tbuckley/cabot-search huggingface dataset:
Randomized, Double-Blind, Placebo-Controlled Trial of Erythropoietin in Non–Small-Cell Lung Cancer With Disease-Related Anemia
Authors: James R. Wright, Yee C. Ung, Jim A. Julian, Kathleen I. Pritchard, Timothy J. Whelan, Column Smith, Barbara Szechtman, Wilson Roa, Liam Mulroy, Leona Rudinskas, Bruno Gagnon, Gord S. Okawara, Mark N. Levine
Journal: Journal of Clinical Oncology (2007)

Previous trials have suggested a quality-of-life (QOL) improvement for anemic cancer patients treated with erythropoietin, but few used QOL as the primary outcome. We designed a trial to investigate the effects of epoetin alfa therapy on the QOL of anemic patients with advanced non-small-cell carcinoma of the lung (NSCLC).A multicenter, randomized, double-blind, placebo-controlled trial was conducted. The proposed sample size was 300 patients. Eligible patients were required to have NSCLC unsuitable for curative therapy and baseline hemoglobin (Hgb) levels less than 121 g/L. Patients were assigned to 12 weekly injections of subcutaneous epoetin alpha or placebo, targeting Hgb levels between 120 and 140 g/L. The primary outcome was the difference in the change in Functional Assessment of Cancer Therapy-Anemia scores between baseline and 12 weeks.Reports of thrombotic events in other epoetin trials prompted an unplanned safety analysis after 70 patients had been randomly assigned (33 to the active arm and 37 to the placebo arm). This revealed a significant difference in the median survival in favor of the patients on the placebo arm of the trial (63 v 129 days; hazard ratio, 1.84; P = .04). The Steering Committee closed the trial. Patient numbers compromised the interpretation of the QOL analysis, but a positive Hgb response was noted with epoetin alfa treatment.An unplanned safety analysis suggested decreased overall survival in patients with advanced NSCLC treated with epoetin alfa. Although infrequent, other similar reports highlight the need for ongoing trials evaluating erythropoietin receptor agonists to ensure that overall survival is monitored closely.
TLR9 Agonists Oppositely Modulate DNA Repair Genes in Tumor versus Immune Cells and Enhance Chemotherapy Effects
Authors: Michele Sommariva, Loris De Cecco, Michelandrea De Cesare, Lucia Sfondrini, Sylvie Ménard, Cecilia Melani, Domenico Delia, Nadia Zaffaroni, Graziella Pratesi, Valentina Uva, Elda Tagliabue, Andrea Balsari
Journal: Cancer Research (2011)

Synthetic oligodeoxynucleotides expressing CpG motifs (CpG-ODN) are a Toll-like receptor 9 (TLR9) agonist that can enhance the antitumor activity of DNA-damaging chemotherapy and radiation therapy in preclinical mouse models. We hypothesized that the success of these combinations is related to the ability of CpG-ODN to modulate genes involved in DNA repair. We conducted an in silico analysis of genes implicated in DNA repair in data sets obtained from murine colon carcinoma cells in mice injected intratumorally with CpG-ODN and from splenocytes in mice treated intraperitoneally with CpG-ODN. CpG-ODN treatment caused downregulation of DNA repair genes in tumors. Microarray analyses of human IGROV-1 ovarian carcinoma xenografts in mice treated intraperitoneally with CpG-ODN confirmed in silico findings. When combined with the DNA-damaging drug cisplatin, CpG-ODN significantly increased the life span of mice compared with individual treatments. In contrast, CpG-ODN led to an upregulation of genes involved in DNA repair in immune cells. Cisplatin-treated patients with ovarian carcinoma as well as anthracycline-treated patients with breast cancer who are classified as "CpG-like" for the level of expression of CpG-ODN modulated DNA repair genes have a better outcome than patients classified as "CpG-untreated-like," indicating the relevance of these genes in the tumor cell response to DNA-damaging drugs. Taken together, the findings provide evidence that the tumor microenvironment can sensitize cancer cells to DNA-damaging chemotherapy, thereby expanding the benefits of CpG-ODN therapy beyond induction of a strong immune response.
Mouse models for the study of HCV infection and virus–host interactions
Authors: Heidi Barth, Eric Robinet, T. Jake Liang, Thomas F. Baumert
Journal: Journal of Hepatology (2008)

Hepatitis C virus (HCV) is a major cause of chronic liver disease including steatosis, cirrhosis and hepatocellular carcinoma. The development of transgenic mice expressing HCV proteins and the successful repopulation of SCID/Alb-uPA mice with human hepatocytes provides an important tool for unraveling virus-host interactions in vivo. Several of these mouse models exhibit aspects of HCV-related liver disease. Thus, these in vivo models play an important role to further understand the pathogenesis of HCV infection and to evaluate the pre-clinical safety and efficacy of new antiviral compounds against HCV. This review summarizes the most important mouse models currently used to study HCV pathogenesis and infection. Finally, the perspective of these models for future HCV research as well as the design of novel small animal models is discussed.
Induction of autoantibodies to the adrenal cortex and pancreatic islet cells by interferon alpha therapy for chronic hepatitis C
Authors: B Wesche
Journal: Gut (2001)

<h3>BACKGROUND/AIMS</h3> Interferon alpha (IFN-α) therapy for chronic hepatitis C may trigger induction of autoimmunity against several organs. Immune reactions against distinct adrenocortical protein antigens involved in adrenal autoimmune disease have not been reported to date. Therefore, we investigated the development of highly sensitive and specific adrenal autoantibodies in patients with chronic hepatitis C in response to IFN-α treatment. In addition, we studied induction of pancreatic islet and thyroid autoantibodies. <h3>PATIENTS/METHODS</h3> Sera of 75 patients (42 males, 33 females; mean age 47 (13) years) were analysed before, during, and after IFN-α therapy (9–18×10<sup>6</sup> IE/week; mean duration 8.3 (3.5) months). Autoantibodies (Abs) to adrenal 21-hydroxylase (21OH-Abs), and to islet glutamic acid decarboxylase (GAD65-Abs) and protein tyrosine phosphatase (IA2-Abs) were determined by a radiobinding assay using<sup>35</sup>S labelled protein generated by an in vitro translation system. Thyroid antibodies were measured by a commercially available ELISA. <h3>RESULTS</h3> Thirteen of 75 patients were initially positive for some of the autoantibodies. During or after IFN-α therapy, 3/62 initially negative patients (4.8%) developed 21OH-Abs. GAD65-Abs or IA2-Abs appeared in 5/62 and 1/62 patients, respectively (9.7% in total). In 12/62 patients (19.4%), thyroid specific antibodies appeared. In none of the 21OH-Ab positive subjects was adrenal dysfunction observed, and no patient with islet autoantibodies developed diabetes mellitus or impaired glucose tolerance. <h3>CONCLUSIONS</h3> IFN-α induces 21OH-Abs in some cases, while islet and thyroid specific autoantibodies are more frequently found. However, our results indicate for the first time that the adrenal cortex also has to be considered as a potential target of IFN-α related autoimmunity.
Ductal Carcinoma In Situ, Complexities and Challenges
Authors: G. D. Leonard, S. M. Swain
Journal: JNCI Journal of the National Cancer Institute (2004)

The incidence of ductal carcinoma in situ (DCIS), a noninvasive form of breast cancer, has increased markedly in recent decades, and DCIS now accounts for approximately 20% of breast cancers diagnosed by mammography. Laboratory and patient data suggest that DCIS is a precursor lesion for invasive cancer. The appropriate classification of DCIS has provoked much debate; a number of classification systems have been developed, but there is a lack of uniformity in the diagnosis and prognostication of this disease. Further investigation of molecular markers should improve the classification of DCIS and our understanding of its relationship to invasive disease. Controversy also exists with regard to the optimal management of DCIS patients. In the past, mastectomy was the primary treatment for patients with DCIS, but as with invasive cancer, breast-conserving surgery has become the standard approach. Three randomized trials have reported a statistically significant decrease in the risk of recurrence with radiation therapy in combination with lumpectomy compared with lumpectomy alone, but there was no survival advantage with the addition of radiotherapy. Two randomized trials have suggested an additional benefit, in terms of recurrence, with the addition of adjuvant tamoxifen therapy, although in one trial the benefit was not statistically significant. Current data suggest that tamoxifen use should be restricted to patients with estrogen receptor–positive DCIS. Neither trial demonstrated a survival benefit with adjuvant tamoxifen. Ongoing and recently completed studies should provide information on outcomes in patients treated with lumpectomy alone and on the effectiveness of aromatase inhibitors as an alternative to tamoxifen.
Activation-Induced Inhibition of Interleukin 6–Mediated T Cell Survival and Signal Transducer and Activator of Transcription 1 Signaling
Authors: T. Kent Teague, Brian C. Schaefer, David Hildeman, Jeremy Bender, Tom Mitchell, John W. Kappler, Philippa Marrack
Journal: The Journal of Experimental Medicine (2000)

The cytokines interleukin (IL)-2, IL-4, IL-6, IL-7, and IL-15 have all previously been shown to inhibit resting T cell death in vitro. We have found a difference in the response of T cells to IL-6, depending on the activation status of the cells. IL-6 inhibited the death of naive T cells, but had no effect on the death of either superantigen-activated T cells, or T cells bearing memory markers. This was true even when the resting and activated T cells were isolated from the same animal; thus, the determining factor for IL-6 insensitivity was the activation status or activation history of the cell, and not the milieu in the animal from which the cells were isolated. Activated T cells expressed lower levels of IL-6 receptors on their surfaces, yet there were sufficient levels of receptors for signaling, as we observed similar levels of signal transducer and activator of transcription (Stat)3 phosphorylation in resting and activated T cells treated with IL-6. However, there was profound inhibition of IL-6–induced Stat1 phosphorylation in activated T cells compared with resting T cells. These data suggest that there is activation-induced inhibition of IL-6 receptor signaling in T cells. This inhibition appears to be specific for some but not all of the IL-6–mediated signaling cascades in these cells.
Tissue Factor Pathway Inhibitor and Other Endothelium-Dependent Hemostatic Factors in Elderly Individuals With Normal or Impaired Glucose Tolerance and Type 2 Diabetes
Authors: Paul B. Leurs, Ronald P. Stolk, Karly Hamulyak, René van Oerle, Diederick E. Grobbee, Bruce H. R. Wolffenbuttel
Journal: Diabetes Care (2002)

Impaired glucose tolerance (IGT) is believed to be a prediabetic phase that precedes the development of type 2 diabetes. In elderly subjects, IGT and diabetes are both independently associated with the occurrence of cardiovascular disease. Endothelial damage precedes atherosclerotic changes of the vascular wall. Therefore, several markers of endothelial dysfunction were examined in elderly subjects with IGT and elderly patients with type 2 diabetes.Von Willebrand factor (vWF), tissue plasminogen activator (t-PA), plasminogen activator inhibitor type-1 (PAI-1), and thrombomodulin were studied as markers of endothelial dysfunction in a population-based study of elderly subjects with normal glucose tolerance (NGT) or IGT and type 2 diabetes. In addition to these endothelium-dependent factors, we also investigated tissue factor pathway inhibitor (TFPI) activity in relation to metabolic parameters and cardiovascular risk factors.All data were adjusted for age. Increased levels of vWF antigen, t-PA antigen, and PAI-1 activity were seen in the IGT and diabetic group compared with the NGT group. TFPI activity and thrombomodulin levels were increased in all elderly subjects, and no differences were seen between the groups. There was a positive association between HbA(1c) and TFPI activity and vWF antigen. Fasting blood glucose levels correlated with vWF antigen, t-PA antigen, and PAI-1 activity, whereas urine albumin excretion correlated with TFPI activity, vWF antigen, and PAI-1 activity. Serum insulin levels correlated strongly not only with vWF antigen and t-PA antigen but also with PAI-1 activity. This correlation did not change after further adjustment for serum glucose and HbA(1c), which may suggest that in the elderly subjects, impaired fibrinolysis is probably associated with insulin resistance. There were no associations between the endothelium-dependent hemostatic factors and lipids, except for a negative correlation between HDL cholesterol and thrombomodulin.In elderly subjects with IGT, several endothelium-dependent hemostatic factors are already consistently increased, indicating endothelial damage in this stage.
Comparison of the Accuracies of Several Phylogenetic Methods Using Protein and DNA Sequences
Authors: Barry G. Hall
Journal: Molecular Biology and Evolution (2004)

A biologically realistic method was used to simulate evolutionary trees. The method uses a real DNA coding sequence as the starting point, simulates mutation according to the mutational spectrum of Escherichia coli—including base substitutions, insertions, and deletions—and separates the processes of mutation and selection. Trees of 8, 16, 32, and 64 taxa were simulated with average branch lengths of 50, 100, 150, 200, and 250 changes per branch. The resulting sequences were aligned with ClustalX, and trees were estimated by Neighbor Joining, Parsimony, Maximum Likelihood, and Bayesian methods from both DNA sequences and the corresponding protein sequences. The estimated trees were compared with the true trees, and both topological and branch length accuracies were scored. Over the variety of conditions tested, Bayesian trees estimated from DNA sequences that had been aligned according to the alignment of the corresponding protein sequences were the most accurate, followed by Maximum Likelihood trees estimated from DNA sequences and Parsimony trees estimated from protein sequences.
Diagnostic and clinical value of anti-cyclic citrullinated peptide antibodies compared with rheumatoid factor isotypes in rheumatoid arthritis
Authors: I Vallbracht, J Rieber, M Oppermann, F Förger, U Siebert, Knut Helmke
Journal: Annals of the Rheumatic Diseases (2004)

To assess the additional diagnostic and clinical value of the second test generation of anti-cyclic citrullinated peptide antibodies (CCP2) compared with rheumatoid factor isotypes (IgG-RF, IgA-RF, IgM-RF) in patients with rheumatoid arthritis.This was a prospective study on 715 patients: rheumatoid arthritis (n = 295), degenerative or other inflammatory joint disease (n = 163), connective tissue disease or vasculitis (n = 103), and healthy controls (n = 154). Sera from each subject were tested for CCP2 and RF isotypes by enzyme linked immunosorbent assay (ELISA). Agreement with clinical indices such as disease activity, joint destruction, disease duration, and other laboratory tests was assessed. Sensitivity and specificity of the tests were evaluated taking the clinical diagnosis as the gold standard.Highest sensitivity was found for IgM-RF (66.4%) and CCP (64.4%). Highest specificity was achieved by CCP (97.1%) and IgG-RF (91.0%). In rheumatoid patients with high disease activity or severe joint damage, CCP was more often present (81.4% and 83.6%) than all RF isotypes. Of special diagnostic value was the detection of positive CCP in 34.5% of all patients with rheumatoid arthritis when all measured RF isotypes (IgG-RF, IgA-RF, and IgM-RF) were negative.As a screening method for rheumatoid arthritis the IgM-RF and the CCP assays are superior to other RF isotypes. Positivity in the highly specific CCP ELISA supports the diagnosis of rheumatoid arthritis. CCP proved to be a powerful diagnostic tool, especially in ambiguous cases or RF negative patients with rheumatoid arthritis.
Preoperative Pulmonary Risk Stratification for Noncardiothoracic Surgery: Systematic Review for the American College of Physicians
Authors: Gerald W. Smetana, Valerie A. Lawrence, John E. Cornell
Journal: Annals of Internal Medicine (2006)

Background: The importance of clinical risk factors for postoperative pulmonary complications and the value of preoperative testing to stratify risk are the subject of debate. Purpose: To systematically review the literature on preoperative pulmonary risk stratification before noncardiothoracic surgery. Data Sources: MEDLINE search from 1 January 1980 through 30 June 2005 and hand search of the bibliographies of retrieved articles. Study Selection: English-language studies that reported the effect of patient- and procedure-related risk factors and laboratory predictors on postoperative pulmonary complication rates after noncardiothoracic surgery and that met predefined inclusion criteria. Data Extraction: The authors used standardized abstraction instruments to extract data on study characteristics, hierarchy of research design, study quality, risk factors, and laboratory predictors. Data Synthesis: The authors determined random-effects pooled estimate odds ratios and, when appropriate, trim-and-fill estimates for patient- and procedure-related risk factors from studies that used multivariable analyses. They assigned summary strength of evidence scores for each factor. Good evidence supports patient-related risk factors for postoperative pulmonary complications, including advanced age, American Society of Anesthesiologists class 2 or higher, functional dependence, chronic obstructive pulmonary disease, and congestive heart failure. Good evidence supports procedure-related risk factors for postoperative pulmonary complications, including aortic aneurysm repair, nonresective thoracic surgery, abdominal surgery, neurosurgery, emergency surgery, general anesthesia, head and neck surgery, vascular surgery, and prolonged surgery. Among laboratory predictors, good evidence exists only for serum albumin level less than 30 g/L. Insufficient evidence supports preoperative spirometry as a tool to stratify risk. Limitations: For certain risk factors and laboratory predictors, the literature provides only unadjusted estimates of risk. Prescreening, variable selection algorithms, and publication bias limited reporting of risk factors among studies using multivariable analysis. Conclusions: Selected clinical and laboratory factors allow risk stratification for postoperative pulmonary complications after noncardiothoracic surgery.
Effectiveness of First‐Line Treatment With Recombinant Interleukin‐1 Receptor Antagonist in Steroid‐Naive Patients With New‐Onset Systemic Juvenile Idiopathic Arthritis: Results of a Prospective Cohort Study
Authors: Sebastiaan J. Vastert, Wilco de Jager, Bo Jan Noordman, Dirk Holzinger, Wietse Kuis, Berent J. Prakken, Nico M. Wulffraat
Journal: Arthritis & Rheumatology (2013)

Objective To conduct a prospective cohort study using anakinra, a recombinant IL‐1 receptor antagonist (IL‐1Ra), as first‐line therapy in patients with new‐onset systemic juvenile idiopathic arthritis (JIA). Methods Therapy with recombinant IL‐1Ra (2 mg/kg) was initiated in 20 patients who fulfilled the International League of Associations for Rheumatology criteria for systemic JIA, before systemic steroid treatment was administered. Patients were monitored clinically and immunologically. The protocol contained a stop strategy for patients who met at least the adapted American College of Rheumatology 90% criteria for improvement in JIA (ACR Pediatric 90 [ACR Pedi 90]) after 3 months. Results We included consecutive patients with new‐onset systemic JIA. The mean followup period was 32 months (range 12–54 months). At the 3‐month time point, 85% of the patients showed an adapted ACR Pedi 90 response or had inactive disease; 75% of the patients achieved this response while receiving recombinant IL‐1Ra alone. After 1 year, 17 of the 20 patients met the criteria for clinically inactive disease, and 13 of these patients met these criteria while receiving monotherapy with recombinant IL‐1Ra. However, because of persistent disease activity, 7 of the 20 patients required additional therapy besides recombinant IL‐1Ra. According to our stop strategy, 73% of patients with at least an adapted ACR Pedi 90 response at 3 months could stop recombinant IL‐1Ra treatment within 1 year. After 2 years, 12 (86%) of 14 patients met the criteria for disease remission, either while receiving (n = 4) or not receiving (n = 8) medication. After 3 years, 10 (91%) of 11 patients met the criteria for disease remission, either while receiving (n = 2) or not receiving (n = 8) medication. Conclusion This is the first prospective study in which recombinant IL‐1Ra was used as first‐line therapy in patients with systemic JIA. We observed excellent responses in nearly all patients within 3 months. In the majority of responding patients, treatment with recombinant IL‐1Ra could be stopped within 1 year, with remission being preserved during followup. In approximately one‐third of patients, concomitant therapy was required for maintenance of clinical response.
Changing patterns of infant death over the last 100 years: autopsy experience from a specialist children's hospital
Authors: JW Pryce, MA Weber, MT Ashworth, SEA Roberts, M Malone, NJ Sebire
Journal: Journal of the Royal Society of Medicine (2012)

Objectives Infant mortality has undergone a dramatic reduction in the UK over the past century because of improvements in public health policy and medical advances. Postmortem examinations have been performed at Great Ormond Street Hospital for over 100 years, and analysis of cases across this period has been performed to assess changing patterns of infant deaths undergoing autopsy. Design Autopsy reports from 1909 and 2009 were examined. Age, major pathology and cause of death was reviewed from these cases and entered into an anonymized database. A subsequent comparative analysis was performed. Setting All postmortems performed and reported at Great Ormond Street Hospital in 1909 and 2009. Participants Infant deaths, aged 0–365 days, were identified and subsequently analysed for the two years. Main outcome measures Comparative proportional analysis of postmortem findings from the two time periods. Results Three-hundred and fifty-seven and 347 autopsy reports were identified from 1909 and 2009 including 178 and 128 infant deaths, respectively. The commonest cause of death in 1909 was infection (74%) compared to 20% of deaths in 2009. The most frequent final ‘diagnosis’ in 2009 was ‘unexplained sudden unexpected infant death (SUDI)’, despite a full postmortem including ancillary investigations. In contrast, there were no such cases recorded in 1909, but there were frequent deaths due to gastroenteritis and malnutrition together accounting for 16% of cases, compared to one case of gastroenteritis in 2009. Fifteen percent of 1909 cases had infections which are almost never fatal with appropriate treatment in 2009, including tuberculosis, diphtheria and syphilis. Congenital anomalies were detected with similar frequencies at both time points, (21% and 19% in 1909 and 2009, respectively). Conclusion In the UK, significant changes in patterns of pathology have occurred in paediatric autopsy cases performed at a single specialist centre. Fatal infections and malnutrition (both poverty-related) have reduced yet the incidence of congenital anomalies has remained similar.
96 PERFORMANCES OF FIBROSCAN® FOR DIAGNOSIS OF SIGNIFICANT FIBROSIS AND CIRRHOSIS. A PROSPECTIVE STUDY OF 1993 PATIENTS WITH CHRONIC VIRAL HEPATITIS
Authors: F. Degos, P. Perez, B. Roche, A. Mahmoudi, J. Asselineau, H. Voitot, P. Bedossa, L. Groupe Fibrostic
Journal: Journal of Hepatology (2009)