tbuckley/cabot-search huggingface dataset:
Molecular Characterization of Pediatric Gastrointestinal Stromal Tumors
Authors: Narasimhan P. Agaram, Michael P. Laquaglia, Berrin Ustun, Tianhua Guo, Grace C. Wong, Nicholas D. Socci, Robert G. Maki, Ronald P. DeMatteo, Peter Besmer, Cristina R. Antonescu
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Pediatric gastrointestinal stromal tumors (GIST) are rare and occur preferentially in females as multifocal gastric tumors, typically lacking mutations in KIT and PDGFRA. As KIT oncoprotein is consistently overexpressed in pediatric GIST, we sought to investigate the activation of KIT downstream targets and alterations of KIT/PDGFRA gene copy number, mine novel therapeutic targets by gene expression, and test tyrosine kinase receptor activation by proteomic profiling. Experimental Design: Seventeen pediatric GISTs were investigated for KIT/PDGFRA genotype and biochemical activation of KIT downstream targets. The transcriptional profile of 13 nodules from 8 pediatric patients was compared with 8 adult wild-type (WT) GISTs, including 3 young adults. The drug sensitivity of second-generation kinase inhibitors was tested in murine Ba/F3 cells expressing human WT KIT, as well as in short-term culture of explants of WT GIST cells. Results: A KIT/PDGFRA WT genotype was identified in all 12 female patients, whereas two of five males had either a KIT exon 11 or PDGFRA exon 18 mutation. KIT downstream targets were consistently activated. Pediatric GISTs showed a distinct transcriptional signature, with overexpression of BAALC, PLAG1, IGF1R, FGF4, and NELL1. In vitro studies showed that nilotinib, sunitinib, dasatinib, and sorafenib are more effective than imatinib against WT KIT. Conclusions: Rare cases of pediatric GIST may occur in male patients and harbor activating KIT/PDGFRA mutations. Pediatric GISTs show distinct transcriptional signature, suggesting a different biology than WT GIST in adults. In vitro drug screening showed that second-generation kinase inhibitors may provide greater clinical benefit in pediatric GIST.
Distal renal tubular acidosis in mice that lack the forkhead transcription factor Foxi1
Authors: Sandra Rodrigo Blomqvist, Hilmar Vidarsson, Sharyn Fitzgerald, Bengt R. Johansson, Anna Ollerstam, Russell Brown, A. Erik G. Persson, Göran Bergström, Sven Enerbäck
Journal: Journal of Clinical Investigation (2004)

While macro- and microscopic kidney development appear to proceed normally in mice that lack Foxi1, electron microscopy reveals an altered ultrastructure of cells lining the distal nephron. Northern blot analyses, cRNA in situ hybridizations, and immunohistochemistry demonstrate a complete loss of expression of several anion transporters, proton pumps, and anion exchange proteins expressed by intercalated cells of the collecting ducts, many of which have been implicated in hereditary forms of distal renal tubular acidosis (dRTA). In Foxi1-null mutants the normal epithelium with its two major cell types — principal and intercalated cells — has been replaced by a single cell type positive for both principal and intercalated cell markers. To test the functional consequences of these alterations, Foxi1–/– mice were compared with WT littermates in their response to an acidic load. This revealed an inability to acidify the urine as well as a lowered systemic buffer capacity and overt acidosis in null mutants. Thus, Foxi1–/– mice seem to develop dRTA due to altered cellular composition of the distal nephron epithelium, thereby denying this epithelium the proper gene expression pattern needed for maintaining adequate acid-base homeostasis.
Syndecan-4 Clustering Induces Cell Migration in a PDZ-Dependent Manner
Authors: Eugene Tkachenko, Arye Elfenbein, Daniela Tirziu, Michael Simons
Journal: Circulation Research (2006)

Cell migration is a dynamic process involving formation of a leading edge in the direction of migration and adhesion points from which tension is generated to move the cell body forward. At the same time, disassembly of adhesion points occurs at the back of the cell, a region known as the trailing edge. Syndecan-4 (S4) is a transmembrane proteoglycan thought to be involved in the formation of focal adhesions. Recent studies have shown that its cytoplasmic domain can engage in signal transduction, making S4 a bona fide receptor. Here, we show that ligand clustering of cell surface S4 on endothelial cells initiates a signaling cascade that results in activation of Rac1, induction of cell polarization, and stimulation of cell migration that depends on S4 interaction with its PDZ-binding partner. Expression of an S4 mutant lacking its PDZ-binding region (S4-PDZ − ) leads to decreased cell motility and a failure to form a trailing edge. On clustering S4, but not S4-PDZ − , targets activated Rac1 to the leading edge of live cells. Cells lacking synectin, a PDZ domain containing protein that interacts with S4, fail to migrate in response to S4 clustering. Both S4-PDZ − –expressing and synectin −/− endothelial cells exhibit elevated basal levels of Rac1. Thus, our data suggest that S4 promotes endothelial cell migration in response to ligand binding by activating Rac1 and localizing it to the leading edge, and that these processes are dependent on its PDZ-binding domain interaction with synectin.
Comparison of Weighted Performance Measurement and Dichotomous Thresholds for Glycemic Control in the Veterans Health Administration
Authors: Leonard M. Pogach, Mangala Rajan, David C. Aron
Journal: Diabetes Care (2006)

OBJECTIVE—Quality measures of glycemic control using threshold values do not assess incremental quality improvement. We compared health care system performance using weighted continuous versus dichotomous measures for glycemic control. RESEARCH DESIGN AND METHODS—We performed retrospective cross-sectional analysis of chart abstraction data on 37,142 diabetic patients from 141 Veterans Health Administration medical centers in 2000–2001. RESULTS—Subjects per facility ranged from 163 to 740 (mean 263). Mean overall HbA1c (A1C) was 7.58%. A continuous measure for glycemic control was calculated based on percentage of maximal quality-adjusted life-years saved (QALYsS). Overall mean facility performance using the dichotomous measure was 62% &amp;lt;8% A1C (range 48–75%) and 39% &amp;lt;7% A1C (21–57%), in comparison with 45% maximal QALYsS (31–60%). Correlation between QALYsS and A1C thresholds of &amp;lt;8 (0.848) and &amp;lt;7 (0.838) for facility rankings was excellent; correlation between facility level performance using thresholds of &amp;lt;8 and 7% was poor (r = 0.13, P = 0.14). Comparison of facility rankings between the &amp;lt;7% dichotomous measure and the QALYsS-weighted measure showed that 22% changed their ranking by ≥2 deciles with marked changes in top and bottom deciles. CONCLUSIONS—Facility rankings vary by threshold or continuous methodology. However, because significant numbers of individuals are unable to reach “optimal” target goals (thresholds) even in clinical trials with extensive exclusion criteria, we propose that a continuous measure assessing improvement toward optimal A1C, rather than a pass/fail optimal target, is both a fairer assessment clinical practice and a more accurate reflection of population health improvement.
Dissemination and evaluation of the 3E initiative recommendations for use of methotrexate in rheumatic disorders: results of a study among 2233 rheumatologists
Authors: L. Gossec, J. W. J. Bijlsma, C. Bombardier, H. Canhao, J. Devlin, C. J. Edwards, V. Hamuryudan, T. K. Kvien, B. F. Leeb, E. M. Martin-Mola, H. Mielants, U. Muller-Ladner, M. Ostergaard, I. A. Pereira, C. Ramos-Remus, J. Zochling, M. Dougados
Journal: Annals of the Rheumatic Diseases (2010)

Ten recommendations for the use of methotrexate were recently developed, based on published data and expert opinion in the 3E initiative1 (table 1). Clinical guidelines may induce small improvements both in processes and in the outcomes of care.2 However, if recommendations are to have effect, it is necessary after they have been published to facilitate their dissemination.3 In order to improve the implementation of these recommendations in daily practice, an initiative was performed in 2008 according to published methodology4 which aimed …
Assessing the standard and accuracy of chest x-ray reporting by medical physicians in an acute medical take
Authors: Imran Satia, Razwana Ahmed, Fawad Zaman, Stuart Mellor
Journal: European Respiratory Journal (2012)

Introduction: The reporting of CXRs for medical patients admitted to hospital vary across Europe. Comparison between physicians and radiology reporting has suggested radiologists provide improved quality (1) and accuracy (2) of reporting. In our trust the radiologist report on all the admission CXRs but this may not be available at the time of physician review.  Aim: To assess if disagreement in reporting between general physicians and a radiologist would have an impact on the medical management of a patient.  Method: We retrospectively compared the reporting of 50 CXRs by the medical physician with that of a radiologist.  Results: The overall concordance of reporting was 78%. There were 21/50 normal CXRs of which the physician correctly reported 20/21 (95%) as normal. The remaining were either acutely abnormal (14/50, 28%) or had chronic abnormal changes (15/50, 30%). Only 6/14 (43%) acutely abnormal CXRs were reported correctly and 11/15 (73%) reported on chronic changes by the physician.  Conclusion: Correctly identifying an acute diagnosis was less than 50%, particularly differentiating between pneumonia and heart failure, yet many trusts require the physician to report on CXRs. Undergraduate and post-graduate training in internal medicine does not formally train or examine in radiology and given these findings more training and service development needs addressing for patient safety.  References:  1. Weiner SN. Radiology by nonradiologists: is report documentation adequate?Am J Manag Care. 2005 Dec; 11(12)  2. Zohair Al Aseri. Accuracy of chest radiograph interpretation by emergency physicians. Emergency Radiology, 2009; 16(2).
Pulmonary Congestion Predicts Cardiac Events and Mortality in ESRD
Authors: Carmine Zoccali, Claudia Torino, Rocco Tripepi, Giovanni Tripepi, Graziella D’Arrigo, Maurizio Postorino, Luna Gargani, Rosa Sicari, Eugenio Picano, Francesca Mallamaci
Journal: Journal of the American Society of Nephrology (2013)

Pulmonary congestion is highly prevalent and often asymptomatic among patients with ESRD treated with hemodialysis, but whether its presence predicts clinical outcomes is unknown. Here, we tested the prognostic value of extravascular lung water measured by a simple, well validated ultrasound B-lines score (BL-US) in a multicenter study that enrolled 392 hemodialysis patients. We detected moderate-to-severe lung congestion in 45% and very severe congestion in 14% of the patients. Among those patients with moderate-to-severe lung congestion, 71% were asymptomatic or presented slight symptoms of heart failure. Compared with those patients having mild or no congestion, patients with very severe congestion had a 4.2-fold risk of death (HR=4.20, 95% CI=2.45–7.23) and a 3.2-fold risk of cardiac events (HR=3.20, 95% CI=1.75–5.88) adjusted for NYHA class and other risk factors. Including the degree of pulmonary congestion in the model significantly improved the risk reclassification for cardiac events by 10% (P<0.015). In summary, lung ultrasound can detect asymptomatic pulmonary congestion in hemodialysis patients, and the resulting BL-US score is a strong, independent predictor of death and cardiac events in this population.
FALSE POSITIVE FINDINGS IN 320 SLICE CARDIAC CT FOR THE DETECTION OF SEVERE CORONARY STENOSIS INDICATE POOR PROGNOSIS FOR THE OCCURRENCE OF MAJOR ADVERSE CARDIOVASCULAR EVENTS
Authors: Hiroyuki Takaoka, Nobusada Funabashi, Masae Uehara, Koya Ozawa, Yoshihide Fujimoto, Yoshio Kobayashi
Journal: Journal of the American College of Cardiology (2014)
Anaemia in rheumatoid arthritis: the role of iron, vitamin B12, and folic acid deficiency, and erythropoietin responsiveness.
Authors: G Vreugdenhil, A W Wognum, H G van Eijk, A J Swaak
Journal: Annals of the Rheumatic Diseases (1990)

Thirty six patients with rheumatoid arthritis (RA) (25 with anaemia) were studied to establish the role of iron, vitamin B12, and folic acid deficiency, erythropoietin responsiveness, and iron absorption in the diagnosis and pathogenesis of anaemia in RA. Iron deficiency, assessed by stainable bone marrow iron content, occurred in 13/25 (52%), vitamin B12 deficiency in 7/24 (29%), and folic acid deficiency in 5/24 (21%) of the anaemic patients. Only 8/25 (32%) had just one type of anaemia. The iron deficiency of anaemia of chronic disease (ACD) was distinguished by ferritin concentration, which was higher in that group. Mean cell volume (MCV) and mean cell haemoglobin (MCH) were lower in both anaemic groups, but most pronounced in iron deficient patients. Folic acid, and especially vitamin B12 deficiency, masked iron deficiency by increasing the MCV and MCH. Iron absorption tended to be highest in iron deficiency and lowest in ACD, suggesting that decreased iron absorption is not a cause of ACD in RA. No specific causes were found for vitamin B12 or folic acid deficiency. Haemoglobin concentration was negatively correlated with erythrocyte sedimentation rate in the group with ACD. Erythropoietin response was lower in ACD than in iron deficient patients. It was concluded that generally more than one type of anaemia is present simultaneously in anaemic patients with RA. The diagnosis of each type may be masked by another. Studies on pathogenesis of the anaemia are difficult as deficiencies generally coexist with ACD. Disease activity and, possibly, erythropoietin responsiveness are major factors in ACD pathogenesis.
STUDIES WITH THE ELECTROCARDIOGRAPH ON THE ACTION OF THE VAGUS NERVE ON THE HUMAN HEART
Authors: G. Canby Robinson, George Draper
Journal: The Journal of Experimental Medicine (1911)

In hearts showing auricular fibrillation mechanical stimulation of the right vagus nerve causes, as a rule, marked slowing or stoppage of ventricular rhythm, without producing any appreciable effect in the electrocardiographic record of the auricular fibrillation. The ventricular pauses are apparently due to the blocking of stimuli from the auricles. The force of ventricular systole is distinctly weakened for several beats after vagus stimulation, and ectopic ventricular systoles have been seen in several instances, apparently the result of the vagus action. There may, in some cases, be lowered excitability of the ventricles, while no constant change is seen in the size of the electrical complexes representing ventricular systole.
A Dynamic Inflammatory Cytokine Network in the Human Ovarian Cancer Microenvironment
Authors: Hagen Kulbe, Probir Chakravarty, D. Andrew Leinster, Kellie A. Charles, Joseph Kwong, Richard G. Thompson, Jermaine I. Coward, Tiziana Schioppa, Stephen C. Robinson, William M. Gallagher, Laura Galletta, Michael A. Salako, John F. Smyth, Thorsten Hagemann, Donal J. Brennan, David D. Bowtell, Frances R. Balkwill
Journal: Cancer Research (2011)

Constitutive production of inflammatory cytokines is a characteristic of many human malignant cell lines; however, the in vitro and in vivo interdependence of these cytokines, and their significance to the human cancer microenvironment, are both poorly understood. Here, we describe for the first time how three key cytokine/chemokine mediators of cancer-related inflammation, TNF, CXCL12, and interleukin 6, are involved in an autocrine cytokine network, the "TNF network," in human ovarian cancer. We show that this network has paracrine actions on angiogenesis, infiltration of myeloid cells, and NOTCH signaling in both murine xenografts and human ovarian tumor biopsies. Neutralizing antibodies or siRNA to individual members of this TNF network reduced angiogenesis, myeloid cell infiltration, and experimental peritoneal ovarian tumor growth. The dependency of network genes on TNF was shown by their downregulation in tumor cells from patients with advanced ovarian cancer following the infusion of anti-TNF antibodies. Together, the findings define a network of inflammatory cytokine interactions that are crucial to tumor growth and validate this network as a key therapeutic target in ovarian cancer.
The Pathogenesis of Chronic Lymphocytic Leukemia
Authors: Suping Zhang, Thomas J. Kipps
Journal: Annual Review of Pathology Mechanisms of Disease (2013)

Chronic lymphocytic leukemia (CLL) is characterized by the clonal expansion of CD5 + CD23 + B cells in blood, marrow, and second lymphoid tissues. Gene-expression profiling and phenotypic studies suggest that CLL is probably derived from CD5 + B cells similar to those found in the blood of healthy adults. Next-generation sequencing has revealed recurrent genetic lesions that are implicated in CLL pathogenesis and/or disease progression. The biology of CLL is entwined with its microenvironment, in which accessory cells can promote leukemia cell growth and/or survival. Recently, much attention has been focused on the CLL B cell receptor (BCR) and on chemokine receptors that enable CLL cells to home to lymphoid tissues and to establish the leukemia microenvironment. Agents that can interfere with BCR signaling or chemokine–receptor signaling, or that target surface antigens selectively expressed on CLL cells, promise to have significant therapeutic benefit in patients with this disease.
Bacteraemia following orotracheal intubation and oesophageal balloon dilatation.
Authors: C P Hansen, H Westh, K E Brok, R Jensen, S Bertelsen
Journal: Thorax (1989)

Asymptomatic bacteraemia following balloon dilatation was assessed in 20 adults with oesophageal stricture. Asymptomatic bacteraemia occurred in 12 of 19 patients. The source of the bacteraemia appeared to be the patients9 oropharyngeal flora. The bacteraemia was not of clinical importance in our patients, but might lead to endocarditis in predisposed individuals.
Children's Concepts of Research Hospitalization
Authors: A. Herbert Schwartz
Journal: New England Journal of Medicine (1972)

Abstract Current concern for legal and ethical aspects of informed consent in children prompted this study of 50 hospitalizations of 36 children, four to 17 years of age, to determine their concepts of the research nature of their hospitalization. In spite of careful preparation, none of the 17 children under and only six of the 19 over the age of 11 showed awareness during admission that their hospitalization had anything to do with research. Five of the six who showed some awareness of research presented symptoms of overwhelming anxiety. This study suggests that even after careful preparation the child subject most often is not aware of the research nature of his hospitalization. It further suggests that only after 11 years of age may a child be aware of being a research subject and that such an awareness may result in overwhelming anxiety.
Benefits and risks of combination therapy for hepatitis B
Authors: Norah A. Terrault
Journal: Hepatology (2009)

In successful antiviral therapy of hepatitis B, drug combinations, particularly combinations without cross-resistance, can delay or prevent the emergence of drug-resistant mutants. Because drug-resistant mutants are archived and may limit future therapeutic options, prevention is important for long-term therapeutic efficacy. Additionally, combining drugs may achieve synergistic or additive antiviral effects compared with single drug therapy. Undesirable aspects of combination therapy include higher treatment costs and possibly lower adherence rates (due to pill number or complexity of regimen). Potentially harmful effects of combination therapy include higher rates of side effects, reduced efficacy due to drug competition, and the risk of multidrug-resistant hepatitis B virus (HBV) if combination therapy is insufficient to prevent resistance. Combination therapy has been shown to reduce the rate of drug resistance in chronic hepatitis B, but only when drugs with a low barrier to resistance are used (lamivudine, adefovir). Combination therapies may achieve greater degrees of HBV DNA suppression, but this has not been associated with higher rates of seroconversion (hepatitis B e antigen or hepatitis B surface antigen) compared to single drug therapy. The benefit of combination therapy has yet to be demonstrated with agents that are associated with a high barrier to resistance (tenofovir, entecavir). The use of combination therapy is recommended in specific patient groups: those with decompensated cirrhosis, those coinfected with human immunodeficiency virus and HBV who are on antiretroviral therapy, those who have undergone liver transplantation, and those with drug-resistant HBV infection. There is insufficient evidence to recommend combination therapy as first-line therapy for all patients with chronic hepatitis B.
Construction and validation of a photographic guide for assessing severity of chronic hand dermatitis
Authors: P.J. Coenraads, H. Van Der Walle, K. Thestrup-Pedersen, T. Ruzicka, B. Dreno, C. De La Loge, M. Viala, S. Querner, T. Brown, M. Zultak
Journal: British Journal of Dermatology (2005)

A standardized instrument is needed to rate the overall severity of chronic hand dermatitis (CHD), in particular during clinical trials.To design and validate a photographic guide.Initially, five experts were asked to grade 50 photographs of CHD, first individually, then as a consensus-building group, in order to select the photographs included in the guide. Then, a validation session with 11 different dermatologists evaluating 28 patients was conducted to assess the interrater reliability and test-retest reproducibility of the assessment of disease severity, relying on the photographic guide, on two consecutive days. Patient order was randomized, and only diseased hands were visible to prevent any bias in evaluation.The experts reached a consensus for development of a photographic guide composed of five severity levels and four photographs per severity level. Results of the validation session showed a high level of interrater reliability and test-retest reproducibility.The photographic guide is a reliable tool for assessing the morphological severity of hand dermatitis, and can be used as part of a comprehensive evaluation of disease in international multicentre clinical trials.