tbuckley/cabot-search huggingface dataset:
Ductal Carcinoma In Situ of the Breast: a New Model
Authors: D. F. Hayes
Journal: JNCI Journal of the National Cancer Institute (1997)

Several therapeutic options are available for patients with breast cancer. These include ‘‘local’’ therapies, such as surgery and radiation therapy, and ‘‘systemic’’ therapies, such as chemotherapy and hormone therapy. Unfortunately, few, if any, patients with detectable, metastatic disease are cured with currently available treatment options (1). Therefore, at least in 1997, our best chance to cure patients with breast cancer is to find and treat it early or to prevent it altogether. The strategy of early diagnosis and treatment may be contributing to the decreasing risk of dying from breast cancer in the Western world (2). Screening mammography permits early detection of breast cancer (3). Randomized studies have demonstrated that early local treatment for screened patients reduces mortality by 20%-30% over a 10-year period compared with women who are followed without screening (4). Early systemic therapy also saves lives (5). Regardless of the risk of subsequent recurrence for a patient with newly diagnosed, nonmetastatic breast cancer, adjuvant systemic therapy of some sort decreases the odds of distant recurrence and death by 20%-30% over a 10-15-year period. These observations raise the question: What is early breast cancer? Many investigators have proposed a model in which breast epithelial cells, like other solid tumors of epithelial origin, appear to proceed through a spectrum of biologic states from normal to frankly metastatic (6). According to this model, a series of random yet important chronologic events occurs in which epithelial cells escape normal growth control, develop the ability to invade the basement membrane, survive in the surrounding interstitial tissue of normal breast, migrate to other tissues, and multiply. Clinically, when carcinoma cells are confined to the basement membrane, they are designated in situ. Those cells that escape the basement membrane gain the designation of invasive or infiltrating carcinomas. Those that travel to other sites of the body are known as micrometastases, and if they grow in other tissues, they become detectable metastases. Ultimately, it is this process that causes the morbidity and mortality of breast cancer: the uncontrolled growth of malignant ductal breast cells in other tissues at the expense of the normal function of the host tissue. However, as the old saying goes, ‘‘All dogs are animals, but not all animals are dogs.’’ Presumably, all detectable metastases arise from the preceding state(s), but not all cells in the preceding state progress to detectable metastases. Multiple clinical implications arise from this model. If breast cancer really does represent a stepwise progressive process, the following assumptions and corollaries might be made: 1) In an individual patient, breast cancer is not a ‘‘disease’’
Continuing Stability of Center Differences in Pediatric Diabetes Care: Do Advances in Diabetes Treatment Improve Outcome?
Authors: Carine E. de Beaufort, Peter G.F. Swift, Chas T. Skinner, Henk J. Aanstoot, Jan Åman, Fergus Cameron, Pedro Martul, Francesco Chiarelli, Dennis Daneman, Thomas Danne, Harry Dorchy, Hilary Hoey, Eero A. Kaprio, Francine Kaufman, Mirjana Kocova, Henrik B. Mortensen, Pal R. Njølstad, Moshe Phillip, Kenneth J. Robertson, Eugen J. Schoenle, Tatsuhiko Urakami, Maurizio Vanelli
Journal: Diabetes Care (2007)

To reevaluate the persistence and stability of previously observed differences between pediatric diabetes centers and to investigate the influence of demography, language communication problems, and changes in insulin regimens on metabolic outcome, hypoglycemia, and ketoacidosis.This was an observational cross-sectional international study in 21 centers, with clinical data obtained from all participants and A1C levels assayed in one central laboratory. All individuals with diabetes aged 11-18 years (49.4% female), with duration of diabetes of at least 1 year, were invited to participate. Fourteen of the centers participated in previous Hvidoere Studies, allowing direct comparison of glycemic control across centers between 1998 and 2005.Mean A1C was 8.2 +/- 1.4%, with substantial variation between centers (mean A1C range 7.4-9.2%; P < 0.001). There were no significant differences between centers in rates of severe hypoglycemia or diabetic ketoacidosis. Language difficulties had a significant negative impact on metabolic outcome (A1C 8.5 +/- 2.0% vs. 8.2 +/- 1.4% for those with language difficulties vs. those without, respectively; P < 0.05). After adjustement for significant confounders of age, sex, duration of diabetes, insulin regimen, insulin dose, BMI, and language difficulties, the center differences persisted, and the effect size for center was not reduced. Relative center ranking since 1998 has remained stable, with no significant change in A1C.Despite many changes in diabetes management, major differences in metabolic outcome between 21 international pediatric diabetes centers persist. Different application between centers in the implementation of insulin treatment appears to be of more importance and needs further exploration.
Using Time-Structured Data to Estimate Evolutionary Rates of Double-Stranded DNA Viruses
Authors: C. Firth, A. Kitchen, B. Shapiro, M. A. Suchard, E. C. Holmes, A. Rambaut
Journal: Molecular Biology and Evolution (2010)

Double-stranded (ds) DNA viruses are often described as evolving through long-term codivergent associations with their hosts, a pattern that is expected to be associated with low rates of nucleotide substitution. However, the hypothesis of codivergence between dsDNA viruses and their hosts has rarely been rigorously tested, even though the vast majority of nucleotide substitution rate estimates for dsDNA viruses are based upon this assumption. It is therefore important to estimate the evolutionary rates of dsDNA viruses independent of the assumption of host-virus codivergence. Here, we explore the use of temporally structured sequence data within a Bayesian framework to estimate the evolutionary rates for seven human dsDNA viruses, including variola virus (VARV) (the causative agent of smallpox) and herpes simplex virus-1. Our analyses reveal that although the VARV genome is likely to evolve at a rate of approximately 1 × 10−5 substitutions/site/year and hence approaching that of many RNA viruses, the evolutionary rates of many other dsDNA viruses remain problematic to estimate. Synthetic data sets were constructed to inform our interpretation of the substitution rates estimated for these dsDNA viruses and the analysis of these demonstrated that given a sequence data set of appropriate length and sampling depth, it is possible to use time-structured analyses to estimate the substitution rates of many dsDNA viruses independently from the assumption of host-virus codivergence. Finally, the discovery that some dsDNA viruses may evolve at rates approaching those of RNA viruses has important implications for our understanding of the long-term evolutionary history and emergence potential of this major group of viruses.
Managers warn that NHS is facing a 15bn shortfall after 2011
Authors: A. O'Dowd
Journal: BMJ (2009)

The NHS could be hit by a £15bn (€18bn; $25bn) budget shortfall in a few years time because of reduced government investment, rising costs, and the recession, says the body that represents NHS organisations.

The NHS Confederation has said that services may have to be cut, staff numbers trimmed, limits imposed on new drugs, and possible new efficiency savings set in areas such as prescribing in primary care to cope with the anticipated shortfall.

In its report published at its annual conference this week in Liverpool, the confederation warns that the NHS will face “the most severe constriction ever in its finances” …
Fear-Conditioning Mechanisms Associated with Trait Vulnerability to Anxiety in Humans
Authors: Iole Indovina, Trevor W. Robbins, Anwar O. Núñez-Elizalde, Barnaby D. Dunn, Sonia J. Bishop
Journal: Neuron (2011)

Investigations of fear conditioning in rodents and humans have illuminated the neural mechanisms underlying cued and contextual fear. A critical question is how personality dimensions such as trait anxiety act through these mechanisms to confer vulnerability to anxiety disorders, and whether humans' ability to overcome acquired fears depends on regulatory skills not characterized in animal models. In a neuroimaging study of fear conditioning in humans, we found evidence for two independent dimensions of neurocognitive function associated with trait vulnerability to anxiety. The first entailed increased amygdala responsivity to phasic fear cues. The second involved impoverished ventral prefrontal cortical (vPFC) recruitment to downregulate both cued and contextual fear prior to omission (extinction) of the aversive unconditioned stimulus. These two dimensions may contribute to symptomatology differences across anxiety disorders; the amygdala mechanism affecting the development of phobic fear and the frontal mechanism influencing the maintenance of both specific fears and generalized anxiety.
Inhibition of the Sodium-Hydrogen Exchanger With Cariporide to Prevent Myocardial Infarction in High-Risk Ischemic Situations
Authors: P. Théroux, B.R. Chaitman, N. Danchin, L. Erhardt, T. Meinertz, J.S. Schroeder, G. Tognoni, H.D. White, J.T. Willerson, A. Jessel
Journal: Circulation (2000)

The transmembrane sodium/hydrogen exchanger maintains myocardial cell pH integrity during myocardial ischemia but paradoxically may precipitate cell necrosis. The development of cariporide, a potent and specific inhibitor of the exchanger, prompted this investigation of the potential of the drug to prevent myocardial cell necrosis.A total of 11 590 patients with unstable angina or non-ST-elevation myocardial infarction (MI) or undergoing high-risk percutaneous or surgical revascularization were randomized to receive placebo or 1 of 3 doses of cariporide for the period of risk. The trial failed to document benefit of cariporide over placebo on the primary end point of death or MI assessed after 36 days. Doses of 20 and 80 mg every 8 hours had no effect, whereas a dose of 120 mg was associated with a 10% risk reduction (98% CI 5.5% to 23.4%, P=0.12). With this dose, benefit was limited to patients undergoing bypass surgery (risk reduction 25%, 95% CI 3.1% to 41.5%, P=0.03) and was maintained after 6 months. No effect was seen on mortality. The rate of Q-wave MI was reduced by 32% across all entry diagnostic groups (2.6% versus 1.8%, P=0.03), but the rate of non-Q-wave MI was reduced only in patients undergoing surgery (7.1% versus 3.8%, P=0.005). There were no increases in clinically serious adverse events.No significant benefit of cariporide could be demonstrated across a wide range of clinical situations of risk. The trial documented safety of the drug and suggested that a high degree of inhibition of the exchanger could prevent cell necrosis in settings of ischemia-reperfusion.
Evolutionary Dynamics and Functional Specialization of Plant Paralogs Formed by Whole and Small-Scale Genome Duplications
Authors: Lorenzo Carretero-Paulet, Mario A. Fares
Journal: Molecular Biology and Evolution (2012)

Gene duplicates are a major source of evolutionary novelties in the form of new or specialized functions and play a key role in speciation. Gene duplicates are generated through whole genome duplications (WGD) or small-scale genome duplications (SSD). Although WGD preserves the stoichiometric relationships between duplicates, those arising from SSD are usually unbalanced and are expected to follow different evolutionary dynamics than those formed by WGD. To dissect the role of the mechanism of duplication in these differential dynamics and determine whether this role was shared across species, we performed a genome wide evolutionary analysis of gene duplications arising from the most recent WGD events and contemporary episodes of SSD in four model species representing distinct plant evolutionary lineages. We found an excess of relaxed purifying selection after duplication in SSD paralogs compared with WGD, most of which may have been the result of functional divergence events between gene copies as estimated by measures of genetic distances. These differences were significant in three angiosperm genomes but not in the moss species Physcomitrella patens. Although the comparison of models of evolution does not attribute a relevant role to the mechanism of duplication in the evolution duplicates, distribution of retained genes among Gene Ontology functional categories support the conclusion that evolution of gene duplicates depends on its origin of duplication (WGD and SSD) but, most importantly, on the species. Similar lineage-specific biases were also observed in protein network connectivity, translational efficiency, and selective constraints acting on synonymous codon usage. Although the mechanism of duplication may determine gene retention, our results attribute a dominant role to the species in determining the ultimate pattern of duplicate gene retention and reveal an unanticipated complexity in the evolutionary dynamics and functional specialization of duplicated genes in plants.
TCT-477 Major Adverse Cardiovascular Events And Bleeding Risk Analysis In Elderly Afibrillation Patients Undergoing Percutaneous Coronary Intervention: The AVIATOR Registry
Authors: Aarti Bhasin, Georgios Christodoulidis, Marco G. Mennuni, Samantha Sartori, Usman Baber, George Dangas, Samin Sharma, Annapoorna Kini, Corrado Tamburino, Alaide Chieffo, Antonio Colombo, Patrizia Presbitero, Roxana Mehran
Journal: Journal of the American College of Cardiology (2014)
Development of Autoantibody Signatures as Biomarkers for Early Detection of Colorectal Carcinoma
Authors: Wenjun Chang, Lingling Wu, Fuao Cao, Yan Liu, Liye Ma, Mei Wang, Dongbao Zhao, Ping Li, Qi Zhang, Xiaojie Tan, Yongwei Yu, Zheng Lou, Jinfeng Zhao, Hongwei Zhang, Chuangang Fu, Guangwen Cao
Journal: Clinical Cancer Research (2011)

To select autoantibody signatures for early detection of colorectal cancer (CRC).A phage cDNA expression library was constructed with fresh tumors from 30 CRC patients and biopanned by using serum pools of 20 CRC patients and 20 healthy controls. A classifier was discovered in the training set of 30 CRC patients at stages I and II and 30 matched healthy controls and then blindly validated in an independent set of 60 CRC patients, 60 healthy controls, 52 polyps patients, and 30 autoimmune diseases patients. Expression of proteins was examined by using immunohistochemistry.Five-phage peptide clones showing higher discriminatory power than others in training set were selected for validation. The five-phage peptide classifier was able to discriminate between early CRC patients and healthy controls, with sensitivities of 90.0% to 92.7% and specificities of 91.7% to 93.3%. In those with serum carcinoembryonic antigen less than 5 ng/mL, the classifier was efficient in discriminating CRC from healthy controls, with an area under the curve of 0.975. The classifier was able to discriminate all of the 9 patients with serrated adenoma from healthy controls. Thirteen (43.3%) of the patients with autoimmune diseases were misclassified. Of the five phage peptides, one encoded a peptide identical to immunoglobulin G (IgG) heavy-chain constant region. IgG immunostaining was stronger in mesenchymal cells than in cancer cells in the tumors and was apparent in serrated adenoma.The five-phage peptide classifier stands out as promising early diagnostic biomarkers for CRC, but it is unsuitable for discriminating CRC from autoimmune diseases. Truncated IgGs generated from the tumors might be novel CRC-associated antigens.
The Surgical Treatment of Bronchial Fistulas After Lung Resection for Pulmonary Tuberculosis
Authors: O. Monod, G. Babou, J. Lo
Journal: Thorax (1951)

Post-operative fistula is the most distressing complication after lung resection for pulmonary tuberculosis.It occurs after every variety of operation: pneumonectomy, lobectomy, amputation of the apex with or without thoracoplasty.Fistula is extremely serious after the amputation of the whole lung, and occurs on the main bronchus.Those cases of fistula which we have observed, unless the patient was submitted to re-operation, caused the patient's death, except in one case in which the fistula was due to a suture evacuated by the bronchus.This was easily cured.
Lack of Evidence for Activation of the Inflammasome in Typical Physical Urticarias
Authors: H.D. Komarow, B. Yang, C. Nelson, M. Young, M. O'Brien, N. Medic, S. Chew, J. Milner, M. Gadina, D.D. Metcalfe
Journal: Journal of Allergy and Clinical Immunology (2011)
A1.18 From tissue- and cell-specific transcriptomes to candidate markers in rheumatoid arthritis
Authors: Biljana Smiljanovic, Bruno Stuhlmüller, Wlodzimierz Maslinski, Thomas Vogl, Silvia Pade, Marina Backhaus, Gerd-R Burmester, Andreas Radbruch, Andreas Grützkau, Thomas Häupl
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background and Objectives</h3> A main challenge in disease-management of rheumatoid arthritis (RA) is to establish objective criteria relevant for diagnosis and therapeutic stratification of patients. Clinical signs and symptoms, radiographic changes and routine laboratory tests have indispensable roles in diagnosis of RA. Nevertheless, a high degree of heterogeneity between RA patients and an increasing numbers of treatment opportunities, demands identification of personalised profiles that might indicate on and/or predict response to particular treatment. In this study we applied global gene-expression profiling of cells from various body locations, including synovial tissue as a principal place of destruction and inflammation, and blood and bone marrow monocytes, as a cell type that acts as biosensor for revealing on-going alterations in the body. Based on transcriptome data candidate markers were selected and validated at the protein level. <h3>Materials and Methods</h3> Affymetrix arrays were used for gene-expression profiles of synovial tissues, blood and bone marrow monocytes from RA and osteoarthritis (OA) patients. ELISA and multiplex immunoassays were used for validation of 28 markers in synovial fluid (SF) and matched serum samples from RA and OA patients. <h3>Results</h3> Transcriptome analyses of synovial tissues from RA and OA indicated on infiltration and activation of various cell types in synovial tissue including monocytes/macrophages, T-, B-, NK-cells, fibroblast. Monocyte transcriptomes from blood and bone marrow showed a minor overlap, indicating that pathophysiological changes in RA were disease- and tissue-specific. Candidate markers from these 3 transcripomtes were selected for measurement at the protein level in SF and serum. Out of 28 markers, 23 reached statistical significance when measured in SF, while 16 were significant when measured in serum. ROC analyses of individual markers from SF and serum enabled ranking for the best candidates, whose combinations allowed almost perfect classification of RA. <h3>Conclusions</h3> RA transcriptome was the most robust in synovial tissue. Nevertheless, systemic nature of RA was also demonstrated by transcriptomes from blood and bone marrow monocytes. All transcriptomes demonstrated a great potential in identifying biomarkers whose concentrations were strongly diluted and neutralised in serum. Interestingly, none of the measured markers in serum perform well enough to stratify all RA patients. However, combination of markers as a disease-pattern allowed correct stratification of RA patients and demonstrated their heterogeneity. Further prediction analyses should indicate on a minimal number of top markers relevant for disease and therapeutic stratification, and this would be an indispensable step for establishment of personalised medicine in RA.
Factor V Leiden Mutation and Thromboembolism Risk in Women Receiving Adjuvant Tamoxifen for Breast Cancer
Authors: J. E. Garber, S. Halabi, S. M. Tolaney, E. Kaplan, L. Archer, J. N. Atkins, S. Edge, C. L. Shapiro, L. Dressler, E. M. Paskett, G. Kimmick, J. Orcutt, A. Scalzo, E. Winer, E. Levine, N. Shahab, N. Berliner
Journal: JNCI Journal of the National Cancer Institute (2010)

BackgroundTamoxifen use has been associated with increased risk of thromboembolic events (TEs) in women with breast cancer and women at high risk for the disease. Factor V Leiden (FVL) is the most common inherited clotting factor mutation and also confers increased thrombosis risk. We investigated whether FVL was associated with TE risk in women with early-stage breast cancer who took adjuvant tamoxifen.
Computer-based quantification of the mean Achilles tendon thickness in ultrasound images: effect of tendinosis
Authors: R Syha, M Peters, H Birnesser, A Niess, A Hirschmueller, H-H Dickhuth, M Sandrock
Journal: British Journal of Sports Medicine (2007)

B-mode measurement of the sagital diameter of the Achilles tendon based on a manual tracing (MT) procedure is partly dependent on the subjectivity of the reader. The aim of this study is to establish a standardised automatic procedure to differentiate between normal and chronically degenerated tendons. For this comparison, the tracing results of the tendon boundaries of an automatic identification (AI) process, already established with the detection of intima-media thickness, are compared with computer-assisted MT.The detection of the tendon boundaries was performed in 115 ultrasound images including the cranial border of the calcaneal tuberosity. The measured section (starting point 4 cm away from the anterior boundary of the calcaneal tuberosity) amounted to 3 cm, and was divided into three sub-segments (1 cm each). Intra- and inter-reader/observer variability for mean and maximum Achilles tendon thickness (ATT) with AI and MT were evaluated. A normal group and a group with clinically diagnosed chronic tendon degeneration had mean and maximum ATT readings compared.Using MT, the intra- and inter-reader variability was 3.0% and 6.8%, respectively, using AI the variability was 1.6% and 3.9%, respectively. Mean and maximum ATT were measured systematically lower by AI compared to MT in all regions by 0.4 mm. The AI procedure was most accurate in the second segment. The mean ATT and maximum ATT were correctly detected in 93.9% and 96.6% of the images.The AI procedure detected the ATT with a high level of precision in all three segments. The most robust measurement was reached in the second segment. It eliminates most of the inter-/intra-reader variability in ATT measurement using MT. We suggest this new method could be a new gold standard for quantification of chronic disorder in Achilles tendons.