tbuckley/cabot-search huggingface dataset:
Effect of implementation of the mass breast cancer screening programme in older women in the Netherlands: population based study
Authors: N. A. de Glas, A. J. M. de Craen, E. Bastiaannet, E. G. Op 't Land, M. Kiderlen, W. van de Water, S. Siesling, J. E. A. Portielje, H. M. Schuttevaer, G. H. de Bock, C. J. H. van de Velde, G.-J. Liefers
Journal: BMJ (2014)

<b>Objective</b> To assess the incidence of early stage and advanced stage breast cancer before and after the implementation of mass screening in women aged 70-75 years in the Netherlands in 1998. <b>Design</b> Prospective nationwide population based study. <b>Setting</b> National cancer registry, the Netherlands. <b>Participants</b> Patients aged 70-75 years with a diagnosis of invasive or ductal carcinoma in situ breast cancer between 1995 and 2011 (n=25 414). Incidence rates were calculated using population data from Statistics Netherlands. <b>Main outcome measure</b> Incidence rates of early stage (I, II, or ductal carcinoma in situ) and advanced stage (III and IV) breast cancer before and after implementation of screening. Hypotheses were formulated before data collection. <b>Results</b> The incidence of early stage tumours significantly increased after the extension for implementation of screening (248.7 cases per 100 000 women before screening up to 362.9 cases per 100 000 women after implementation of screening, incidence rate ratio 1.46, 95% confidence interval 1.40 to 1.52, P&lt;0.001). However, the incidence of advanced stage breast cancers decreased to a far lesser extent (58.6 cases per 100 000 women before screening to 51.8 cases per 100 000 women after implementation of screening, incidence rate ratio 0.88, 0.81 to 0.97, P&lt;0.001). <b>Conclusions</b> The extension of the upper age limit to 75 years has only led to a small decrease in incidence of advanced stage breast cancer, while that of early stage tumours has strongly increased.
German Diabetes Disease Management Programs Are Appropriate for Restructuring Care According to the Chronic Care Model
Authors: Joachim Szecsenyi, Thomas Rosemann, Stefanie Joos, Frank Peters-Klimm, Antje Miksch
Journal: Diabetes Care (2008)

OBJECTIVE—With the introduction of diabetes disease management programs (DMPs) in Germany, there is a necessity to evaluate whether patients receive care that is congruent to the Chronic Care Model (CCM) and evidence-based behavioral counseling. We examined differences as perceived and experienced by patients with type 2 diabetes between those enrolled in a DMP compared with patients receiving usual care in two federal states of Germany. RESEARCH DESIGN AND METHODS—A random, heterogeneous sample of 3,546 patients (59.3% female) received a mailed questionnaire from their regional health fund, including the German version of the Patient Assessment of Chonic Illness Care (PACIC) instrument, which had additional items for behavioral advice (5A). Two weeks later, a general reminder was sent out. RESULTS—A total of 1,532 questionnaires were returned (response rate 42.2%), and valid data could be obtained for 1,399 patients. Mean age of responders was 70.3 years, of which 53.6% were female. Overall, patients enrolled in a DMP scored significantly higher (3.21 of a possible 5) than patients not enrolled in a DMP (2.86) (P &amp;lt; 0.001). Significant differences in the same direction were found on all five subscales of the PACIC. For the 5A scales, similar differences were found for all five subscales plus the sum score (P &amp;lt; 0.001; mean for DMP = 3.08, mean for non-DMP = 2.78). CONCLUSIONS—DMPs, as currently established in primary care in Germany, may impact provided care significantly. The changes in daily practice that have been induced by the DMPs are recognized by patients as care that is more structured and that to a larger extent reflects the core elements of the CCM and evidence-based counseling compared with usual care.
Adenovirus Vector E4 Gene Regulates Connexin 40 and 43 Expression in Endothelial Cells via PKA and PI3K Signal Pathways
Authors: Fan Zhang, Joseph Cheng, George Lam, David K. Jin, Loïc Vincent, Neil R. Hackett, Shiyang Wang, Lauren M. Young, Barbara Hempstead, Ronald G. Crystal, Shahin Rafii
Journal: Circulation Research (2005)

Connexins (Cxs) provide a means for intercellular communication and play important roles in the pathophysiology of vascular cardiac diseases. Infection of endothelial cells (ECs) with first-generation E1/E3-deleted E4+ adenovirus (AdE4+) selectively modulates the survival and angiogenic potential of ECs by as of yet unrecognized mechanisms. We show here that AdE4+ vectors potentiate Cx expression in ECs in vitro and in mouse heart tissue. Infection of ECs with AdE4+, but not AdE4-, resulted in a time- and dose-dependent induction of junctional Cx40 expression and suppression of Cx43 protein and mRNA expression. Treatment of ECs with PKA inhibitor H89 or PI3K inhibitor LY294002 prevented the AdE4+-mediated regulation of Cx40 and Cx43 that was associated with diminished AdE4+-mediated survival of ECs. Moreover, both PKA activity and cAMP-response element (CRE)-binding activity were enhanced by treatment of ECs with AdE4+. However, there is no causal evidence of a cross-talk between the 2 modulatory pathways, PKA and PI3K. Remarkably, Cx40 immunostaining was markedly increased and Cx43 was decreased in the heart tissue of mice treated with intra-tracheal AdE4+. Taken together, these results suggest that AdE4+ may play an important role in the regulation of Cx expression in ECs, and that these effects are mediated by both the PKA/CREB and PI3K signaling pathways.
Varenicline, an α4β2 Nicotinic Acetylcholine Receptor Partial Agonist, vs Sustained-Release Bupropion and Placebo for Smoking Cessation&lt;SUBTITLE&gt;A Randomized Controlled Trial&lt;/SUBTITLE&gt;
Authors: David Gonzales, Stephen I. Rennard, Mitchell Nides, Cheryl Oncken, Salomon Azoulay, Clare B. Billing, Eric J. Watsky, Jason Gong, Kathryn E. Williams, Karen R. Reeves
Journal: JAMA (2006)

ALTHOUGH NEARLY 41% OF smokers try to quit smoking each year, relapse is common, and only about 10% achieve and maintain abstinence. 1 The negative effects of nicotine withdrawal account, in part, for low success rates. 2,3Approved pharmacotherapies to treat nicotine dependence (eg, nicotine replacement therapy and bupropion) have had important, albeit moderate, efficacy, with reported rates of quitting generally twice those of placebo. 4Thus, additional and more efficacious therapies are needed.6][7][8] It See also pp 56, 64, and 94.
Crystal structure of the TRANCE/RANKL cytokine reveals determinants of receptor-ligand specificity
Authors: Jonathan Lam, Christopher A. Nelson, F. Patrick Ross, Steven L. Teitelbaum, Daved H. Fremont
Journal: Journal of Clinical Investigation (2001)

RANK, the receptor activator of NF-kappaB, and its ligand RANKL (initially termed TRANCE, also termed ODF and OPGL), are a TNF superfamily receptor-ligand pair that govern the development and function of osteoclasts, lymphoid tissue, and mammary epithelium. While TNF family cytokines share a common structural scaffold, individual receptor-ligand pairs associate with high specificity. Given the low level of amino acid conservation among members of the TNF superfamily, the means by which these molecules achieve specificity cannot be completely understood without knowledge of their three-dimensional structures. To determine the elements of RANKL that mediate RANK activation, we have crystallized the ectodomain of murine RANKL and solved its structure to a resolution of 2.6 A. RANKL self-associates as a homotrimer with four unique surface loops that distinguish it from other TNF family cytokines. Mutagenesis of selected residues in these loops significantly modulates RANK activation, as evidenced by in vitro osteoclastogenesis, thereby establishing their necessity in mediating the biological activities of RANKL. Such structural determinants of RANKL-RANK specificity may be of relevance in the pharmacologic design of compounds to ameliorate osteopenic disorders of bone.
Asthma and occupation in the 1958 birth cohort
Authors: Rebecca Elisabeth Ghosh, Paul Cullinan, David Fishwick, Jennifer Hoyle, Chris J Warburton, David P Strachan, Barbara K Butland, Debbie Jarvis
Journal: Thorax (2013)

<h3>Objective</h3> To examine the association of adult onset asthma with lifetime exposure to occupations and occupational exposures. <h3>Methods</h3> We generated lifetime occupational histories for 9488 members of the British 1958 birth cohort up to age 42 years. Blind to asthma status, jobs were coded to the International Standard Classification of Occupations 1988 and an Asthma Specific Job Exposure Matrix (ASJEM) with an expert re-evaluation step. Associations of jobs and ASJEM exposures with adult onset asthma were assessed in logistic regression models adjusting for sex, smoking, social class at birth and childhood hay fever. <h3>Results</h3> Of the 7406 cohort members with no asthma or wheezy bronchitis in childhood, 639 (9%) reported asthma by age 42 years. Adult onset asthma was associated with 18 occupations, many previously identified as risks for asthma (eg, farmers: OR 4.26, 95% CI 2.06 to 8.80; hairdressers: OR 1.88, 95% CI 1.24 to 2.85; printing workers: OR 3.04, 95% CI 1.49 to 6.18). Four were cleaning occupations and a further three occupations were likely to use cleaning agents. Adult onset asthma was associated with five of the 18 high-risk specific ASJEM exposures (flour exposure: OR 2.12, 95% CI 1.17 to 3.85; enzyme exposure: OR 2.32, 95% CI 1.22 to 4.42; cleaning/disinfecting products: OR 1.67, 95% CI 1.26 to 2.22; metal and metal fumes: OR 1.45, 95% CI 1.02 to 2.07; textile production: OR 1.71, 95% CI 1.12 to 2.61). Approximately 16% (95% CI 3.8% to 27.1%) of adult onset asthma was associated with known asthmagenic occupational exposures. <h3>Conclusions</h3> This study suggests that about 16% of adult onset asthma in British adults born in the late 1950s could be due to occupational exposures, mainly recognised high-risk exposures.
Genesis and Regulatory Wiring of Retroelement-Derived Domesticated Genes: A Phylogenomic Perspective
Authors: Janez Kokošar, Dušan Kordiš
Journal: Molecular Biology and Evolution (2013)

Molecular domestications of transposable elements have occurred repeatedly during the evolution of eukaryotes. Vertebrates, especially mammals, possess numerous single copy domesticated genes (DGs) that have originated from the intronless multicopy transposable elements. However, the origin and evolution of the retroelement-derived DGs (RDDGs) that originated from Metaviridae has been only partially elucidated, due to absence of genome data or to limited analysis of a single family of DGs. We traced the genesis and regulatory wiring of the Metaviridae-derived DGs through phylogenomic analysis, using whole-genome information from more than 90 chordate genomes. Phylogenomic analysis of these DGs in chordate genomes provided direct evidence that major diversification has occurred in the ancestor of placental mammals. Mammalian RDDGs have been shown to originate in several steps by independent domestication events and to diversify later by gene duplications. Analysis of syntenic loci has shown that diverse RDDGs and their chromosomal positions were fully established in the ancestor of placental mammals. By analysis of active Metaviridae lineages in amniotes, we have demonstrated that RDDGs originated from retroelement remains. The chromosomal gene movements of RDDGs were highly dynamic only in the ancestor of placental mammals. During the domestication process, de novo acquisition of regulatory regions is shown to be a prerequisite for the survival of the DGs. The origin and evolution of de novo acquired promoters and untranslated regions in diverse mammalian RDDGs have been explained by comparative analysis of orthologous gene loci. The origin of placental mammal-specific innovations and adaptations, such as placenta and newly evolved brain functions, was most probably connected to the regulatory wiring of DGs and their rapid fixation in the ancestor of placental mammals.
Cytomegalovirus Pneumonia after Bone Marrow Transplantation Successfully Treated with the Combination of Ganciclovir and High-Dose Intravenous Immune Globulin
Authors: David Emanuel
Journal: Annals of Internal Medicine (1988)

To assess the efficacy of the combination of the antiviral agent ganciclovir (9-1,3 dihydroxy-2-propoxymethylguanine) and high-dose intravenous immune globulin for treating cytomegalovirus interstitial pneumonitis after allogeneic bone marrow transplantation.Nonrandomized prospective trial of combined treatment with two drugs; findings in these patients were compared with those in control patients treated with either of the two drugs alone.Medical, pediatric, and intensive care units of a tertiary-care cancer treatment center.Consecutive cases of 10 patients in the study group and of 11 patients in a historical control group with evidence of cytomegalovirus pneumonia after bone marrow transplantation for treatment of leukemia or congenital immune deficiency.Study Group (10 patients): ganciclovir, 2.5 mg/kg body weight, three times daily for 20 days, plus intravenous immune globulin, 500 mg/kg every other day for ten doses. Patients were then given ganciclovir, 5 mg/kg.d three to five times a week for 20 more doses, and intravenous immune globulin, 500 mg/kg twice a week for 8 more doses. Control Group (11 patients): ganciclovir alone (2 patients), 5 mg/kg twice a day for 14 to 21 days; cytomegalovirus hyperimmune globulin (5 patients), 400 mg/kg.d for 10 days; and intravenous immune globulin (4 patients), 400 mg/kg.d for 10 days.Responses were observed in all patients treated with combination therapy; 7 of 10 patients were alive and well, and had no recurrence of disease at a median of 10 months after therapy. No therapeutic benefit was observed, and none of the 11 patients treated with either ganciclovir or intravenous immune globulin alone survived (P = 0.001 by Fisher exact test).Ganciclovir, when combined with high-dose intravenous immune globulin, appears to have significantly altered the outcome of patients with cytomegalovirus pneumonia after allogeneic bone marrow transplantation.
Reorganisation of the NHS in England
Authors: K. Walshe
Journal: BMJ (2010)

Diagnosis of bronchiectasis is usually made using chest computed tomography (CT) scan, the current gold standard method. A bronchiectatic airway can show abnormal widening and thickening of its airway wall. In addition, it can show an irregular wall and lack of tapering, and/or can be visible in the periphery of the lung. Its diagnosis is still largely expert based. More recently, it has become clear that airway dimensions on CT and therefore the diagnosis of bronchiectasis are highly dependent on lung volume. Hence, control of lung volume is required during CT acquisition to standardise the evaluation of airways. Automated image analysis systems are in development for the objective analysis of airway dimensions and for the diagnosis of bronchiectasis. To use these systems, clear and objective definitions for the diagnosis of bronchiectasis are needed. Furthermore, the use of these systems requires standardisation of CT protocols and of lung volume during chest CT acquisition. In addition, sex- and age-specific reference values are needed for image analysis outcome parameters. This review focusses on today9s issues relating to the radiological diagnosis of bronchiectasis using state-of-the-art CT imaging techniques.
Expression of p73 and Its Relation to Histopathology and Prognosis in Hepatocellular Carcinoma
Authors: A. Tannapfel, M. Wasner, K. Krause, F. Geissler, A. Katalinic, J. Hauss, J. Mossner, K. Engeland, C. Wittekind
Journal: JNCI Journal of the National Cancer Institute (1999)

BACKGROUND: The protein p73, the first identified homologue of the tumor suppressor gene p53 (also known as TP53), has been shown to induce apoptosis (programmed cell death), but its function in tumor development has not been established. This study was undertaken to investigate the expression of p73 in liver tissue of patients with hepatocellular carcinoma (HCC) and to determine whether this expression has any impact on prognosis. METHODS: In situ hybridization and immunohistochemistry for the detection of p73 RNA transcripts and protein, respectively, were performed in tissues from 193 patients with curatively (R0-) resected HCC. Patients receiving liver transplantation were excluded. The results obtained were analyzed with respect to their association with pathohistologic stage, Edmondson grade, p53 expression status and several histopathologic factors of possible prognostic value, and, finally, with patient survival. RESULTS: RNA transcripts encoding p73 were detected by in situ hybridization in tumor cells but not in stromal, endothelial, or inflammatory cells or in cholangiocytes. Transcripts were also found occasionally in non-neoplastic hepatocytes. By immunohistochemistry, we detected p73 protein in 61 (32%) of the 193 carcinomas examined. Positive immunohistochemical staining was confined to the cell nucleus. Univariate survival analysis showed that p73 expression status was statistically significantly related to prognosis (two-sided P <.0001). Patients with p73-positive tumors had a poorer prognosis than those with p73-negative carcinomas. Multivariate Cox survival analysis identified the age of the patient, p73 expression status, co-existing cirrhosis, and Edmondson grade as independent prognostic factors. CONCLUSION: The protein p73 is overexpressed by a subset of HCCs and could serve as a useful indicator of prognosis in patients with this disease.
Low <i>ERG</i> and <i>BAALC</i> Expression Identifies a New Subgroup of Adult Acute T-Lymphoblastic Leukemia With a Highly Favorable Outcome
Authors: Claudia D. Baldus, Peter Martus, Thomas Burmeister, Stefan Schwartz, Nicola Gökbuget, Clara D. Bloomfield, Dieter Hoelzer, Eckhard Thiel, Wolf K. Hofmann
Journal: Journal of Clinical Oncology (2007)

Expression of the genes ERG (v-ets erythroblastosis virus E26 oncogene homolog) and BAALC (brain and acute leukemia, cytoplasmic) shows similarity during hematopoietic maturation and predicts outcome in acute myeloid leukemia. We hypothesized that like ERG, BAALC expression might be of prognostic significance in acute T-lymphoblastic leukemia (T-ALL) and that ERG and BAALC expression together would better identify the patient's risk profile.ERG and BAALC mRNA expression were determined by real-time reverse transcriptase polymerase chain reaction in 153 adults with T-ALL. Patients were designated low or high ERG expressers and low or high BAALC expressers.High BAALC expression correlated with a higher frequency of early T-ALL (P < .0001), CD34 positivity (P < .0001), coexpression of myeloid markers (P = .0001), and high ERG expression (P = .03). High BAALC compared with low BAALC patients had an inferior relapse-free survival (RFS; P = .0008) and overall survival (OS; P = .0001). In contrast, patients with low expression of both ERG and BAALC (representing 41% of all T-ALL patients) had the most favorable outcome (P < .0001; 4-year RFS: low ERG/low BAALC 81%; P < .0001; 4-year OS: low ERG/low BAALC 69%). On multivariable analysis, low ERG/low BAALC expression was of independent favorable prognostic significance (RFS, P = .001; OS, P = .003).Low expression of both ERG and BAALC identifies T-ALL patients with a distinctly favorable long-term outcome.
Genetic risk factors for variant Creutzfeldt–Jakob disease: a genome-wide association study
Authors: Simon Mead, Mark Poulter, James Uphill, John Beck, Jerome Whitfield, Thomas EF Webb, Tracy Campbell, Gary Adamson, Pelagia Deriziotis, Sarah J Tabrizi, Holger Hummerich, Claudio Verzilli, Michael P Alpers, John C Whittaker, John Collinge
Journal: The Lancet Neurology (2008)

Human and animal prion diseases are under genetic control, but apart from PRNP (the gene that encodes the prion protein), we understand little about human susceptibility to bovine spongiform encephalopathy (BSE) prions, the causal agent of variant Creutzfeldt-Jakob disease (vCJD).We did a genome-wide association study of the risk of vCJD and tested for replication of our findings in samples from many categories of human prion disease (929 samples) and control samples from the UK and Papua New Guinea (4254 samples), including controls in the UK who were genotyped by the Wellcome Trust Case Control Consortium. We also did follow-up analyses of the genetic control of the clinical phenotype of prion disease and analysed candidate gene expression in a mouse cellular model of prion infection.The PRNP locus was strongly associated with risk across several markers and all categories of prion disease (best single SNP [single nucleotide polymorphism] association in vCJD p=2.5 x 10(-17); best haplotypic association in vCJD p=1 x 10(-24)). Although the main contribution to disease risk was conferred by PRNP polymorphic codon 129, another nearby SNP conferred increased risk of vCJD. In addition to PRNP, one technically validated SNP association upstream of RARB (the gene that encodes retinoic acid receptor beta) had nominal genome-wide significance (p=1.9 x 10(-7)). A similar association was found in a small sample of patients with iatrogenic CJD (p=0.030) but not in patients with sporadic CJD (sCJD) or kuru. In cultured cells, retinoic acid regulates the expression of the prion protein. We found an association with acquired prion disease, including vCJD (p=5.6 x 10(-5)), kuru incubation time (p=0.017), and resistance to kuru (p=2.5 x 10(-4)), in a region upstream of STMN2 (the gene that encodes SCG10). The risk genotype was not associated with sCJD but conferred an earlier age of onset. Furthermore, expression of Stmn2 was reduced 30-fold post-infection in a mouse cellular model of prion disease.The polymorphic codon 129 of PRNP was the main genetic risk factor for vCJD; however, additional candidate loci have been identified, which justifies functional analyses of these biological pathways in prion disease.
Back to the Barber's Pole
Authors: B. W. Howell
Journal: BMJ (1954)

The class I gene family of the major histocompatibility complex (MHC) of the miniature swine (SLA) contains seven members. Six of these are highly homologous, whereas the seventh, PD6, is only distantly related. A genomic clone containing PD6 has been isolated and characterized. The PD6 SLA gene, although only 55% homologous to the other SLA class I sequences, is still a member of the family; its size and exon/intron organization are similar to other class I genes. When aligned with other SLA genes, exons 1 to 6 of PD6 have open reading frames; exon 7 contains a termination codon. PD6 is transcribed in transfected mouse L cells where its expression is enhanced by interferon. In vivo expression of PD6 is observed in a variety of tissues, with the highest levels in mature lymphoid tissues. Peripheral T cells contain high levels of PD6-specific RNA relative to B cells, whereas no PD6 transcripts are detectable in thymocytes.