tbuckley/cabot-search huggingface dataset:
Economic evaluation of a pneumococcal vaccine in a high-risk population
Authors: Sushil Agarwal
Journal: Thorax (2013)

Economic evaluation of a pneumococcal vaccine in a high-risk populationThis economic evaluation study was performed to estimate the cost effectiveness of a 13-valent pneumococcal conjugate vaccine against invasive pneumococcal disease in a highrisk population.Herd immunity has developed as a result of pneumococcal serotypes used in 7-valent pneumococcal conjugate vaccine in infants.Assuming a similar effect with 13-valent pneumococcal conjugate vaccine would mean a reduction in disease burden over time.High-risk groups included those aged 2 years and older with chronic kidney, heart, liver or respiratory disease, splenic dysfunction, HIV infection or diabetes.It was assumed that the vaccine would have no effect in preventing non-bacteraemic pneumococcal pneumonia and vaccination of the high-risk group would start 2-3 years after the infant pneumococcal vaccination.A 23-valent polysaccharide vaccine was expected to continue on top of the high risk programme.A cohort model was developed from 22 298 patients admitted to hospitals in England with invasive pneumococcal disease between April 2002 and March 2009.Cost, gains in life years, quality adjusted life years and incremental cost-effectiveness ratios were measured.Using a threshold of £30 000 for a willingness to pay for quality adjusted life years gained, the incremental cost-effectiveness ratio was higher in all high-risk groups except patients with chronic liver disease.Cost-effectiveness would increase if the vaccine did protect against nonbacteraemic pneumococcal pneumonia or was introduced along with the infant vaccination programme or targeted towards a specific subgroup.It was concluded that the 13-valent conjugated pneumococcal vaccine programme is unlikely to be cost-effective in a high-risk group.
Immune-complex mediated colitis in rabbits. An experimental model.
Authors: H J Hodgson, B J Potter, J Skinner, D P Jewell
Journal: Gut (1978)

An experimental colitis in rabbits is described, following the intravenous injection of preformed immune complexes of human serum albumin (HSA) and anti-HSA into non-sensitised rabbits. Tissue damage was localised to the colon by the Auer technique of inducing local non-specific inflammation, by the rectal instillation of dilute formalin. Formalin alone gave transient changes that reverted to normal within 24 hours. In rabbits given intravenous immune complexes formed in antigen-excess, a severe colitis was initiated, with histological features including mucosal ulceration, mixed inflammatory cell infiltration in the lamina propria, and crypt abscess formation. It is possible that immune-complex damage may be one of the pathogenic mechanisms involved in human ulcerative colitis.
Epidermal growth factor receptor regulates β-catenin location, stability, and transcriptional activity in oral cancer
Authors: Chien-Hsing Lee, Hsing-Wen Hung, Pei-Hsin Hung, Yi-Shing Shieh
Journal: Molecular Cancer (2010)

Abstract Background Many cancerous cells accumulate β-catenin in the nucleus. We examined the role of epidermal growth factor receptor (EGFR) signaling in the accumulation of β-catenin in the nuclei of oral cancer cells. Results We used two strains of cultured oral cancer cells, one with reduced EGFR expression (OECM1 cells) and one with elevated EGFR expression (SAS cells), and measured downstream effects, such as phosphorylation of β-catenin and GSK-3β, association of β-catenin with E-cadherin, and target gene regulation. We also studied the expression of EGFR, β-catenin, and cyclin D1 in 112 samples of oral cancer by immunostaining. Activation of EGFR signaling increased the amount of β-catenin in the nucleus and decreased the amount in the membranes. EGF treatment increased phosphorylation of β-catenin (tyrosine) and GSK-3β(Ser-(9), resulting in a loss of β-catenin association with E-cadherin. TOP-FLASH and FOP-FLASH reporter assays demonstrated that the EGFR signal regulates β-catenin transcriptional activity and mediates cyclin D1 expression. Chromatin immunoprecipitation experiments indicated that the EGFR signal affects chromatin architecture at the regulatory element of cyclin D1, and that the CBP, HDAC1, and Suv39h1 histone/chromatin remodeling complex is involved in this process. Immunostaining showed a significant association between EGFR expression and aberrant accumulation of β-catenin in oral cancer. Conclusions EGFR signaling regulates β-catenin localization and stability, target gene expression, and tumor progression in oral cancer. Moreover, our data suggest that aberrant accumulation of β-catenin under EGFR activation is a malignancy marker of oral cancer.
Processing Renal Biopsies for Diagnostic mRNA Quantification
Authors: MICHAEL EIKMANS, HANS J. BAELDE, EMILE DE HEER, JAN ANTHONIE BRUIJN
Journal: Journal of the American Society of Nephrology (2000)

Abstract. The goal of this study was to improve a procedure for the extraction and storage of RNA from minute quantities of human renal tissue in clinical practice, using kidney biopsies and cadaveric donor kidneys unsuitable for transplantation. Collagen α1(IV) mRNA was analyzed as a measure for RNA integrity. The results show that at least 3 h may pass between microdissecting the renal tissue and the onset of cDNA synthesis without degradation of the glomerular mRNA. To extract the glomerular mRNA, microdissected glomeruli were incubated in a permeabilization solution. Treating glomeruli with collagenase IV before permeabilization had a deteriorating effect on the mRNA yield. The addition of reverse transcription mixture to the permeabilization solution in the presence of the glomeruli resulted in the highest cDNA yields. Storage of glomerular tissue in the presence of Nonidet P-40-based buffer for 1 wk at -70°C did not significantly affect the mRNA, but storage for 2 or 4 wk resulted in deterioration of the mRNA by approximately 40 and 95%, respectively. Furthermore, three methods for total RNA isolation from microdissected interstitial tissue were compared. An approximately 2.5 times higher yield of collagen α1(IV) mRNA was obtained with silica gel-based membrane spin technology than with a guanidine isothiocyanate/phenol chloroform or a lithium chloride/phenol chloroform method. Finally, this study shows for the first time reliable detection of collagen α1(IV) mRNA in biopsies that had been frozen for at least 10 yr at -70°C. These experiments have helped to improve a procedure for the processing of glomerular and interstitial tissue acquired from human kidney biopsies for mRNA analysis. This method is suitable for implementation in routine clinical practice.
Matrix Metalloproteinase 7 Mediates Mammary Epithelial Cell Tumorigenesis through the ErbB4 Receptor
Authors: Conor C. Lynch, Tracy Vargo-Gogola, Michelle D. Martin, Barbara Fingleton, Howard C. Crawford, Lynn M. Matrisian
Journal: Cancer Research (2007)

Abstract To delineate the role of matrix metalloproteinase 7 (MMP7) in mammary tumorigenesis, MMP7 was expressed in the normal murine mammary gland cell line, c57MG. MMP7 markedly enhanced the growth rate of the c57MG cells in three-dimensional culture and promoted tumor formation in vivo. Subsequent investigation showed that MMP7 (a) up-regulated ErbB4 receptor levels, (b) solubilized the ErbB4 receptor cognate ligand heparin-bound epidermal growth factor, and (c) mediated the proteolytic processing of ErbB4 to yield a soluble intracellular domain (ICD) that localized to the cytoplasm and the nucleus. Furthermore, overexpression of the ErbB4 ICD in the c57MG cell line recapitulated the proliferative effects of MMP7 in vitro and in vivo. These data indicate a novel mechanism for mammary epithelial cell transformation by MMP7. [Cancer Res 2007;67(14):6760–7
United Kingdom Becomes the Cancer Clinical Trials Recruitment Capital of the World
Authors: G. Sinha
Journal: JNCI Journal of the National Cancer Institute (2007)

at a specialized care facility was often longer than 1 month. To address the disparity, the NHS created a cancer care network during the late 1990s by dividing the country into regions and making hospitals and specialists responsible for cancer care within their designated region. Scotland and Wales followed suit. Each region set up a structured referral system, streamlining access to specialized cancer care, Kaplan explained. But these regional cancer care clusters did not coordinate clinical research. That task was added in 2000 when a consortium of health care groups and funding agencies created the NCRN. As part of its overall cancer plan, the U.K. health department joined with other government agencies and large charities to pledge substantial funds to set up the research network’s infrastructure. By 2004, the NHS had allocated an additional £570 million ($1.1 billion) each year to improve patient access to cancer care and boost clinical research.
Greater body mass independently predicts less radiographic progression on X-ray and MRI over 1–2 years
Authors: Joshua F Baker, Mikkel Østergaard, Michael George, Justine Shults, Paul Emery, Daniel G Baker, Philip G Conaghan
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Introduction</h3> Greater body mass index (BMI) has been associated with less radiographic progression in rheumatoid arthritis (RA). We evaluated the association between BMI and joint damage progression as measured by X-ray and MRI. <h3>Methods</h3> 1068 subjects with RA from two clinical trials of golimumab (GO-BEFORE and GO-FORWARD) had radiographs performed at weeks 0, 52 and 104 and evaluated using the van der Heijde–Sharp (vdHS) scoring system. Contrast-enhanced MRIs of the dominant wrist and hand were obtained at weeks 0, 12, 24, 52 and 104. Multivariable logistic regression evaluated the risk of radiographic progression for each BMI category (&lt;25, 25–30, &gt;30 kg/m<sup>2</sup>). Within GO-BEFORE, piecewise, robust generalised estimating equations marginal models assessed the probability of MRI erosion progression for each BMI category. Multivariable linear regression models assessed baseline associations between BMI and bone oedema (a precursor of bone erosion). <h3>Results</h3> Higher BMI category was associated with a lower probability of progression in vdHS score at weeks 52 and 104 independent of potential confounders. Higher BMI was also independently associated with a lower probability of progression in MRI erosion score over 2 years. Subjects with greater BMI demonstrated less bone oedema independent of differences in other disease severity measures, including MRI synovitis in the same joints. <h3>Conclusions</h3> Greater BMI is associated with a lower risk of progression on X-ray and MRI over 2 years. Subjects with greater BMI also demonstrate less bone oedema at baseline. Greater BMI may indicate a less aggressive RA phenotype and aid in risk stratification.
Screening for Diabetes and Prediabetes With Proposed A1C-Based Diagnostic Criteria
Authors: John B. Buse
Journal: Diabetes Care (2010)

I read with interest the article of Olson et al. (1) detailing the performance of A1C as a diagnostic test in comparison with the “gold standard” oral glucose tolerance test (OGTT) and its ensuing press coverage. The fundamental challenge regarding the diagnosis of diabetes is how to identify a population at risk for complications. It is a fallacy that the OGTT is a gold standard. In fact, for …
THE EFFECT OF EXPERIMENTAL REDUCTION OF KIDNEY SUBSTANCE UPON THE PARATHYROID GLANDS AND SKELETAL TISSUE
Authors: Alwin M. Pappenheimer
Journal: The Journal of Experimental Medicine (1936)

Reduction of renal tissue in young rats regularly leads to a marked increase in the volume of the parathyroid glands. If partially nephrectomized rats are maintained on a low calcium diet, growth is stunted, and skeletal lesions are produced, of far greater severity than can be ascribed to the dietary calcium deficiency alone. The picture closely resembles that found in cases of renal rickets in children.
Sustained high-level expression of human factor IX (hFIX) after liver-targeted delivery of recombinant adeno-associated virus encoding the hFIX gene in rhesus macaques
Authors: Amit C. Nathwani, Andrew M. Davidoff, Hideki Hanawa, Yunyu Hu, Fredric A. Hoffer, Alexander Nikanorov, Clive Slaughter, Catherine Y. C. Ng, Junfang Zhou, Jay N. Lozier, Timothy D. Mandrell, Elio F. Vanin, Arthur W. Nienhuis
Journal: Blood (2002)
Gout: why is this curable disease so seldom cured?
Authors: Michael Doherty, Tim L Jansen, George Nuki, Eliseo Pascual, Fernando Perez-Ruiz, Leonardo Punzi, Alexander K So, Thomas Bardin
Journal: Annals of the Rheumatic Diseases (2012)

Gout is the most common inflammatory arthritis and one in which pathogenesis and risk factors are best understood. One of the treatment objectives in current guidelines is ‘cure’. However, audits show that only a minority of patients with gout receive adequate advice and treatment. Suboptimal care and outcomes reflect inappropriately negative perceptions of the disease, both in patients and providers. Historically, gout has been portrayed as a benign and even comical condition that is self-inflicted through overeating and alcohol excess. Doctors often focus on managing acute attacks rather than viewing gout as a chronic progressive crystal deposition disease. Urate-lowering treatment is underprescribed and often underdosed. Appropriate education of patients and doctors, catalysed by recent introduction of new urate-lowering treatments after many years with no drug development in the field, may help to overcome these barriers and improve management of this easily diagnosed and curable form of potentially severe arthritis.
Nuclear Localization of KLF4 Is Associated with an Aggressive Phenotype in Early-Stage Breast Cancer
Authors: Ashka Y. Pandya, Lynya I. Talley, Andra R. Frost, Thomas J. Fitzgerald, Vivek Trivedi, Mithun Chakravarthy, David C. Chhieng, William E. Grizzle, Jeffrey A. Engler, Helen Krontiras, Kirby I. Bland, Albert F. LoBuglio, Susan M. Lobo-Ruppert, J. Michael Ruppert
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The Krüppel-like transcription factor KLF4/GKLF induces both malignant transformation and a slow-growth phenotype in vitro. Although KLF4 expression is increased in most cases of breast cancer, it was unknown whether these cases represent a distinct subtype with a different clinical outcome. Experimental Design: We examined expression of KLF4 by immunostaining 146 cases of human primary infiltrating ductal carcinoma of the breast. Staining patterns were correlated with clinical outcome and with established prognostic factors. Results: Subcellular localization exhibited case-to-case variation. Tumors with high nuclear staining and low cytoplasmic staining were termed type 1. For patients with early-stage disease (i.e., stage I or IIA), type 1 staining was associated with eventual death because of breast cancer (hazard ratio, 2.8; 95% confidence interval, 1.23–6.58; P = 0.011). The association was stronger in patients with early-stage cancer and small primary tumors (i.e., ≤2.0 cm in diameter; hazard ratio, 4.3; 95% confidence interval, 1.75–10.62; P &amp;lt; 0.001). For patients with early-stage disease, multivariate analysis indicated that type 1 staining was independently associated with outcome (adjusted hazard ratio 2.6; 95% confidence interval, 1.10–6.05; P = 0.029). Type 1 staining was also associated with high histological grade (P = 0.032), increased expression of Ki67 (P = 0.016), and reduced expression of BCL2 (P = 0.032). In vitro, KLF4 was localized within the nucleus of transformed RK3E epithelial cells, consistent with a nuclear function of this transcription factor during induction of malignant transformation. Conclusions: The results suggest that localization of KLF4 in the nucleus of breast cancer cells is a prognostic factor and identify KLF4 as a marker of an aggressive phenotype in early-stage infiltrating ductal carcinoma.
Natriuretic peptides enhance the oxidative capacity of human skeletal muscle
Authors: Stefan Engeli, Andreas L. Birkenfeld, Pierre-Marie Badin, Virginie Bourlier, Katie Louche, Nathalie Viguerie, Claire Thalamas, Emilie Montastier, Dominique Larrouy, Isabelle Harant, Isabelle de Glisezinski, Stefanie Lieske, Julia Reinke, Bibiana Beckmann, Dominique Langin, Jens Jordan, Cedric Moro
Journal: Journal of Clinical Investigation (2012)

Cardiac natriuretic peptides (NP) are major activators of human fat cell lipolysis and have recently been shown to control brown fat thermogenesis. Here, we investigated the physiological role of NP on the oxidative metabolism of human skeletal muscle. NP receptor type A (NPRA) gene expression was positively correlated to mRNA levels of PPARγ coactivator-1α (PGC1A) and several oxidative phosphorylation (OXPHOS) genes in human skeletal muscle. Further, the expression of NPRA, PGC1A, and OXPHOS genes was coordinately upregulated in response to aerobic exercise training in human skeletal muscle. In human myotubes, NP induced PGC-1α and mitochondrial OXPHOS gene expression in a cyclic GMP–dependent manner. NP treatment increased OXPHOS protein expression, fat oxidation, and maximal respiration independent of substantial changes in mitochondrial proliferation and mass. Treatment of myotubes with NP recapitulated the effect of exercise training on muscle fat oxidative capacity in vivo. Collectively, these data show that activation of NP signaling in human skeletal muscle enhances mitochondrial oxidative metabolism and fat oxidation. We propose that NP could contribute to exercise training–induced improvement in skeletal muscle fat oxidative capacity in humans.
Altered Retinoblastoma Protein Expression and Prognosis in Early-Stage Non-Small-Cell Lung Carcinoma
Authors: H.-J. Xu, D. C. Quinlan, A. G. Davidson, S.-X. Hu, C. L. Summers, J. Li, W. F. Benedict
Journal: JNCI Journal of the National Cancer Institute (1994)

Altered retinoblastoma (RB [also known as RBI]) gene expression was initially found in a small cohort study to occur in five (22%) of 23 patients with primary stage I and II non-small-cell lung carcinomas (NSCLCs). Putative mutation of the p53 gene (also known as TP53) has also been found to occur frequently in stage I and II NSCLCs and to be associated with more aggressive disease and a poorer prognosis. Purpose : Our purpose was to determine the Rb protein status in the same cohort that had been previously studied for their p53 protein status and to document whether loss of Rb protein expression was also an important factor in overall survival. Methods : One hundred one stage I or II NSCLC specimens were analyzed by immunohistochemical staining. These paraffin-embedded tumor sections were obtained from individual paraffin blocks prepared for each patient in the previous study. Patient survival status was obtained from hospital and tumor registry records. Results : Altered Rb protein expression was found in 24 of 101 stage I and II NSCLCs. The median survival was 32 months for patients with Rb-positive (Rb + ) tumors and 18 months for individuals in whom expression of Rb protein was absent or altered (Rb − ) in tumor cells. Logrank analysis of the differences in overall survival was statistically significant (P = .007). When these results were combined with the p53 status in the same tumor, the median survival was 12 months for those individuals who had theoretically the worst pattern (Rb − / p53 + ) and 46 months for those patients with theoretically the best pattern (Rb + /p53 − ) (P<.001). The Rb + and Rb − groups in this cohort were well balanced with respect to the distribution of age, disease stage, histologic types, p53 status, and sex. Using a mul-tivariate proportional hazards regression model, both altered Rb and p53 status were found to be significantly associated with poor prognosis (P = .005 and .012, respectively) in the overall cohort. Conclusion : Altered Rb protein expression is an independent prognostic marker for overall decreased survival in early-stage NSCLC as detected by absence of nuclear Rb protein staining. There appears to be a poorer prognosis when loss of Rb protein function and mutated p53 protein occur in the same tumor. Implications: If these findings can be confirmed in larger prospective studies, the results would suggest that both the Rb and p53 status should be utilized as independent prognostic factors in early-stage NSCLC. [J Natl Cancer Inst 86: 695–699, 1994]
Decreased expression of haem oxygenase-1 by alveolar macrophages in idiopathic pulmonary fibrosis
Authors: Q. Ye, Y. Dalavanga, N. Poulakis, S. U. Sixt, J. Guzman, U. Costabel
Journal: European Respiratory Journal (2008)

Haem oxygenase (HO)-1 is an oxidative stress responsive protein that may be involved in the pathogenesis of interstitial lung disease. HO-1 expression in alveolar macrophages from bronchoalveolar lavage was investigated in 24 patients with idiopathic pulmonary fibrosis (IPF), 16 with sarcoidosis, 14 with hypersensitivity pneumonitis (HP) and 13 controls. Using immunocytochemistry, HO-1 expression in macrophages was scored semiquantitatively from 0–3 according to increasing intensity. The mean score of 100 macrophages was calculated. Macrophages were cultured and levels of interleukin (IL)-12 and IL-18 in the culture supernatants were measured by ELISA. The mean score of HO-1 was significantly lower in IPF (67) than in sarcoidosis (105), HP (106) or controls (106). There was no significant difference between sarcoidosis, HP and controls. The score of HO-1 correlated positively with the lymphocyte percentage in sarcoidosis and HP. Positive correlations were found between the score of HO-1 and the release of IL-12 and IL-18 by macrophages in IPF. The expression of haem oxygenase-1, a critical defender against oxidative stress, is decreased in macrophages of idiopathic pulmonary fibrosis patients compared with those with granulomatous lung disorders. This supports the hypothesis of an oxidant–antioxidant imbalance in the pathogenesis of idiopathic pulmonary fibrosis.
Reliability, sensitivity to change and feasibility of three radiographic scoring methods for hand osteoarthritis
Authors: J. Bijsterbosch, I. K. Haugen, C. Malines, E. Maheu, F. R. Rosendaal, I. Watt, F. Berenbaum, T. K. Kvien, D. M. van der Heijde, T. W. J. Huizinga, M. Kloppenburg
Journal: Annals of the Rheumatic Diseases (2011)

<h3>Objective</h3> To compare the reliability, sensitivity to change and feasibility of three radiographic scoring methods for hand osteoarthritis (OA). <h3>Methods</h3> Baseline, 2-year and 6-year hand radiographs of 90 patients with hand OA were read in triplicate in chronological order by three readers from different European centres using the OARSI atlas (OARSI), Kellgren–Lawrence grading scale (KL) and Verbruggen–Veys anatomical phase score (VV). Reliability was determined using intraclass correlation coefficients and smallest detectable change (SDC). Sensitivity to change was assessed by the proportion of progression above the SDC. Feasibility was reflected by the mean performance time. <h3>Results</h3> Intra- and inter-reader reliability was similar across methods. Inter-reader SDCs (% maximum score) for KL, OARSI and VV were 2.9 (3.2), 4.1 (2.9) and 2.7 (1.8) over 2 years and 3.8 (4.1), 4.6 (3.3) and 4.0 (2.5) over 6 years, respectively. KL detected a slightly higher proportion of progression. There were differences between readers, despite methods to enhance consistency. The mean performance time (SD, minutes) for KL, OARSI and VV was 4.3 (2.5), 9.3 (6.0) and 2.8 (1.5), respectively. <h3>Conclusion</h3> Methods had comparable reliability and sensitivity to change. Global methods were fastest to perform. For multicentre trials use of a central reading centre and multiple readers may minimise inter-reader variation.
Activation of biliary tree stem cells within peribiliary glands in primary sclerosing cholangitis
Authors: Guido Carpino, Vincenzo Cardinale, Anastasia Renzi, Johannes R. Hov, Pasquale Bartolomeo Berloco, Massimo Rossi, Tom H. Karlsen, Domenico Alvaro, Eugenio Gaudio
Journal: Journal of Hepatology (2015)