, Abca1–/–Abcg1–/– BM recipients showed accelerated atherosclerosis and extensive infiltration of the myocardium and spleen with macrophage foam cells. In experiments with isolated macrophages, combined ABCA1 and ABCG1 deficiency resulted in impaired cholesterol efflux to HDL or apoA-1, profoundly decreased apoE secretion, and increased secretion of inflammatory cytokines and chemokines. In addition, these cells showed increased apoptosis when challenged with free cholesterol or oxidized LDL loading. These results suggest that the combined effects of ABCA1 and ABCG1 in mediating macrophage sterol efflux are central to the antiatherogenic properties of HDL.
Cytological and Transcript Analyses Reveal Fat and Lazy Persister-Like Bacilli in Tuberculous Sputum
Authors: Natalie J Garton, Simon J Waddell, Anna L Sherratt, Su-Min Lee, Rebecca J Smith, Claire Senner, Jason Hinds, Kumar Rajakumar, Richard A Adegbola, Gurdyal S Besra, Philip D Butcher, Michael R Barer
Journal: PLoS Medicine (2008)

Tuberculous sputum provides a sample of bacilli that must be eliminated by chemotherapy and that may go on to transmit infection. A preliminary observation that Mycobacterium tuberculosis cells contain triacylglycerol lipid bodies in sputum, but not when growing in vitro, led us to investigate the extent of this phenomenon and its physiological basis.Microscopy-positive sputum samples from the UK and The Gambia were investigated for their content of lipid body-positive mycobacteria by combined Nile red and auramine staining. All samples contained a lipid body-positive population varying from 3% to 86% of the acid-fast bacilli present. The recent finding that triacylglycerol synthase is expressed by mycobacteria when they enter in vitro nonreplicating persistence led us to investigate whether this state was also associated with lipid body formation. We found that, when placed in laboratory conditions inducing nonreplicating persistence, two M. tuberculosis strains had lipid body levels comparable to those found in sputum. We investigated these physiological findings further by comparing the M. tuberculosis transcriptome of growing and nonreplicating persistence cultures with that obtained directly from sputum samples. Although sputum has traditionally been thought to contain actively growing tubercle bacilli, our transcript analyses refute the hypothesis that these cells predominate. Rather, they reinforce the results of the lipid body analyses by revealing transcriptional signatures that can be clearly attributed to slowly replicating or nonreplicating mycobacteria. Finally, the lipid body count was highly correlated (R(2) = 0.64, p < 0.03) with time to positivity in diagnostic liquid cultures, thereby establishing a direct link between this cytological feature and the size of a potential nonreplicating population.As nonreplicating tubercle bacilli are tolerant to the cidal action of antibiotics and resistant to multiple stresses, identification of this persister-like population of tubercle bacilli in sputum presents exciting and tractable new opportunities to investigate both responses to chemotherapy and the transmission of tuberculosis.
Epidemiology of Tuberculosis in a High HIV Prevalence Population Provided with Enhanced Diagnosis of Symptomatic Disease
Authors: Elizabeth L Corbett, Tsitsi Bandason, Yin Bun Cheung, Shungu Munyati, Peter Godfrey-Faussett, Richard Hayes, Gavin Churchyard, Anthony Butterworth, Peter Mason
Journal: PLoS Medicine (2006)

Directly observed treatment short course (DOTS), the global control strategy aimed at controlling tuberculosis (TB) transmission through prompt diagnosis of symptomatic smear-positive disease, has failed to prevent rising tuberculosis incidence rates in Africa brought about by the HIV epidemic. However, rising incidence does not necessarily imply failure to control tuberculosis transmission, which is primarily driven by prevalent infectious disease. We investigated the epidemiology of prevalent and incident TB in a high HIV prevalence population provided with enhanced primary health care.Twenty-two businesses in Harare, Zimbabwe, were provided with free smear- and culture-based investigation of TB symptoms through occupational clinics. Anonymised HIV tests were requested from all employees. After 2 y of follow-up for incident TB, a culture-based survey for undiagnosed prevalent TB was conducted. A total of 6,440 of 7,478 eligible employees participated. HIV prevalence was 19%. For HIV-positive and -negative participants, the incidence of culture-positive tuberculosis was 25.3 and 1.3 per 1,000 person-years, respectively (adjusted incidence rate ratio = 18.8; 95% confidence interval [CI] = 10.3 to 34.5: population attributable fraction = 78%), and point prevalence after 2 y was 5.7 and 2.6 per 1,000 population (adjusted odds ratio = 1.7; 95% CI = 0.5 to 6.8: population attributable fraction = 14%). Most patients with prevalent culture-positive TB had subclinical disease when first detected.Strategies based on prompt investigation of TB symptoms, such as DOTS, may be an effective way of controlling prevalent TB in high HIV prevalence populations. This may translate into effective control of TB transmission despite high TB incidence rates and a period of subclinical infectiousness in some patients.
Interferon γ Regulates Acute and Latent Murine Cytomegalovirus Infection and Chronic Disease of the Great Vessels
Authors: Rachel M. Presti, Jessica L. Pollock, Albert J. Dal Canto, Andrew K. O'Guin, Herbert W. Virgin
Journal: The Journal of Experimental Medicine (1998)

To define immune mechanisms that regulate chronic and latent herpesvirus infection, we analyzed the role of interferon γ (IFN-γ) during murine cytomegalovirus (MCMV) infection. Lethality studies demonstrated a net protective role for IFN-γ, independent of IFN-α/β, during acute MCMV infection. Mice lacking the IFN-γ receptor (IFN-γR−/−) developed and maintained striking chronic aortic inflammation. Arteritis was associated with inclusion bodies and MCMV antigen in the aortic media. To understand how lack of IFN-γ responses could lead to chronic vascular disease, we evaluated the role of IFN-γ in MCMV latency. MCMV-infected IFN-γR−/− mice shed preformed infectious MCMV in spleen, peritoneal exudate cells, and salivary gland for up to 6 mo after infection, whereas the majority of congenic control animals cleared chronic productive infection. However, the IFN-γR was not required for establishment of latency. Using an in vitro explant reactivation model, we showed that IFN-γ reversibly inhibited MCMV reactivation from latency. This was at least partly explained by IFN-γ– mediated blockade of growth of low levels of MCMV in tissue explants. These in vivo and in vitro data suggest that IFN-γ regulation of reactivation from latency contributes to control of chronic vascular disease caused by MCMV. These studies are the first to demonstrate that a component of the immune system (IFN-γ) is necessary to regulate MCMV-associated elastic arteritis and latency in vivo and reactivation of a herpesvirus from latency in vitro. This provides a new model for analysis of the interrelationships among herpesvirus latency, the immune system, and chronic disease of the great vessels.
Cathepsin S-mediated fibroblast trans-differentiation contributes to left ventricular remodelling after myocardial infarction
Authors: Han Chen, Jing Wang, Mei-Xiang Xiang, Yan Lin, Aina He, Chun-Na Jin, Jian Guan, Galina K. Sukhova, Peter Libby, Jian-An Wang, Guo-Ping Shi
Journal: Cardiovascular Research (2013)

Extracellular matrix (ECM) turnover plays an important role in left ventricular (LV) remodelling following myocardial infarction (MI). Cysteinyl cathepsins contribute to ECM catabolism in arterial diseases, suggesting their participation in post-MI remodelling. Left anterior descending artery ligation-induced MI in mice showed increased expression and activity of cathepsin S (CatS). Administration of a non-selective cathepsin inhibitor, E64d, aggravated LV dysfunction at 7 and 28 days post-MI. Mechanistic studies showed that E64d increased post-MI inflammatory cell accumulation and cytokine expression, but did not affect apoptosis or angiogenesis in infarcted myocardium. Furthermore, E64d suppressed TGF-β1-induced Smad2 and Smad3 activation and expression of fibronectin extra domain A (ED-A), an alternatively spliced fibronectin variant, and subsequently prevented cardiac fibroblast trans-differentiation into myofibroblast, which contributed to post-MI collagen and fibronectin synthesis and deposition. Consistently, selective inhibition or genetically determined deficiency of CatS also reduced myocardial Smad2 and Smad3 activation and ED-A fibronectin expression, thus suppressing fibroblast trans-differentiation and resulting in adverse collagen turnover and impaired cardiac function—recapitulating the findings in mice treated with E64d. Along with its established activities in ECM degradation, CatS plays novel roles in TGF-β1 signalling, myofibroblast trans-differentiation, and ECM protein synthesis, thereby regulating scar formation in the infarcted myocardium and preserving LV function after experimental MI.
Population-specificity of human DNA methylation
Authors: Hunter B Fraser, Lucia L Lam, Sarah M Neumann, Michael S Kobor
Journal: Genome biology (2012)

Abstract Background Ethnic differences in human DNA methylation have been shown for a number of CpG sites, but the genome-wide patterns and extent of these differences are largely unknown. In addition, whether the genetic control of polymorphic DNA methylation is population-specific has not been investigated. Results Here we measure DNA methylation near the transcription start sites of over 14, 000 genes in 180 cell lines derived from one African and one European population. We find population-specific patterns of DNA methylation at over a third of all genes. Furthermore, although the methylation at over a thousand CpG sites is heritable, these heritabilities also differ between populations, suggesting extensive divergence in the genetic control of DNA methylation. In support of this, genetic mapping of DNA methylation reveals that most of the population specificity can be explained by divergence in allele frequencies between populations, and that there is little overlap in genetic associations between populations. These population-specific genetic associations are supported by the patterns of DNA methylation in several hundred brain samples, suggesting that they hold in vivo and across tissues. Conclusions These results suggest that DNA methylation is highly divergent between populations, and that this divergence may be due in large part to a combination of differences in allele frequencies and complex epistasis or gene × environment interactions.
A three-item scale for the early prediction of stroke recovery
Authors: Alison E Baird, James Dambrosia, Sok-Ja Janket, Quentin Eichbaum, Claudia Chaves, Brian Silver, P Alan Barber, Mark Parsons, David Darby, Stephen Davis, Louis R Caplan, Robert E Edelman, Steven Warach
Journal: The Lancet (2001)
Non-isotopic RNase cleavage assay for mutation detection in MEFV, the gene responsible for familial Mediterranean fever, in a cohort of Greek patients
Authors: K Ritis
Journal: Annals of the Rheumatic Diseases (2004)

The MEFV gene is responsible for familial Mediterranean fever (FMF). Several disease associated mutations have been identified. The range of genetic variation in MEFV in Greek patients has not been determined.To describe a method that facilitates the routine screening of the entire coding sequence of MEFV (excluding exon 1).The non-isotopic RNase cleavage assay (NIRCA) was optimised and used as a first step screening method to screen exons 2 to 10 of MEFV. Exons 2 and 10 were analysed separately at DNA level, while exons 3 to 9 were analysed together at cDNA level. The sample group consisted of 26 FMF patients diagnosed using established clinical criteria, six asymptomatic relatives, 12 patients with atypical clinical manifestations, nine patients suffering from various inflammatory diseases, and three normal individuals. All were analysed by NIRCA for mutations in the MEFV gene and direct sequencing was applied subsequently to confirm the results.MEFV mutations were identified in 25 of 26 typical FMF patients and in two of 12 patients with atypical manifestations. NIRCA results were in concordance with sequencing findings in all sequences analysed, suggesting that the method is highly reliable in this disease. Sixteen alterations of MEFV were identified (eight missense mutations and eight single nucleotide polymorphisms).NIRCA can be used for rapid screening of the coding sequence of the MEFV gene in patients suspected of suffering from FMF.
Assessment of 72-kilodalton gelatinase and TIMP-1 gene expression in normal and sclerotic murine glomeruli.
Authors: M A Carome, L J Striker, E P Peten, S J Elliot, C W Yang, W G Stetler-Stevenson, P Reponen, K Tryggvason, G E Striker
Journal: Journal of the American Society of Nephrology (1994)

Mice transgenic for bovine growth hormone (bGH) develop progressive diffuse glomerulosclerosis. Because murine mesangial cells in vitro were found to express the genes for 72-kd gelatinase and the metalloproteinase inhibitor TIMP-1, the expression of these genes in vivo in isolated whole glomeruli from bGH mice and normal control littermates was examined. Intact glomeruli were isolated by microdissection and subjected to reverse transcription. TIMP-1 cDNA was not detected by standard polymerase chain reaction (PCR) in glomeruli from bGH or control mice. In contrast, cDNA for 72-kd gelatinase was detected by standard PCR in both bGH and control mice, and the level was subsequently measured by quantitative competitive PCR. The gelatinase cDNA level was 14.7 +/- 2.8 x 10(-4) attomoles/glomerulus in 2- to 3-month-old control mice and was unchanged in 6-month-old controls. The bGH mice had 3.5-fold and 4.5-fold higher cDNA levels at 2 to 3 months and 6 months of age, respectively. Finally, zymography of glomerular extracts revealed increased levels of 72-kd and 96- to 100-kd gelatinase activity in bGH glomeruli in comparison to that in controls. In summary, whereas the genes for both TIMP-1 and 72-kd gelatinase are expressed in vitro in cultured mesangial cells, only the gelatinase gene appeared to be expressed in vivo in intact glomeruli. In addition, there was an up-regulation in the glomerular expression of the 72-kd gelatinase in bGH mice, a murine model of glomerulosclerosis.
Transport and intracellular distribution of copper in a human hepatoblastoma cell line, HepG2
Authors: Richard J. Stockert, Phyllis S. Grushoff, Anatol G. Morell, Glenn E. Bentley, Harold A. O'Brien, Herbert I. Scheinberg, Irmin Sternlieb
Journal: Hepatology (1986)

The uptake of radiocopper by HepG2 cells is a saturable, temperature–dependent and cellular energy–independent process with a V max of 7.1 ± 0.2 pmoles min -1 mg protein -1 andan estimated K m of 3.3 ± 0.5 μM . The rate of copper uptake is reduced at an equimolar concentrationof albumin and is unaffected by zinc at a 10–fold molar excess. Approximately 70% of the newly incorporated radiocopper binds to membranes and organelles, while 30% is recovered in the cytosol. The soluble fraction can be resolved intotwo copper–binding protein peaks. Incubation of HepG2 with nonisotopic copper results in displacement of radiocopper associated with the proteins contained in the lower molecular weight peak. Exposure of the cells to cycloheximide inhibits the incorporation of the isotope into this fraction.
Efficacy of mesalazine in IBS
Authors: Thazin Min, Alexander C Ford
Journal: Gut (2015)

<b>Aim:</b> To describe the incidence and risk factors of vision reducing cataract in skin smear positive lepromatous patients. <b>Methods:</b> Prospective longitudinal cohort study: 212 newly diagnosed lepromatous patients were followed during the two years of treatment with multidrug therapy and for a further five years, with biannual ocular examinations. Incidence of vision reducing (⩽6/18) cataract was calculated as the number of patients with cataract per person year of cataract-free follow up among those who did not have cataract at baseline. <b>Results:</b> Cataract was present in 27 (11%) of lepromatous patients at diagnosis. Forty nine patients (2.87%/person year (95% confidence interval (CI), 2.17% to 3.80%)) developed cataract during a total follow up period of 1704 person years; 45 of these were ⩾41 years old and were followed for a total of 638 person years with an incident rate of 0.070 (95% CI, 0.0523 to 0.094). Stepwise multiple regression confirmed the association of age (per decade) (hazard ratio (HR) = 2.50 (95% CI, 1.82 to 2.78), p&lt;0.001), clofazimine crystals on the cornea (HR = 49.92 (5.48 to 454.82), p = 0.001), grade 2 deformity in all limbs (HR = 3.17 (1.12 to 8.97), p = 0.029), and uveal inflammation (HR = 3.52 (1.42 to 8.67), p = 0.006). No significant association was found with oral steroids. <b>Conclusions:</b> Cataract develops at the rate of 7%/person year in lepromatous patients over 40 years of age. It is associated with increasing age, subclinical intraocular inflammation, and grade 2 deformity.
Overview of Advances in Head and Neck Cancer
Authors: Danny Rischin, Robert L. Ferris, Quynh-Thu Le
Journal: Journal of Clinical Oncology (2015)

The term head and neck cancer may refer exclusively to cancers arising from the upper aerodigestive tract or more broadly to any malignancy originating in the head and neck region.In this Special Series issue of Journal of Clinical Oncology, there is a major focus on squamous cell carcinomas arising from the upper aerodigestive tract mucosa.In addition, we also address nasopharyngeal cancer, nonmelanoma cutaneous head and neck cancer, and squamous carcinoma of the neck of unknown primary origin.The 16 articles in this issue provide the reader with an overview of current evidence and management, recent developments, and insights into future directions.The relatively recent recognition that human papillomavirus (HPV) is a cause of oropharyngeal cancer (OPC)and that this is a distinct entity with different clinical and molecular features-has had a profound impact on the field.In this series, we include three articles that review our rapidly evolving understanding of HPV-related head and neck cancers.Hayes et al 1 review the molecular landscape of HPV-positive and -negative head and neck cancers after the recently published Cancer Genome Atlas analysis, 2 demonstrating significant molecular differences that may have therapeutic implications in the future.Gillison et al 3 review the epidemiology of HPV head and neck cancer and oral HPV infection, including the geographic variation in incidence and in the HPV-attributable fraction and the prospects for virus-specific cancer prevention.The overall better prognosis of HPV-associated OPC and the identification of a low-risk population with an excellent prognosis have led to concerns that our current treatments, mainly derived from trials of HPV-negative head and neck cancer, may be more intensive than is necessary.Bhatia and Burtness 4 review what is known about risk groups and describe de-escalation trials designed to maintain high cure rates with less toxicity.The emergence of HPV-associated OPC went unrecognized for many years and masked the lack of progress in improving outcomes for HPV-negative head and neck cancer.Dillon and Harrington 5 review current and investigational treatments for HPV-negative OPC and hypopharyngeal cancer.Larynx preservation has been a major focus of research over the last 25 years.Forastiere et al 6 discuss the evidence for current approaches, including some of the ongoing controversies, and critical factors to consider when weighing surgical versus nonsurgical primary treatment.The oral cavity remains the archetypical head and neck cancer site that is managed with initial surgery as the mainstay of pathologic staging and treatment.Chinn and Myers 7 discuss current evidence, including recent randomized
Diagnostic accuracy of cytology and biopsy in primary bronchial carcinoma.
Authors: C R Payne, P G Stovin, V Barker, S McVittie, J E Stark
Journal: Thorax (1979)

The accuracy of diagnosis of cell type obtained from sputum cytology, bronchial aspirate, bronchial biopsy, or percutaneous lung biopsy in 161 cases of confirmed primary lung cancer has been examined and the pretreatment histological diagnosis has been compared with the final diagnosis made after surgical resection or necropsy. The yield of positive diagnoses of malignancy obtained by each method of investigation in each cell type showed that cytological examination of sputum was the most accurate method, but a high degree of accuracy was also obtained by bronchoscopic aspiration and bronchial biopsy. Percutaneous lung biopsy was the most effective, but the least accurate, means of obtaining carcinoma cells. The level of diagnostic accuracy was highest in patients with squamous cell carcinoma. Accurate pretreatment diagnosis of patients with adenocarcinoma was particularly difficult, and only 20% of these cases were correctly diagnosed by investigation. Of seven patients with adenocarcinoma and a positive diagnosis of malignancy made on percutaneous lung biopsy, none was correctly diagnosed. The causes of error in diagnosis of cell type of primary lung cancer are discussed.
Non-coding RNA as lung disease biomarkers: Figure 1
Authors: Sebastian F Vencken, Catherine M Greene, Paul J McKiernan
Journal: Thorax (2014)

Biomarkers are quantifiable indicators of disease. These surrogates should be specific, sensitive, predictive, robust and easily accessible. A major class of RNA described as non-coding RNA fulfils many of these criteria, and recent studies have demonstrated that the two major subclasses of non-coding RNA, long non-coding RNA and, in particular, microRNA are promising potential biomarkers. The ability to detect non-coding RNAs in biofluids has highlighted their usefulness as non-invasive markers of lung disease. Because expression of specific non-coding RNAs is altered in many lung diseases and their levels in the circulation often reflect the changes in expression of their lung-specific counterparts, exploiting these biomolecules as diagnostic tools seems an obvious goal. New technology is driving developments in this area and there has been significant recent progress with respect to lung cancer diagnostics. The non-coding RNA biomarker field represents a clear example of modern-day bench-to-bedside research.
Ranolazine Before and During Trastuzumab Treatment, Prevents Cardiotoxicity in Mice
Authors: N. Maurea, C. Coppola, G. Piscopo, D. Rea, F. Galletta, C. Maurea, I. Capasso, C. Arra, R.V. Iaffaioli
Journal: Annals of Oncology (2014)