tbuckley/cabot-search huggingface dataset:
Randomized, Double-Blind Trial of Carboplatin and Paclitaxel With Either Daily Oral Cediranib or Placebo in Advanced Non–Small-Cell Lung Cancer: NCIC Clinical Trials Group BR24 Study
Authors: Glenwood D. Goss, Andrew Arnold, Frances A. Shepherd, Mircea Dediu, Tudor-Eliade Ciuleanu, David Fenton, Mauro Zukin, David Walde, Francis Laberge, Mark D. Vincent, Peter M. Ellis, Scott A. Laurie, Keyue Ding, Eliot Frymire, Isabelle Gauthier, Natasha B. Leighl, Cheryl Ho, Jonathan Noble, Christopher W. Lee, Lesley Seymour
Journal: Journal of Clinical Oncology (2009)

PURPOSE This phase II/III double-blind study assessed efficacy and safety of cediranib with standard chemotherapy as initial therapy for advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS Paclitaxel (200 mg/m(2)) and carboplatin (area under the serum concentration-time curve 6) were given every 3 weeks, with daily oral cediranib or placebo at 30 mg (first 45 patients received 45 mg). Progression-free survival (PFS) was the primary outcome of the phase II interim analysis; phase III would proceed if the hazard ratio (HR) for PFS < or = 0.77 and toxicity were acceptable. Results A total of 296 patients were enrolled, 251 to the 30-mg cohort. The phase II interim analysis demonstrated a significantly higher response rate (RR) for cediranib than for placebo, HR of 0.77 for PFS, no excess hemoptysis, and a similar number of deaths in each arm. The study was halted to review imbalances in assigned causes of death. In the primary phase II analysis (30-mg cohort), the adjusted HR for PFS was 0.77 (95% CI, 0.56 to 1.08) with a higher RR for cediranib than for placebo (38% v 16%; P < .0001). Cediranib patients had more hypertension, hypothyroidism, hand-foot syndrome, and GI toxicity. Hypoalbuminemia, age > or = 65 years, and female sex predicted increased toxicity. Survival update (N = 296) 10 months after study unblinding favored cediranib over placebo (median of 10.5 months v 10.1 months; HR, 0.78; 95% CI, 0.57 to 1.06; P = .11). Causes of death in the cediranib 30-mg cohort were NSCLC (81%), protocol toxicity +/- NSCLC (13%), and other (6%); for the placebo group, they were 98%, 0%, and 2%, respectively. CONCLUSION The addition of cediranib to carboplatin/paclitaxel results in improved response and PFS, but does not appear tolerable at a 30-mg dose. Consequently, the National Cancer Institute of Canada Clinical Trials Group and the Australasian Lung Cancer Trials Group initiated a randomized, double-blind, placebo-controlled trial of cediranib 20 mg with carboplatin and paclitaxel in advanced NSCLC.
Solar Drinking Water Disinfection (SODIS) to Reduce Childhood Diarrhoea in Rural Bolivia: A Cluster-Randomized, Controlled Trial
Authors: Daniel Mäusezahl, Andri Christen, Gonzalo Duran Pacheco, Fidel Alvarez Tellez, Mercedes Iriarte, Maria E. Zapata, Myriam Cevallos, Jan Hattendorf, Monica Daigl Cattaneo, Benjamin Arnold, Thomas A. Smith, John M. Colford
Journal: PLoS Medicine (2009)

Daniel Maeusezahl and colleagues conducted a cluster-randomized controlled trial in rural Bolivia of solar drinking water disinfection, and find only moderate compliance with the intervention and no evidence of reduction in diarrhea among children.
Concorde trial of immediate versus deferred zidovudine
Authors: Matthias Egger, JamesD Neaton, AndrewN Phillips, George Davey Smith, NeilM.H Graham, JulioS.G Montaner, Janet Raboud, Michael O'Shaughnessy, PeterA Laing, SheilaM Gore, A Graham Bird, Bernard Hirschel, J-P Aboulker, A.G Babiker, J.H Darbyshire, J Dormont, T.E.A Peto, M Seligmann, A.M Swart, I.V.D Weller
Journal: The Lancet (1994)
Modification of Cysteine Residue in p65 Subunit of Nuclear Factor-κB (NF-κB) by Picroliv Suppresses NF-κB–Regulated Gene Products and Potentiates Apoptosis
Authors: Preetha Anand, Ajaikumar B. Kunnumakkara, Kuzhuvelil B. Harikumar, Kwang Seok Ahn, Vladimir Badmaev, Bharat B. Aggarwal
Journal: Cancer Research (2008)

Abstract Picroliv, an iridoid glycoside derived from the plant Picrorhiza kurroa, is used traditionally to treat fever, asthma, hepatitis, and other inflammatory conditions. However, the exact mechanism of its therapeutic action is still unknown. Because nuclear factor-κB (NF-κB) activation plays a major role in inflammation and carcinogenesis, we postulated that picroliv must interfere with this pathway by inhibiting the activation of NF-κB–mediated signal cascade. Electrophoretic mobility shift assay showed that pretreatment with picroliv abrogated tumor necrosis factor (TNF)–induced activation of NF-κB. The glycoside also inhibited NF-κB activated by carcinogenic and inflammatory agents, such as cigarette smoke condensate, phorbol 12-myristate 13-acetate, okadaic acid, hydrogen peroxide, lipopolysaccharide, and epidermal growth factor. When examined for the mechanism of action, we found that picroliv inhibited activation of IκBα kinase, leading to inhibition of phosphorylation and degradation of IκBα. It also inhibited phosphorylation and nuclear translocation of p65. Further studies revealed that picroliv directly inhibits the binding of p65 to DNA, which was reversed by the treatment with reducing agents, suggesting a role for a cysteine residue in interaction with picroliv. Mutation of Cys38 in p65 to serine abolished this effect of picroliv. NF-κB inhibition by picroliv leads to suppression of NF-κB–regulated proteins, including those linked with cell survival (inhibitor of apoptosis protein 1, Bcl-2, Bcl-xL, survivin, and TNF receptor–associated factor 2), proliferation (cyclin D1 and cyclooxygenase-2), angiogenesis (vascular endothelial growth factor), and invasion (intercellular adhesion molecule-1 and matrix metalloproteinase-9). Suppression of these proteins enhanced apoptosis induced by TNF. Overall, our results show that picroliv inhibits the NF-κB activation pathway, which may explain its anti-inflammatory and anticarcinogenic effects. [Cancer Res 2008;68(21):8861–70]
Another Confirmation of the Inactivity of Topotecan in Ovarian Cancer
Authors: William P. McGuire
Journal: JNCI Journal of the National Cancer Institute (2010)

One decade ago, in an editorial in the Journal (1), I challenged investigators who were interested in improving outcomes to discontinue conducting multiple trials that addressed similar questions in the treatment of advanced ovarian carcinoma except when the purpose of such studies was to confirm possible practice-changing new treatment strategies. A negative report that appears in this issue (2) is the fifth study to investigate the addition of topotecan to the platinum and taxane backbone, the current standard of care for ovarian cancer that was confirmed here a decade ago (3). The authors even include a table in the article that demonstrates the accrual of 4451 patients to explore various permutations of the question: Does the addition of topotecan to a platinum and taxane backbone improve outcomes in patients with advanced ovarian carcinoma? The answer is a resounding “no” whether topotecan is used in a triplet (4), as part of a sequential doublet (2,5), or as consolidation (6,7). In the recently published trial by the Gynecologic Cancer Intergroup (5), 4321 ovarian cancer patients were accrued internationally from the United States, United Kingdom, Italy, Australia, and New Zealand. This five-arm study (GOG182/ICON5) explored the addition of topotecan, gemcitabine, or liposomal doxorubicin to the platinum and taxane backbone. None of the new agents improved any outcome measure, and each was more toxic in some fashion than the backbone alone. The accrual spanned the years 2001–2004. The current study (2) was developed during the same time period and accrued 819 patients from Canada, Spain, and several countries from the European Organization for Research and Treatment of Cancer between 2001 and 2005.
Association between dietary patterns and asthma and allergic diseases: Data from the French six cities study
Authors: Danielle Saadeh, Pascale Salameh, Denis Caillaud, Denis Charpin, Frederic de Blay, Christine Kopferschmitt, François Lavaud, Isabella Annesi-Maesano, Isabelle Baldi, Chantal Raherison
Journal: European Respiratory Journal (2013)

Background:  The prevalence of asthma and allergies has risen in recent decades, especially among children in the western world. The increasing prevalence of allergies in children might be related to diet. A study was undertaken to assess the association between dietary patterns, asthma, allergic rhinitis and atopic dermatitis in schoolchildren in France.   Methods:  A cross-sectional study was performed in six cities of France using ISAAC protocol. Parental questionnaires were used to collect information on allergic diseases and diet with a food frequency questionnaire (FFQ). Data from 7 432 randomly selected schoolchildren aged 9-11 years old were analyzed. The mean intakes of 13 main food items were calculated and used to establish four dietary patterns by principal component analysis.   Results:  Soft  drinks was positively associated with atopic wheeze [OR = 1.61, 95% CI [1.01 -2.58]] for those drinking 3–6 times per week (compared with never drink) and current eczema (OR = 1.63, 95%CI [1.12 -2.37]) for those drinking less than once per week. Intake of fresh fruit juice and citrus fruits were protective factors for lifetime asthma (OR = 0.71, 95%CI [0.54 -0.94]) for those drinking fresh fruit juice 1–2 times per week, and for those eating citrus fruits 3-6 times per week as well as for intake of fresh fish (OR= 0.74, 95%CI [0.56-0.96]. The frequent consumption of fresh fruit juice (p = 0.006), raw vegetables (p = 0.019), red meat (p = 0.008), white fish (p = 0.003), breaded fish (p= 0.015) and dairy products (p = 0.000) were positively associated with atopic wheeze.   Conclusion:  Consumption of fruits, vegetables and fish may provide some protective effect against allergies.
Peptide length determines the outcome of TCR/peptide-MHCI engagement
Authors: Julia Ekeruche-Makinde, John J. Miles, Hugo A. van den Berg, Ania Skowera, David K. Cole, Garry Dolton, Andrea J. A. Schauenburg, Mai Ping Tan, Johanne M. Pentier, Sian Llewellyn-Lacey, Kim M. Miles, Anna M. Bulek, Mathew Clement, Tamsin Williams, Andrew Trimby, Mick Bailey, Pierre Rizkallah, Jamie Rossjohn, Mark Peakman, David A. Price, Scott R. Burrows, Andrew K. Sewell, Linda Wooldridge
Journal: Blood (2012)
Binding of monomeric immunoglobulins to Fc receptors of mouse macrophages.
Authors: J C Unkeless, H N Eisen
Journal: The Journal of Experimental Medicine (1975)

The binding properties of surface receptors of immunoglobulins on mouse macrophages were studied with mouse myeloma proteins and normal peritoneal macrophages, thioglycollate-stimulated macrophages, and a macrophage cell line, P388D1. Primary cultures of mouse embryo fibroblasts served as controls. IgG2a proteins were bound strongly;IgG2b was bound weakly (one-twentieth as well as IgG2a);IgM, IgA, and IgG1 were not bound significantly. The number of binding sites per cell for IgG2a was 4 X 10(5) for thioglycollate-stimulated cells and 1 X 10(5) for normal and P388D1 cells. Binding was exothermal: with decreasing temperature the equilibrium (association) constants increased and dissociation rate constants decreased (at 37degreesC the respective values were 2 X 10(7) M-1 and 0.26 min-1, the latter value corresponds to a half time for dissociation of 2.6 min). From the rapidity of association and dissociation, it appears that the surface of the macrophage is in a dynamic equilibrium with IgG2a molecules in the cell's immediate microenvironment. The receptors for IgG2a are clearly specific for determinants in the immunoglobulin constant domain: two IgG2a proteins with greatly different isoelectric points (determined by isoelectric focusing) were bound with the same affinity to the same receptors; moreover, the Fc fragment was bound and Fab fragments were not. The Fc receptors for IgG2a proteins were readily eliminated by exposing macrophages briefly to trypsin. The receptors were regenerated during subsequent cultivation in serum-free medium; regeneration was inhibited totally by cycloheximide and partially by actinomycin D.
A Study of the Mechanisms of Edema Formation in Patients with the Nephrotic Syndrome 1
Authors: H. A. Eder, H. D. Lauson, F. P. Chinard, R. L. Greif, G. C. Cotzias, D. D. Van Slyke
Journal: Journal of Clinical Investigation (1954)

Accumulation of edema in the nephrotic syn- drome is the result of renal tubular reabsorption of filtered sodium, chloride, and water in excess of that required for maintenance of a normal extra- cellular fluid volume.This increase in tubular reabsorption ("glomerulo-tubular imbalance" (3, 4) ) could be the consequence of a decrease in the rate of glomerular filtration ("primary glomerular insufficiency") or of stimuli acting directly on the tubules ("primary tubular preponderance").Decreased glomerular filtration rate (GFR) could be due directly to glomerular lesions (2) or might be related to a decrease in renal blood flow secondary to decreased plasma volume with "inadequacy" of the general circulation-a milder form of the insufficiency present in shock (5,6).Changes in GFR due to lesions are the result of changes in the area and/or characteristics of the filtering surface.Adjustment to circulatory "in- adequacy" which results in decreased renal blood flow would presumably be accomplished mainly by constriction of the afferent arterioles with re- duction of pressure in the glomerular capillaries.GFR would diminish if this decrease in net trans- capillary hydrostatic pressure were greater than the decrease in so-called colloid osmotic pressure due to hypoalbuminemia.Circulatory factors would be expected to reduce GFR by roughly the same proportion in most glomeruli (7); however, morphologic alterations may vary greatly from one glomerulus to another.The degree of glomerular insufficiency resulting from the combined effects of 1
Can telemedicine reverse the brain drain?
Authors: V. Venkatramani
Journal: Journal of the Royal Society of Medicine (2005)

Can telemedicine reverse the brain drain?Drs Dodani and LaPorte in their article on brain drain (November 2005 JRSM 1 ) alluded to telemedicine as a tool for doctors in developed countries to 'work' with patients in developing countries, and establish educational cooperation with centres there.Clinical process outsourcing (CPO) is a new phenomenon that can potentially reverse the brain drain.Like the booming business process outsourcing sector, CPO involves a specific procedure being transferred out of a developed country to be performed at a significantly lower cost elsewhere without compromising quality.An excellent example is tele-radiology, wherein X-rays, computerized tomography scans or magnetic resonance images are emailed from a hospital in a developed country.This allows a USA/UK board-certified radiologist living in a developing country to view and report the films.The hospital receives accurate advice around the clock, with a consequent increase in productivity.Currently more than 600 USA hospitals utilize services provided by an Australian radiology company. 2 In addition to cutting the burgeoning healthcare costs in the West, this situation enhances efficiency, reduces waiting times and may be worth considering in the NHS.The need for foreign-trained doctors living in developing countries is bound to grow, helping them reduce the wage differential between the countries of their training and origin.This is an option worth considering for doctors wishing to return home after training abroad.However, time will tell whether this trend can be extended to the entire spectrum of medical services.
Normally occurring NKG2D+CD4+ T cells are immunosuppressive and inversely correlated with disease activity in juvenile-onset lupus
Authors: Zhenpeng Dai, Cameron J. Turtle, Garrett C. Booth, Stanley R. Riddell, Theodore A. Gooley, Anne M. Stevens, Thomas Spies, Veronika Groh
Journal: The Journal of Experimental Medicine (2009)

The NKG2D receptor stimulates natural killer cell and T cell responses upon engagement of ligands associated with malignancies and certain autoimmune diseases. However, conditions of persistent NKG2D ligand expression can lead to immunosuppression. In cancer patients, tumor expression and shedding of the MHC class I–related chain A (MICA) ligand of NKG2D drives proliferative expansions of NKG2D+CD4+ T cells that produce interleukin-10 (IL-10) and transforming growth factor-β, as well as Fas ligand, which inhibits bystander T cell proliferation in vitro. Here, we show that increased frequencies of functionally equivalent NKG2D+CD4+ T cells are inversely correlated with disease activity in juvenile-onset systemic lupus erythematosus (SLE), suggesting that these T cells may have regulatory effects. The NKG2D+CD4+ T cells correspond to a normally occurring small CD4 T cell subset that is autoreactive, primed to produce IL-10, and clearly distinct from proinflammatory and cytolytic CD4 T cells with cytokine-induced NKG2D expression that occur in rheumatoid arthritis and Crohn's disease. As classical regulatory T cell functions are typically impaired in SLE, it may be clinically significant that the immunosuppressive NKG2D+CD4+ T cells appear functionally uncompromised in this disease.
Pharmacodynamic Study Using FLT PET/CT in Patients with Renal Cell Cancer and Other Solid Malignancies Treated with Sunitinib Malate
Authors: Glenn Liu, Robert Jeraj, Matt Vanderhoek, Scott Perlman, Jill Kolesar, Michael Harrison, Urban Simoncic, Jens Eickhoff, Lakeesha Carmichael, Bo Chao, Rebecca Marnocha, Percy Ivy, George Wilding
Journal: Clinical Cancer Research (2011)

To characterize proliferative changes in tumors during the sunitinib malate exposure/withdrawal using 3'-deoxy-3'-[(18)F]fluorothymidine (FLT) positron emission tomography (PET)/computed tomography (CT) imaging.Patients with advanced solid malignancies and no prior anti-VEGF exposure were enrolled. All patients had metastatic lesions amenable to FLT PET/CT imaging. Sunitinib was initiated at the standard dose of 50 mg p.o. daily either on a 4/2 or 2/1 schedule. FLT PET/CT scans were obtained at baseline, during sunitinib exposure, and after sunitinib withdrawal within cycle #1 of therapy. VEGF levels and sunitinib pharmacokinetic (PK) data were assessed at the same time points.Sixteen patients (8 patients on 4/2 schedule and 8 patients on 2/1 schedule) completed all three planned FLT PET/CT scans and were evaluable for pharmacodynamic imaging evaluation. During sunitinib withdrawal (change from scans 2 to 3), median FLT PET standardized uptake value (SUV(mean)) increased +15% (range: -14% to 277%; P = 0.047) for the 4/2 schedule and +19% (range: -5.3% to 200%; P = 0.047) for the 2/1 schedule. Sunitinib PK and VEGF ligand levels increased during sunitinib exposure and returned toward baseline during the treatment withdrawal.The increase of cellular proliferation during sunitinib withdrawal in patients with renal cell carcinoma and other solid malignancies is consistent with a VEGF receptor (VEGFR) tyrosine kinase inhibitor (TKI) withdrawal flare. Univariate and multivariate analysis suggest that plasma VEGF is associated with this flare, with an exploratory analysis implying that patients who experience less clinical benefit have a larger withdrawal flare. This might suggest that patients with a robust compensatory response to VEGFR TKI therapy experience early "angiogenic escape."
Mortality at ages 75 and older in the Cancer Prevention Study (CPS I)
Authors: E. A. Lew, L. Garfinkel
Journal: CA A Cancer Journal for Clinicians (1990)

In the fall of 1959 the American Cancer Society began a comprehensive epidemiologic investigation of more than one million men and women drawn mainly from the middle-class population. The study reported here presents a portion of the investigation relating to the mortality among 49,469 subjects who attained age 75 years and older during the course of the study. Both men and women who at entry into this study (1960) were judged to be in good health registered distinctly lower mortality than those judged to be in poor health. Men and women with some college education had significantly lower death rates than those with lesser schooling. Men and women who reported a good family history of longevity showed consistently lower death rates in each five-year age group than those with average or poor family history of longevity. Persons with an average family history of longevity generally had lower death rates than those with a poor family history of longevity. Analysis of mortality by cause indicated that at ages 75 and older nearly half the deaths were attributed to all forms of heart disease. Coronary heart disease accounted for about 35 percent of all deaths, with the proportion decreasing with age. Deaths from stroke rose from 15 to about 20 percent with increase in age. Deaths from all sites of cancer declined with advancing age in both sexes, from about 16 percent of all deaths at ages 75 to 79 to about six percent at ages 90 to 99. Among men, cancer of the prostate accounted for 3.5 percent of deaths at ages 75 to 84, decreasing to about one half this proportion in the early-90s age group. Colorectal cancer decreased from about three percent of total deaths at ages 75 to 84 to about 1.5 percent in the early 90s. Lung cancer and stomach cancer remained at the same level at these ages.
Predictors of pulmonary exacerbations in patients with cystic fibrosis infected with multi-resistant bacteria
Authors: J K Block, K L Vandemheen, E Tullis, D Fergusson, S Doucette, D Haase, Y Berthiaume, N Brown, P Wilcox, P Bye, S Bell, M Noseworthy, L Pedder, A Freitag, N Paterson, S D Aaron
Journal: Thorax (2006)

<b>Background:</b> This study examined characteristics of adult and adolescent patients with cystic fibrosis (CF) to determine factors associated with an increased risk of pulmonary exacerbations. <b>Methods:</b> 249 patients with CF infected with multidrug resistant bacteria were recruited and prospectively followed for up to 4.5 years until they experienced a pulmonary exacerbation severe enough to require intravenous antibiotics. Multivariable regression analyses were used to compare the characteristics of patients who experienced an exacerbation with those who did not. <b>Results:</b> 124 of the 249 patients (50%) developed a pulmonary exacerbation during the first year and 154 (62%) experienced an exacerbation during the 4.5 year study period. Factors predictive of exacerbations in a multivariable survival model were younger age (OR 0.98, 95% CI 0.96 to 0.99), female sex (OR 1.45, 95% CI 1.07 to 1.95), lower forced expiratory volume in 1 second (FEV<sub>1</sub>) (OR 0.98, 95% CI 0.97 to 0.99), and a previous history of multiple pulmonary exacerbations (OR 3.16, 95% CI 1.93 to 5.17). Chronic use of inhaled corticosteroids was associated with an increased risk of exacerbation (OR 1.92, 95% CI 1.00 to 3.71) during the first study year. <b>Conclusions:</b> Patients who experience pulmonary exacerbations are more likely to be younger, female, using inhaled steroids, have a lower FEV<sub>1</sub>, and a history of multiple previous exacerbations. It is hoped that knowledge of these risk factors will allow better identification and closer monitoring of patients who are at high risk of exacerbations.
Understanding controlled trials: Why are randomised controlled trials important?
Authors: B. Sibbald, M. Roland
Journal: BMJ (1998)

Ritual and signature are fantasy-driven, repetitive crime scene behaviors that have been found to occur in serial sexual homicide. Notwithstanding numerous anecdotal case reports, ritual and signature have rarely been studied empirically. In a national sample of 38 offenders and their 162 victims, we examined behavioral and thematic consistency, as well as the evolution and uniqueness of these crime scene actions. The notion that serial sexual murderers engage in the same rituals and leave unique signatures at every scene was not supported by our data. In fact, the results suggest that the crime scene conduct of this group of offenders is fairly complex and varied. Implications of these findings for forensic assessments and criminal investigations are discussed.