tbuckley/cabot-search huggingface dataset:
Are All Hypotheses Generated Before Data Analysis Prospective?
Authors: Walter J. Urba, W. Gregory Alvord
Journal: Journal of Clinical Oncology (2002)

Article Tools EDITORIALS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2002.20.6.1431 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 11896085 Are All Hypotheses Generated Before Data Analysis Prospective? Walter J. UrbaxWalter J. UrbaSearch for articles by this author , W. Gregory AlvordxW. Gregory AlvordSearch for articles by this author Show More Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, OR, Data Management Services, Inc, National Cancer Institute-Frederick Cancer Research and Development Center, Frederick, MD https://doi.org/10.1200/JCO.2002.20.6.1431 First Page Full Text PDF Figures and Tables © 2002 by American Society of Clinical Oncology
Phase I and pharmacologic study of the vascular disrupting agent ombrabulin (Ob) combined with docetaxel (D) in patients (pts) with advanced solid tumors.
Authors: P. Tresca, D. Tosi, L. van Doorn, H. Fontaine, A. V. Gaast, C. Veyrat-Follet, C. Oprea, V. Dieras, F. Eskens
Journal: Journal of Clinical Oncology (2010)

3023 Background: Ob is a tubulin binding vascular disrupting agent, derivative of combretastatin A4. In preclinical studies synergistic activity between Ob and D has been observed. Methods: Study objectives were to determine maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetic (PK) profile, preliminary antitumor activity, and to assess potential predictive biomarkers of the combination of Ob (day 1) followed by D (day 2) once every 3 weeks. Results: Forty-eight pts (M/F 17/31), median age 53 (range 28-71), were treated in 2 cohorts: D 75 mg/m2 with Ob 11.5, 15.5, 20, 25, 30, 35, or 42 mg/m2 and D 100 mg/m2 with Ob 30 or 35 mg/m2. Median number of cycles per pt was 3.5 (range 1-22). The most common tumor types were breast (n=18, including 6 triple negative pts) and oesophagus (n=9). First cohort MTD was 35/75 mg/m2 with 2 DLTs (grade 3 headache and asthenia) reported at 42/75 mg/m2. Second cohort MTD was 30/100 mg/m2 with grade 3 asthenia and deep vein thrombosis reported at 35/100 mg/m2. Other grade 3/4 drug related adverse events (AEs) were 2 febrile neutropenia (one complicated with fatal respiratory failure and sepsis), neutropenic infection, oesophageal fistula, fatigue, nail toxicity, thrombosis, aminotransferase increase. Main grade 3/4 hematological toxicity was neutropenia (19/48 pts). The PK profile of the drugs was similar to those found in monotherapy studies. Preliminary antitumor activity was observed: 3 partial responses (breast cancer) and 20 stable diseases (including 2 prostate cancer with biological response and 5 pts who received more than 10 cycles). First results on potential biomarkers will be provided. Conclusions: Combination of Ob with D was well tolerated, with preliminary anti-tumor activity observed. Further studies in specific tumors are planned. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis
A Solid-Phase, Enzyme-Linked Immunosorbent Assay for a Human Lung Tumor-Associated Antigen
Authors: J A Braatz, D T Hua, G L Princler
Journal: JNCI Journal of the National Cancer Institute (1984)

A solid-phase, enzyme-linked immunosorbent assay (ELISA) for a human lung tumor-associated antigen (LTA) was based on immobilized LTA that was detected with the use of an antiserum raised in a goat against a highly purified antigen preparation. Bound goat antibodies were detected in a series of steps that included incubation with a) biotinylated rabbit antibodies to goat immunoglobulins, b) glucose oxidase conjugated to avidin, and c) peroxidase and the substrates glucose and 2,2'-azino-di-(3-ethylbenzthiazoline sulfonic acid). The absorbance of the final product was measured at 405 nm, and its formation was dependent on substrate incubation time and antibody concentration. The antigen was immobilized and highly purified, and the goat antiserum was bound to and eluted from an immobilized crude antigen column before use. The ELISA could detect less than 1 ng antigen and was able to discriminate extracts of normal lung tissue from those of lung tumor. As was found earlier with a radioimmunoassay for the same antigen, normal human serum could inhibit in the ELISA but only when used at high concentration, indicating levels of antigen or antigen-like activity in the 100-200 ng/ml range. With the use of this assay, 3 lung cancer patients were monitored 6-12 months prior to death. In all 3 patients, LTA levels rose dramatically 2-4 months before the patients died; in 2 patients the levels exceeded 3,000 ng/ml just before death. In contrast, in 2 of these patients, carcinoembryonic antigen levels remained essentially unchanged, with no more than a twofold increase prior to death.
Family history and breast cancer subtype among women of Mexican descent.
Authors: Kristin Anderson, Patricia Thompson, Betsy Wertheim, Lorena Martin, Ian K. Komenaka, Melissa Bondy, Adrian Daneri-Navarro, Maria Mercedes Meza-Montenegro, Luis Enrigue Gutierrez-Millan, Abenaa M. Brewster, Lisa Madlensky, Maria Elena Martinez
Journal: Journal of Clinical Oncology (2014)

41 Background: A family history of breast cancer in a first-degree relative is associated with a 2-fold increase in breast cancer risk; however, breast cancer is a heterogeneous disease and there may be differences in risk profiles driven by tumor subtype or by racial/ethnic group. Methods: We assessed prevalence of familial breast cancer and its association with tumor subtype among 914 women with breast cancer of Mexican descent enrolled in the Ella Study, a case-only, binational (U.S.-Mexico) breast cancer study. Logistic regression was conducted to compare odds of triple negative breast cancers to non triple-negative breast cancers according to family history. Results: The prevalence of family history of breast cancer in a first- or second-degree relative was 24.1%, with 13.1% having an affected first-degree relative. Among participants who were diagnosed at age &lt; 50, prevalence of family history of breast cancer in a first- or second-degree relative was 27.4%. After adjustment for age and country of residence, women with a first-degree relative with breast cancer were significantly more likely to be diagnosed with triple-negative breast cancers compared to non triple-negative breast cancers (OR = 1.98; 95% CI, 1.26-3.11). Similar results were seen for odds of triple-negative breast cancers compared to non-triple negative breast cancers for women with affected first- or second-degree relatives (OR=2.04; 95% CI, 1.40–2.98). The odds of triple-negative breast cancer compared to non-triple negative breast cancer was 1.93 (95% CI, 1.26–2.97) for women with first-degree relatives affected with breast or ovarian cancer. Conclusions: Findings suggest that familial cancers are most likely to be associated with triple negative subtype, supporting etiologic heterogeneity by tumor subtype in this population of Hispanic women. This association may be related to the prevalence of BRCA1 founder mutations in this population, which are strongly associated with triple-negative breast cancers. Identification of such differences in risk factors can help personalize screening and prevention approaches.
Are there differences in the bronchoalveolar lavage (BAL) cytokine profile in children with and without allergic asthma
Authors: Surendran Thavagnanam, Betina Schock, Evelyn Ervine, Grace Williamson, Liam Heaney, Madeleine Ennis, Michael Shields
Journal: European Respiratory Journal (2014)

Allergic asthma involves chronic airway inflammation. Various  in vivo  systems exists to examining endogenous immunoregulatory pathways but little is known about the initiation of inflammation resulting in asthma in children.We evaluated sixty-eight children with allergic asthma (AA), thirty-two with non-atopic episodic viral induced wheezers (NW), seventy non-wheezing children with other atopy (NA), twenty-seven with non-specific problem cough (C) who had a bronchoalveolar lavage (BAL) while undergoing general anaesthesia for elective surgery. Comparisons were made with one hundred and six non-atopic non-wheezing normal children (NN). Serum immunoglobulin E (IgE) was analysed as an additional measure of atopic status to the clinical features of atopy (eczema, allergic rhinitis). There were differences in the total cell counts in the BAL fluid between the groups. The eosinophils mean AA (%):2.3 (SD=5.2) was significantly higher compared to mean NN (%):0.3 (SD=0.6, p=0.001). Interestingly, the overall mean IL-8 was increased in NW:148.6 (SD=348.9)pg/mL and NA:89.6 (SD=269)pg/mL compared to NN and AA. When analysing the BAL cytokine profile, only mean TNF-α NW: 7.1 (SD=25.2) pg/mL was increased compared to mean NN:0.4 (SD=1.6, p0.03) pg/mL. When BAL cytokine was analysed between C and NN, mean IL-12:0.16 (SD=0.2, p=0.04) pg/mL and mean IFN-γ:3.5 (SD=5.2, p
Optimising treatment of CF pulmonary exacerbation: a tough nut to crack
Authors: Sonya L Heltshe, Christopher H Goss
Journal: Thorax (2016)

Pulmonary exacerbations (PExs) are a common occurrence in cystic fibrosis (CF) and their impact real, detrimentally affecting quality of life,1 ,2 morbidity3 ,4 and mortality.5 Treatment often includes a prolonged course of intravenous aminoglycosides, beta-lactams and increased airway clearance but there is neither consensus nor standard protocol for therapeutic options in the setting of CF PEx. The United States CF Foundation conducted a systematic review and published guidelines6 ,7 for the treatment of a CF PEx; the data presented in the systematic review highlighted the paucity of evidence that guides current clinical management. Recent advances in CF chronic therapies such as inhaled antibiotics, cystic fibrosis transmembrane conductance regulator (CFTR) modulators, mucolytics and macrolides have proven to reduce the occurrence of PEx or delay the time to next exacerbation; however, very limited research8 has occurred in the area of acute management of PEx, including the development of novel therapeutics. This is due, in part, to the challenges in conducting such studies. Randomised, controlled trials of acute PEx management are mired by challenges, including variability in treatment location (home vs inpatient vs both), duration and selection of antibiotics and use of mucolytics or corticosteroids—many of which are driven by differences in physician goals or patient preferences. Conducting a trial in an environment with this constellation of variable treatment factors can be a daunting task, but without such trials, we can never improve the care of acute PEx for our patients with CF.

Dentice et al 9 report findings of a randomised, blinded, placebo controlled trial of hypertonic saline (HS) administered during a hospital admission for PEx in CF adults. HS is an osmotic agent …
Novel uses of coded data in clinical trials.
Authors: A. Daunton, D. Liu, S. I. Collins, A. Pope, D. Barton, D. Ray, N. D. James
Journal: Journal of Clinical Oncology (2010)

6143 Background: The EU Clinical Trials Directive has had an adverse impact on academic clinical research by increasing regulatory burdens that fall to staff whose primary roles are not trial related. In particular, documenting of clinical events is costly and often incomplete. One way to improve compliance whilst decreasing costs would be to use automated National Health Service (NHS) coded data. We set out to assess completeness of reporting of skeletal related events (SREs) post-progression within a clinical trial in bony metastatic prostate cancer (Trapeze, ISRCTN12808747). As these occur outside of the trials clinic environment, we examined the viability of using coded data in place of conventional case report form (CRF) collection. Methods: Hospital notes were reviewed to determine the occurrence of SREs in 86 men (median age 69; range 49-84) enrolled in Trapeze. These figures were used as our gold standard. SREs were classified into: (a) radiotherapy (RT) to treat bone metastases and (b) other (hypercalcaemia, cord compression, fracture and change of cancer therapy). SRE incidence was also determined by review of CRFs, and interrogation of the RT & NHS coding databases. These were both compared to the gold standard and with each other. Results: Sixty SREs were detected by notes review: 39/60 (65%) comprised RT to treat bone metastases, whilst 21/60 (35%) comprised others. Trial CRFs missed 36/39 (92%) RT SREs and 13/21 (62%) non-RT SREs. The departmental RT database detected 39/39 (100%) of RT SREs, whilst the NHS coding database missed 18/21 (86%) non-RT SREs. No SREs were detected by coding that did not appear in the notes review. Conclusions: In this study, post progression CRFs were highly inaccurate and trial procedures are being modified. For bone RT as an SRE, coded data matched the gold standard and could safely be substituted for standard CRF collection. For non-RT SREs both trial CRFs and NHS coded data were inaccurate in comparison with notes review. Data captured in academic trials needs to be carefully targeted to ensure maximum accuracy and minimal impact on personnel not directly associated with the study. For selected events, traditional CRFs can be reliably replaced with automated data capture from NHS databases, and this practice should be encouraged and expanded. No significant financial relationships to disclose.
Analysis of p53/BAX/p16<sup>ink4a/CDKN2</sup> in Esophageal Squamous Cell Carcinoma: High BAX and p16<sup>ink4a/CDKN2</sup> Identifies Patients With Good Prognosis
Authors: Isrid Sturm, Henrik Petrowsky, Roland Volz, Matthias Lorenz, Silke Radetzki, Timo Hillebrand, Gerhard Wolff, Steffen Hauptmann, Bernd Dörken, Peter T. Daniel
Journal: Journal of Clinical Oncology (2001)

PURPOSE: We have previously shown that loss of BAX expression is a negative prognostic factor in metastatic colorectal cancer. In the present study, we addressed the prognostic relevance of BAX and its upstream regulator p53 in squamous cell carcinoma (SCC) of the esophagus. Analysis of p16 ink4a/CDKN2 was included because p16 ink4a/CDKN2 and p53 were shown previously to cooperate during induction of cell cycle arrest and apoptosis. PATIENTS AND METHODS: Retrospective analysis of 53 patients with curative intended R0 resection of esophageal SCC was done. Protein expression of BAX, p53, and p16 ink4a/CDKN2 was investigated by immunohistochemistry. In addition, tumor DNA was screened for BAX frameshift mutations by fragment length analysis and for p53 mutations by single-strand conformation polymorphism–polymerase chain reaction. RESULTS: Overall median survival was 13.7 months. Patients with high BAX protein expression had a median survival of 19.5 months versus 8.0 months with low BAX expression (P &lt; .005). High p16 ink4a/CDKN2 protein expression was associated with a median survival of 23.8 months versus 9.7 months with low p16 ink4a/CDKN2 (P = .011). The best survival (median, 45.8 months) was seen in a subgroup of 12 patients whose tumors bore the combination of both favorite phenotypes (ie, high BAX and high p16 ink4a/CDKN2 protein expression). CONCLUSION: In this retrospective investigation, the combined analysis of BAX and p16 ink4a/CDKN2 shows subgroups in SCC of the esophagus with favorable (p16 ink4a/CDKN2 /BAX high expressing) or poor prognosis (loss of p16 ink4a/CDKN2 /loss of BAX). We suggest that such a multimarker analysis of apoptosis pathways could be useful for individualization of therapeutic strategies in the future, and suggest prospective studies to confirm these results.
Allergen-induced Changes in Bone Marrow and Airway Dendritic Cells in Subjects with Asthma
Authors: Amani El-Gammal, John-Paul Oliveria, Karen Howie, Richard Watson, Patrick Mitchell, Ruchong Chen, Adrian Baatjes, Steven Smith, Dhuha Al-Sajee, Thomas J. Hawke, Kieran J. Killian, Gail M. Gauvreau, Paul M. O’Byrne
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Rationale: Dendritic cells (DCs) are antigen-presenting cells essential for the initiation of T-cell responses. Allergen inhalation increases the number of airway DCs and the release of epithelial-derived cytokines, such as IL-33 and thymic stromal lymphopoietin (TSLP), that activate DCs.Objectives: To examine the effects of inhaled allergen on bone marrow production of DCs and their trafficking into the airways in subjects with allergic asthma, and to examine IL-33 and TSPL receptor expression on DCs.Methods: Bone marrow, peripheral blood, bronchoalveolar lavage (BAL), and bronchial biopsies were obtained before and after inhalation of diluent and allergen from subjects with asthma that develop allergen-induced dual responses. Classical DCs (cDCs) were cultured from bone marrow CD34+ cells. cDC1s, cDC2s, and plasmacytoid DCs were measured in bone marrow aspirates, peripheral blood, and BAL by flow cytometry, and cDCs were quantified in bronchial biopsies by immunofluorescence staining.Measurements and Main Results: Inhaled allergen increased the number of cDCs grown from bone marrow progenitors, and cDCs and plasmacytoid DCs in bone marrow aspirates 24 hours after allergen. Allergen also increased the expression of the TSLP receptor, but not the IL-33 receptor, on bone marrow DCs. Finally, inhaled allergen increased the percentage of cDC1s and cDC2s in BAL but only cDC2s in bronchial tissues.Conclusions: Inhaled allergen increases DCs in bone marrow and trafficking of DCs into the airway, which is associated with the development airway inflammation in subjects with allergic asthma. Inhaled allergen challenge also increases expression of TSLP, but not IL-33, receptors on bone marrow DCs.
Abstract 238: miR-222 is Necessary for Exercise-induced Cardiac Growth and Protects Against Pathological Cardiac Remodeling
Authors: Xiaojun Liu, Junjie Xiao, Han Zhu, Xin Wei, Colin Platt, Federico Damilano, Chunyang Xiao, Vassilios Bezzerides, Anthony Rosenzweig
Journal: Circulation Research (2014)

Exercise induces cardiac growth, protects against adverse remodeling, and may also induce a regenerative response. Since microRNAs (miRNA) play important roles in cardiovascular disease, we investigated their role in the cardiac exercise response. We used the TaqMan rodent miRNA array to profile cardiac miRNA expressed at three weeks in two exercise models (swimming, running) compared to sedentary controls. Sixteen concordantly regulated miRNAs were identified and validated in both models, and examined for functional effects in neonatal rat ventricular cardiomyocytes (CMs). miR-222 was upregulated ~two-fold in both models and increased CM size (22%, p&lt;0.01) and proliferation markers (EdU and Ki67, p&lt;0.01). Bioinformatic and expression analyses identified four potential miR-222 targets (p27, Hipk1, Hipk2, and Hmbox-1) in CMs. These were confirmed as direct targets by luciferase assays, site-directed mutagenesis, and immunoblotting. siRNA knockdown (KD) of p27 or Hipk1 induced neonatal CM proliferation, while siRNA KD of Hmbox-1 increased CM size. To examine miR-222’s role in vivo, LNA-antimiR-222 was injected via tail vein or subcutaneously and shown to reduce cardiac miR-222 levels to 1.5% (p&lt;0.01). Untreated animals subjected to three weeks of swimming had the expected increase in heart size (15% in HW/TL, p&lt;0.05), CM size (26%, p&lt;0.05), and markers of CM proliferation (Ki67 and pHH3, p&lt;0.05). Increases in heart and CM size were unaffected by control LNA-antimiR but completely blocked by LNA-antimiR-222, while CM proliferation markers decreased (60%, p&lt;0.05). To see if miR-222 is sufficient to mediate the benefits of exercise, we made transgenic mice with cardiac-specific, regulated expression of miR-222 (Tg-miR-222). Tg-miR-222 have normal heart size and function at baseline. After ischemia-reperfusion injury (IRI), Tg-miR-222 had similar initial dysfunction but were protected against adverse remodeling over the next six weeks with better function (p&lt;0.01), less cardiac fibrosis (68%, p&lt;0.05), and increased CM proliferation markers (63%, p&lt;0.05). Conclusion: Cardiac miR-222 is upregulated by exercise, necessary for exercise-induced cardiac growth, and protects against pathological cardiac remodeling after IRI.
Electrical impedance tomography signals in the lung are highly position dependent
Authors: Michael Graf, Thomas Riedel
Journal: European Respiratory Journal (2014)

Introduction : Electrical impedance tomography (EIT) detects changes in electrical impedance provoked by air and blood volume variations within the chest. No consensus exists on how to reconstruct EIT images and how to filter cardiac and respiratory related signals. This study aims to investigate the effect of image reconstruction and specific filtering on EIT signals in different body positions.   Methods : Fourteen healthy adults were measured during a breath hold (BH) and while spontaneously breathing (SB) in upright, supine, prone, left and right lateral position. Four different image reconstruction algorithms were applied to the raw data. EIT amplitudes were then calculated with and without filtering for the respiratory and/or heart rate. Amplitudes of cardiac and respiratory related signals in the lung regions were compared between the different body positions.   Results : Independent of the reconstruction method used, the upright and supine positions revealed significantly lower amplitudes than the other postures. Using reconstruction methods with more  a priori  information drastically increased some differences (prone position). Filtering of the SB signal in the frequency domain of the heart rate only showed minimal differences to the unfiltered BH signal with respect to cardiac related impedance amplitudes.   Conclusion : EIT signals are highly dependent on body position and to some extent to the reconstruction algorithm used. This might have several consequences for future EIT studies. Especially researchers studying “perfusion” or “ventilation-perfusion” relationships have to be aware of positional effects on the EIT signal not explained by physiological changes.