tbuckley/cabot-search huggingface dataset:
Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngeal cancer: phase III randomized Intergroup study 0099.
Authors: M Al-Sarraf, M LeBlanc, P G Giri, K K Fu, J Cooper, T Vuong, A A Forastiere, G Adams, W A Sakr, D E Schuller, J F Ensley
Journal: Journal of Clinical Oncology (1998)

PURPOSE The Southwest Oncology Group (SWOG) coordinated an Intergroup study with the participation of Radiation Therapy Oncology Group (RTOG), and Eastern Cooperative Oncology Group (ECOG). This randomized phase III trial compared chemoradiotherapy versus radiotherapy alone in patients with nasopharyngeal cancers. MATERIALS AND METHODS Radiotherapy was administered in both arms: 1.8- to 2.0-Gy/d fractions Monday to Friday for 35 to 39 fractions for a total dose of 70 Gy. The investigational arm received chemotherapy with cisplatin 100 mg/m2 on days 1, 22, and 43 during radiotherapy; postradiotherapy, chemotherapy with cisplatin 80 mg/m2 on day 1 and fluorouracil 1,000 mg/m2/d on days 1 to 4 was administered every 4 weeks for three courses. Patients were stratified by tumor stage, nodal stage, performance status, and histology. RESULTS Of 193 patients registered, 147 (69 radiotherapy and 78 chemoradiotherapy) were eligible for primary analysis for survival and toxicity. The median progression-free survival (PFS) time was 15 months for eligible patients on the radiotherapy arm and was not reached for the chemo-radiotherapy group. The 3-year PFS rate was 24% versus 69%, respectively (P &lt; .001). The median survival time was 34 months for the radiotherapy group and not reached for the chemo-radiotherapy group, and the 3-year survival rate was 47% versus 78%, respectively (P = .005). One hundred eighty-five patients were included in a secondary analysis for survival. The 3-year survival rate for patients randomized to radiotherapy was 46%, and for the chemoradiotherapy group was 76% (P &lt; .001). CONCLUSION We conclude that chemoradiotherapy is superior to radiotherapy alone for patients with advanced nasopharyngeal cancers with respect to PFS and overall survival.
Deoxyribonuclease in the Treatment of Purulent Bronchitis
Authors: P. C. Elmes, J. C. White
Journal: Thorax (1953)

In a previous paper Armstrong and White (1950) described studies on purulent bronchial and pleural exudates, showing that extracellular fibres of deoxyribonucleoprotein were responsible for much of their viscidity.Deoxyribonuclease pre- pared from beef pancreas destroyed these fibres and reduced the viscidity of the exudates both in vitro and in vivo.To determine whether this is of any practical value in the treatment of bronchitis, a controlled experiment was carried out and is reported here. SELECTION OF CASESThe sputum of bronchitics is predominantly purulent only during acute episodes of the disease, when bronchial obstruction is the main cause of the symptoms, and of complications such as atelectasis and bronchopneumonia.The course of such exacerbations is very variable and in order to study the response to treatment in sufficient detail only patients admitted to hospital could be used.Of these, many were too ill to cooperate with treat- ment or tests, and many had had sufficient chemotherapy before admission to convert their sputum from purulent to mucoid.As a result only 23 cases of uncomplicated purulent bronchitis were found suitable in two winters.The patients were observed over a period of 10 days, starting if possible on the day after admission.ASSESSMENT OF PROGRESS CLINICAL.-Inaddition to an assessment of general health a careful history of respiratory ill- ness was taken and the course of the present episode followed with particular reference to these features: (1) Degree of dyspnoea and cyanosis; (2) degree of systemic venous conges- tion; (3) extent and density of added sounds in the chest; (4) the presence of wheezing; (5) severity of cough; (6) vital capacity; (7) maximal volun- tary ventilation.
Safety, cost and effectiveness issues with disease modifying anti-rheumatic drugs in rheumatoid arthritis
Authors: J. F Fries
Journal: Annals of the Rheumatic Diseases (1999)

Safety, cost, and eVectiveness studies are critically important for definitive assessment of disease modifying drugs (DMARDs), particularly when new mechanisms of drug action are likely to be present. This requires post-marketing surveillance, as these dimensions cannot be adequately assessed in pre-marketing studies. “Post-marketing surveillance”, in our definition, is “the asking and answering of important questions the answers to which cannot be ascertained from premarketing trials”. 1 Such questions include assessing the long term toxicity of the new drugs, comparison of the toxicity of the new drugs with alternative treatments, assessment of toxicity in elderly populations and persons with comorbid diseases, noting the characteristics of patients likely to experience toxicity, exploring the eVects of drug combinations on eYcacy and toxicity,and evaluating the long term net cost of treatment. For each of these questions, long term data are required. Such studies may require 1000 to 10 000 patient years of experience for each drug treatment arm. Randomised trials of this scope are not practical. Adverse event reporting systems lack accurate numerators and denominators and cannot validly compare different agents. Hence, prospective, protocol driven, large scale, observational studies are required. These should be started as early in the drug development sequence as possible. Data analysis must be sophisticated and must go far beyond purely descriptive studies without controls. Often, enrollment of early patients in phase 2 and 3 may shorten the time required for adequate follow up.
DNA copy number changes in high-grade malignant peripheral nerve sheath tumors by array CGH
Authors: Stine H Kresse, Magne Skårn, Hege O Ohnstad, Heidi M Namløs, Bodil Bjerkehagen, Ola Myklebost, Leonardo A Meza-Zepeda
Journal: Molecular Cancer (2008)

Abstract Background Malignant peripheral nerve sheath tumors (MPNSTs) are rare and highly aggressive soft tissue tumors showing complex chromosomal aberrations. In order to identify recurrent chromosomal regions of gain and loss, and thereby novel gene targets of potential importance for MPNST development and/or progression, we have analyzed DNA copy number changes in seven high-grade MPNSTs using microarray-based comparative genomic hybridization (array CGH). Results Considerable more gains than losses were observed, and the most frequent minimal recurrent regions of gain included 1q24.1-q24.2, 1q24.3-q25.1, 8p23.1-p12, 9q34.11-q34.13 and 17q23.2-q25.3, all gained in five of seven samples. The 17q23.2-q25.3 region was gained in all five patients with poor outcome and not in the two patients with disease-free survival. cDNA microarray analysis and quantitative real-time reverse transcription PCR were used to investigate expression of genes located within these regions. The gene lysyl oxidase-like 2 ( LOXL2 ) was identified as a candidate target for the 8p23.1-p12 gain. Within 17q, the genes topoisomerase II-α ( TOP2A ), ets variant gene 4 (E1A enhancer binding protein, E1AF ) ( ETV4 ) and baculoviral IAP repeat-containing 5 (survivin) ( BIRC5 ) showed increased expression in all samples compared to two benign tumors. Increased expression of these genes has previously been associated with poor survival in other malignancies, and for TOP2A , in MPNSTs as well. In addition, we have analyzed the expression of five micro RNAs located within the 17q23.2-q25.3 region, but none of them showed high expression levels compared to the benign tumors. Conclusion Our study shows the potential of using DNA copy number changes obtained by array CGH to predict the prognosis of MPNST patients. Although no clear correlations between the expression level and patient outcome were observed, the genes TOP2A , ETV4 and BIRC5 are interesting candidate targets for the 17q gain associated with poor survival.
Randomized phase II trial of gemcitabine plus weekly versus three-weekly paclitaxel in previously untreated advanced non-small-cell lung cancer
Authors: C.P. Belani, S. Dakhil, D.M. Waterhouse, C.E. Desch, D.K. Rooney, R.H. Clark, M.J. Monberg, Z. Ye, C.K. Obasaju
Journal: Annals of Oncology (2006)
Soluble and Membrane-bound Forms of Signaling Lymphocytic Activation Molecule (SLAM) Induce Proliferation and Ig Synthesis by Activated Human B Lymphocytes
Authors: Juha Punnonen, Benjamin G. Cocks, José M. Carballido, Bruce Bennett, David Peterson, Gregorio Aversa, Jan E. de Vries
Journal: The Journal of Experimental Medicine (1997)

In this study it is shown that both membrane-bound and soluble forms of signaling lymphocytic activation molecule (SLAM) induce proliferation and Ig synthesis by activated human B cells. Activated B cells express the membrane-bound form of SLAM (mSLAM), the soluble (s) and the cytoplasmic (c) isoforms of SLAM, and the expression levels of mSLAM on B cells are rapidly upregulated after activation in vitro. Importantly, recombinant sSLAM and L cells transfected with mSLAM efficiently enhance B cell proliferation induced by anti-μ mAbs, anti-CD40 mAbs or Staphylococcus aureus Cowan I (SAC) in the presence or absence of IL-2, IL-4, IL-10, IL-12, or IL-15. sSLAM strongly enhances proliferation of both freshly isolated B cells and B cells derived from long-term in vitro cultures, indicating that SLAM acts not only during the initial phase of B cell activation but also during the expansion of preactivated B cells. In addition, sSLAM enhances production of IgM, IgG, and IgA by B cells activated by antiCD40 mAbs. SLAM has recently been shown to be a high affinity self-ligand, and the present data suggest that signaling through homophilic SLAM–SLAM binding during B–B and B–T cell interactions enhances the expansion and differentiation of activated B cells.
EVIDENCE FOR A CYTOLYTIC FACTOR RELEASED BY MACROPHAGES
Authors: Haakon Melsom, Gilla Kearny, Stanislav Gruca, Rolf Seljelid
Journal: The Journal of Experimental Medicine (1974)

Mouse peritoneal macrophages cultivated in vitro acquire a strong extracellular cytotoxic activity towards isotope labeled syngeneic erythrocytes as demonstrated by isotope release to the medium. This lytic process is mediated by an extremely labile macrophage cytolytic factor (MCF) which is not detected under ordinary tissue culture conditions with serum present in the medium. By the use of serum-free medium containing low doses of 2-mercaptoethanol MCF is stabilized and found to be an easily dialysable, low molecular substance which resists heating at 60 degrees C for 30 min.
Abolished InsP3R2 function inhibits sweat secretion in both humans and mice
Authors: Joakim Klar, Chihiro Hisatsune, Shahid M. Baig, Muhammad Tariq, Anna C.V. Johansson, Mahmood Rasool, Naveed Altaf Malik, Adam Ameur, Kotomi Sugiura, Lars Feuk, Katsuhiko Mikoshiba, Niklas Dahl
Journal: Journal of Clinical Investigation (2014)

There are 3 major sweat-producing glands present in skin; eccrine, apocrine, and apoeccrine glands. Due to the high rate of secretion, eccrine sweating is a vital regulator of body temperature in response to thermal stress in humans; therefore, an inability to sweat (anhidrosis) results in heat intolerance that may cause impaired consciousness and death. Here, we have reported 5 members of a consanguineous family with generalized, isolated anhidrosis, but morphologically normal eccrine sweat glands. Whole-genome analysis identified the presence of a homozygous missense mutation in ITPR2, which encodes the type 2 inositol 1,4,5-trisphosphate receptor (InsP3R2), that was present in all affected family members. We determined that the mutation is localized within the pore forming region of InsP3R2 and abrogates Ca2+ release from the endoplasmic reticulum, which suggests that intracellular Ca2+ release by InsP3R2 in clear cells of the sweat glands is important for eccrine sweat production. Itpr2-/- mice exhibited a marked reduction in sweat secretion, and evaluation of sweat glands from Itpr2-/- animals revealed a decrease in Ca2+ response compared with controls. Together, our data indicate that loss of InsP3R2-mediated Ca2+ release causes isolated anhidrosis in humans and suggest that specific InsP3R inhibitors have the potential to reduce sweat production in hyperhidrosis.
Time to Sputum Culture Conversion in Multidrug-Resistant Tuberculosis: Predictors and Relationship to Treatment Outcome
Authors: Timothy H. Holtz, Maya Sternberg, Steve Kammerer, Kayla F. Laserson, Vija Riekstina, Evija Zarovska, Vija Skripconoka, Charles D. Wells, Vaira Leimane
Journal: Annals of Internal Medicine (2006)

Background: Conversion of sputum mycobacterial cultures from positive growth to negative growth of Mycobacterium tuberculosis in patients with pulmonary tuberculosis (TB) is considered the most important interim indicator of the efficacy of anti-TB pharmacologic treatment for multidrug-resistant disease. Objective: To evaluate and compare time to and predictors of initial sputum culture conversion with predictors of treatment outcome for patients with multidrug-resistant TB. Design: Retrospective cohort study. Setting: Latvia. Patients: All civilian patients with multidrug-resistant TB treated with the DOTS-Plus strategy between 1 January and 31 December 2000. Intervention: Individualized treatment for confirmed sputum culture–positive pulmonary multidrug-resistant TB. Measurements: Time to initial sputum culture conversion and treatment outcome. Results: Among 167 patients who were sputum culture–positive at initiation of second-line therapy, 129 (77%) converted in a median time of 60 days (range, 4 to 462 days) and 38 (23%) did not convert. Independent predictors of a longer sputum culture conversion time, using an accelerated failure time regression model, included previous treatment for multidrug-resistant TB, high initial sputum culture colony count, bilateral cavitations on chest radiography, and the number of drugs the initial isolate was resistant to at treatment initiation. Treatment outcomes were statistically significantly worse for patients who did not convert their sputum culture within 2 months. Limitations: Twenty-five percent of patients missed 5 or more monthly sputum collections. Conclusions: Under program conditions in Latvia, most patients with multidrug-resistant TB achieved sputum culture conversion within 12 weeks of starting treatment. Chest radiography and sputum culture drug susceptibility testing can assist physicians in predicting which patients will convert more slowly. Sputum culture conversion is a useful and appropriate interim indicator of treatment outcome in patients with multidrug-resistant TB.
C-Reactive Protein as a Risk Factor for Coronary Heart Disease: A Systematic Review and Meta-analyses for the U.S. Preventive Services Task Force
Authors: David I. Buckley, Rongwei Fu, Michele Freeman, Kevin Rogers, Mark Helfand
Journal: Annals of Internal Medicine (2009)

Background: C-reactive protein (CRP) may help to refine global risk assessment for coronary heart disease (CHD), particularly among persons who are at intermediate risk on the basis of traditional risk factors alone. Purpose: To assist the U.S. Preventive Services Task Force (USPSTF) in determining whether CRP should be incorporated into guidelines for CHD risk assessment. Data Sources: MEDLINE search of English-language articles (1966 to November 2007), supplemented by reference lists of reviews, pertinent studies, editorials, and Web sites and by expert suggestions. Study Selection: Prospective cohort, case–cohort, and nested case–control studies relevant to the independent predictive ability of CRP when used in intermediate-risk persons. Data Extraction: Included studies were reviewed according to predefined criteria, and the quality of each study was rated. Data Synthesis: The validity of the body of evidence and the net benefit or harm of using CRP for CHD risk assessment were evaluated. The combined magnitude of effect was determined by meta-analysis. The body of evidence is of good quality, consistency, and applicability. For good studies that adjusted for all Framingham risk variables, the summary estimate of relative risk for incident CHD was 1.58 (95% CI, 1.37 to 1.83) for CRP levels greater than 3.0 mg/L compared with levels less than 1.0 mg/L. Analyses from 4 large cohorts were consistent in finding evidence that including CRP improves risk stratification among initially intermediate-risk persons. C-reactive protein has desirable test characteristics, and good data exist on the prevalence of elevated CRP levels in intermediate-risk persons. Limited evidence links changes in CRP level to primary prevention of CHD events. Limitations: Study methods for measuring Framingham risk variables and other covariates varied. Ethnic and racial minority populations were poorly represented in most studies, limiting generalizability. Few studies directly assessed the effect of CRP on risk reclassification in intermediate-risk persons. Conclusion: Strong evidence indicates that CRP is associated with CHD events. Moderate, consistent evidence suggests that adding CRP to risk prediction models among initially intermediate-risk persons improves risk stratification. However, sufficient evidence that reducing CRP levels prevents CHD events is lacking.
Effect of Valsartan on Systemic Right Ventricular Function
Authors: Teun van der Bom, Michiel M. Winter, Berto J. Bouma, Maarten Groenink, Hubert W. Vliegen, Petronella G. Pieper, Arie P.J. van Dijk, Gertjan T. Sieswerda, Jolien W. Roos-Hesselink, Aeilko H. Zwinderman, Barbara J.M. Mulder
Journal: Circulation (2012)

Background— The role of angiotensin II receptor blockers in patients with a systemic right ventricle has not been elucidated. Methods and Results— We conducted a multicenter, double-blind, parallel, randomized controlled trial of angiotensin II receptor blocker valsartan 160 mg twice daily compared with placebo in patients with a systemic right ventricle caused by congenitally or surgically corrected transposition of the great arteries. The primary end point was change in right ventricular ejection fraction during 3-year follow-up, determined by cardiovascular magnetic resonance imaging or, in patients with contraindication for magnetic resonance imaging, multirow detector computed tomography. Secondary end points were change in right ventricular volumes and mass, peak, and quality of life. Primary analyses were performed on an intention-to-treat basis. A total of 88 patients (valsartan, n=44; placebo, n=44) were enrolled in the trial. No serious adverse effects occurred in either group. There was no significant effect of 3-year valsartan therapy on systemic right ventricular ejection fraction (treatment effect, 1.3%; 95% confidence interval, −1.3% to 3.9%; P =0.34), maximum exercise capacity, or quality of life. There was a larger increase in right ventricular end-diastolic volume (15 mL; 95% confidence interval, 3–28 mL; P &lt;0.01) and mass (8 g; 95% confidence interval, 2–14 g; P =0.01) in the placebo group than in the valsartan group. Conclusions— There was no significant treatment effect of valsartan on right ventricular ejection fraction, exercise capacity, or quality of life. Valsartan was associated with a similar frequency of significant clinical events as placebo. Small but significant differences between valsartan and placebo were present for change in right ventricular volumes and mass. Clinical Trial Registration— URL: http://www.controlled-trials.com . Unique identifier: ISRCTN52352170.
A Simple Multiallele Model and Its Application to Identifying Preferred-Unpreferred Codons Using Polymorphism Data
Authors: K. Zeng
Journal: Molecular Biology and Evolution (2010)

Analysis of within-species polymorphism data usually relies on population genetic models that assume two alleles at a locus (e.g., the infinite sites model). However, many problems of interest can be tackled more naturally by multiallele models. In this study, I construct a model that can accommodate an arbitrary number of alleles at a locus, mutational biases, and selective differences between each of the alleles. It is constructed by representing population dynamics by a Markov transition matrix and is based on the assumption that at most two variants exist at each polymorphic site. A likelihood-based method for inferring the selection and mutational parameters of the model is constructed and is shown to have high accuracy. I use this method to jointly infer preferred codons and mutational parameters in Drosophila melanogaster. Twenty-one codons are identified as preferred, 19 of which were found previously by methods that do not use polymorphism data. Interestingly, the selective difference between the fittest and the worst codons encoding the same amino acid is positively correlated with the number of synonymous codons for that amino acid, in agreement with previous analyses of interspecies data using phylogenetic models. The inferred mutation matrix is highly asymmetric, with C→T and G→A being the most common and constituting ∼18% and ∼19% of all mutation events, respectively. These results suggest that the new model provides a useful framework for analyzing polymorphism data sampled from multiallele systems.
Regulatory T cells inhibit stable contacts between CD4+ T cells and dendritic cells in vivo
Authors: Carlos E. Tadokoro, Guy Shakhar, Shiqian Shen, Yi Ding, Andreia C. Lino, Antonio Maraver, Juan J. Lafaille, Michael L. Dustin
Journal: The Journal of Experimental Medicine (2006)

Regulatory T (T reg) cells exert powerful down-modulatory effects on immune responses, but it is not known how they act in vivo. Using intravital two-photon laser scanning microscopy we determined that, in the absence of T reg cells, the locomotion of autoantigen-specific T cells inside lymph nodes is decreased, and the contacts between T cells and antigen-loaded dendritic cells (DCs) are of longer duration. Thus, T reg cells can exert an early effect on immune responses by attenuating the establishment of stable contacts during priming of naive T cells by DCs.
Human exposures to volatile halogenated organic chemicals in indoor and outdoor air.
Authors: J B Andelman
Journal: Environmental Health Perspectives (1985)

Volatile halogenated organic chemicals are found in indoor and outdoor air, often at concentrations substantially above those in remote, unpopulated areas. The outdoor ambient concentrations vary considerably among sampling stations throughout the United States, as well as diurnally and daily. The vapor pressures and air-water equilibrium (Henry's Law) constants of these chemicals influence considerably the likely relative human exposures for the air and water routes. Volatilization of chemicals from indoor uses of water can be a substantial source of exposure, as shown for radon-222. Measurements of air concentrations of trichloroethylene (TCE) in showers using TCE contaminated groundwater show increases with time to as high as one-third of occupational threshold limit values. Using a scaled down experimental shower, such volatilization and subsequent decay in air was also demonstrated. Using a simplified indoor air model and assuming complete volatilization from a full range of typical water uses within the home, calculations indicate that the expected air inhalation exposures can be substantially higher than those from ingestion of these chemicals in drinking water. Although the regulation of toxic chemicals in potable water supplies has focused traditionally on direct ingestion, the volatilization and inhalation from other much greater volume indoor uses of water should be considered as well.