tbuckley/cabot-search huggingface dataset:
Thrombotic Microangiopathy with Targeted Cancer Agents
Authors: John A. Blake-Haskins, Robert J. Lechleider, Robert J. Kreitman
Journal: Clinical Cancer Research (2011)

Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are clinically similar disorders characterized by microvascular thrombosis, hemolysis, thrombocytopenia, and end-organ damage. Although they may present with overlapping symptoms, multiple etiologies have been proposed for these thrombotic microangiopathies (TMA). Chemotherapy-induced TMA, which has been described with the use of mitomycin, gemcitabine, and other drugs, has a poor prognosis. Recently, reports of TMA associated with targeted cancer agents have surfaced in the literature. We discuss the clinical presentation, outcome, and etiology of TMA reported with the use of immunotoxins, monoclonal antibodies, and tyrosine kinase inhibitors. A search of PubMed and meeting abstracts was conducted for cases of TMA with the use of targeted cancer agents. The defining symptoms, laboratory values, time to onset, and patient outcomes were compiled. Consistent definitions of TMA and grading of severity in these cases are lacking. However, presentation of TMA in these cases revealed the importance of monitoring for renal toxicity, hemolysis, and thrombocytopenia. Patient outcomes seem to differ from those seen in cases of chemotherapy-induced TMA and may reflect a different underlying etiology. Little is known about the pathogenesis of TMA with targeted cancer agents. In contrast to chemotherapy-induced TMA, partial to full reversibility may be a common outcome. However, further research is warranted into optimal management of patients diagnosed with TMA following treatment with targeted agents.
The Noncoding RNA <i>MALAT1</i> Is a Critical Regulator of the Metastasis Phenotype of Lung Cancer Cells
Authors: Tony Gutschner, Monika Hämmerle, Moritz Eißmann, Jeff Hsu, Youngsoo Kim, Gene Hung, Alexey Revenko, Gayatri Arun, Marion Stentrup, Matthias Groß, Martin Zörnig, A. Robert MacLeod, David L. Spector, Sven Diederichs
Journal: Cancer Research (2012)

Abstract The long noncoding RNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1), also known as MALAT-1 or NEAT2 (nuclear-enriched abundant transcript 2), is a highly conserved nuclear noncoding RNA (ncRNA) and a predictive marker for metastasis development in lung cancer. To uncover its functional importance, we developed a MALAT1 knockout model in human lung tumor cells by genomically integrating RNA destabilizing elements using zinc finger nucleases. The achieved 1,000-fold MALAT1 silencing provides a unique loss-of-function model. Proposed mechanisms of action include regulation of splicing or gene expression. In lung cancer, MALAT1 does not alter alternative splicing but actively regulates gene expression including a set of metastasis-associated genes. Consequently, MALAT1-deficient cells are impaired in migration and form fewer tumor nodules in a mouse xenograft. Antisense oligonucleotides (ASO) blocking MALAT1 prevent metastasis formation after tumor implantation. Thus, targeting MALAT1 with ASOs provides a potential therapeutic approach to prevent lung cancer metastasis with this ncRNA serving as both predictive marker and therapeutic target. Finally, regulating gene expression, but not alternative splicing, is the critical function of MALAT1 in lung cancer metastasis. In summary, 10 years after the discovery of the lncRNA MALAT1 as a biomarker for lung cancer metastasis, our loss-of-function model unravels the active function of MALAT1 as a regulator of gene expression governing hallmarks of lung cancer metastasis. Cancer Res; 73(3); 1180–9. ©2012 AACR.
Food buying habits of people who buy wine or beer: cross sectional study
Authors: Ditte Johansen, Karina Friis, Erik Skovenborg, Morten Grønbæk
Journal: BMJ (2006)

<h3>Abstract</h3> <b>Objective</b> To investigate whether people who buy wine buy healthier food items than those who buy beer. <b>Design</b> Cross sectional study. <b>Setting</b> Supermarkets in Denmark. <b>Data</b> Information on number, type of item, and total charge from 3.5 million transactions over a period of six months. <b>Results</b> Wine buyers bought more olives, fruit and vegetables, poultry, cooking oil, and low fat cheese, milk, and meat than beer buyers. Beer buyers bought more ready cooked dishes, sugar, cold cuts, chips, pork, butter or margarine, sausages, lamb, and soft drinks than wine buyers. <b>Conclusions</b> Wine buyers made more purchases of healthy food items than people who buy beer.
CTLA-4-Mediated Inhibition in Regulation of T Cell Responses: Mechanisms and Manipulation in Tumor Immunotherapy
Authors: Cynthia A. Chambers, Michael S. Kuhns, Jackson G. Egen, James P. Allison
Journal: Annual Review of Immunology (2001)

The T cell compartment of adaptive immunity provides vertebrates with the potential to survey for and respond specifically to an incredible diversity of antigens. The T cell repertoire must be carefully regulated to prevent unwanted responses to self. In the periphery, one important level of regulation is the action of costimulatory signals in concert with T cell antigen-receptor (TCR) signals to promote full T cell activation. The past few years have revealed that costimulation is quite complex, involving an integration of activating signals and inhibitory signals from CD28 and CTLA-4 molecules, respectively, with TCR signals to determine the outcome of a T cell's encounter with antigen. Newly emerging data suggest that inhibitory signals mediated by CTLA-4 not only can determine whether T cells become activated, but also can play a role in regulating the clonal representation in a polyclonal response. This review primarily focuses on the cellular and molecular mechanisms of regulation by CTLA-4 and its manipulation as a strategy for tumor immunotherapy.
Characteristics of transient outward current in human ventricular myocytes from patients with terminal heart failure.
Authors: M Näbauer, D J Beuckelmann, E Erdmann
Journal: Circulation Research (1993)

A variety of outward currents exists in ventricular myocardium of different species influencing action potential duration and electrical activity. Transient outward currents have been reported in ventricular tissue of some animals but are small or absent in others. This study was conducted to investigate whether a transient outward current exists in human ventricular myocardium and to characterize its basic electrophysiological properties. Currents were recorded from enzymatically isolated human ventricular myocytes obtained from explanted hearts of 22 patients with terminal heart failure. In almost all cells studied, a transient outward current could be recorded on depolarization to between -20 and +80 mV. The size of the transient outward current was usually large enough to mask the Ca2+ current. It could be recorded under conditions in which Ca2+ influx and intracellular Ca2+ transients were suppressed. Basic current characteristics were similar to transient outward currents observed in other species. Inactivation of the transient outward current was monoexponential, with a time constant of 54.8 +/- 3.7 milliseconds at +40 mV. Half-maximal activation occurred at 16.7 +/- 1.6 mV; half-maximal steady-state inactivation occurred at -34.5 +/- 2.3 mV. Frequency-dependent reduction of peak transient outward current was 29.8 +/- 1.4% at 2 Hz compared with resting conditions. Recovery from inactivation was voltage dependent and had a biexponential time course; the faster time constant (41.0 +/- 6.5 milliseconds at -80 mV) accounted for 86.0 +/- 5.2% of total current. The transient outward current was sensitive to 4-aminopyridine (IC50, 1.15 mM). These results indicate that a large Ca(2+)-independent transient outward K+ current is present in human ventricular myocytes that might be regulated by physiological or pathological events and is a potential site for pharmacological intervention.
Health Status of Adult Long-term Survivors of Childhood Cancer: A Report From the Childhood Cancer Survivor Study
Authors: M. M. Hudson
Journal: JAMA (2003)

Adult survivors of childhood cancer are at risk for medical and psychosocial sequelae that may adversely affect their health status.To compare the health status of adult survivors of childhood cancer and siblings and to identify factors associated with adverse outcomes.Health status was assessed in 9535 adult participants of the Childhood Cancer Survivor Study, a cohort of long-term survivors of childhood cancer who were diagnosed between 1970 and 1986. A randomly selected cohort of the survivors' siblings (n = 2916) served as a comparison group.Six health status domains were assessed: general health, mental health, functional status, activity limitations, cancer-related pain, and cancer-related anxiety/fears. The first 4 domains were assessed in the control group.Survivors were significantly more likely to report adverse general health (odds ratio [OR], 2.5; 95% confidence interval [CI], 2.1-3.0; P<.001), mental health (OR, 1.8; 95% CI, 1.6-2.1; P<.001), activity limitations (OR, 2.7; 95% CI, 2.3-3.3; P<.001), and functional impairment (OR, 5.2; 95% CI, 4.1-6.6; P<.001), compared with siblings. Forty-four percent of survivors reported at least 1 adversely affected health status domain. Sociodemographic factors associated with reporting at least 1 adverse health status domain included being female (OR, 1.4; 95% CI, 1.3-1.6; P<.001), lower level of educational attainment (OR, 2.0; 95% CI, 1.8-2.2; P<.001), and annual income less than 20 000 dollars (OR, 1.8; 95% CI, 1.6-2.1; P<.001). Relative to those survivors with childhood leukemia, an increased risk was observed for at least 1 adverse health status domain among those with bone tumors (OR, 2.1; 95% CI, 1.8-2.5; P<.001), central nervous system tumors (OR, 1.7; 95% CI, 1.5-2.0; P<.001), and sarcomas (OR, 1.2; 95% CI, 1.1-1.5; P =.01).Clinicians caring for adult survivors of childhood cancer should be aware of the substantial risk for adverse health status, especially among females, those with low educational attainment, and those with low household incomes.
EULAR/PReS endorsed consensus criteria for the classification of childhood vasculitides
Authors: S Ozen
Journal: Annals of the Rheumatic Diseases (2005)

<b>Background:</b> There has been a lack of appropriate classification criteria for vasculitis in children. <b>Objective:</b> To develop a widely accepted general classification for the vasculitides observed in children and specific and realistic classification criteria for common childhood vasculitides (Henoch-Schönlein purpura (HSP), Kawasaki disease (KD), childhood polyarteritis nodosa (PAN), Wegener's granulomatosis (WG), and Takayasu arteritis (TA)). <b>Methods:</b> The project was divided into two phases: (1) the Delphi technique was used to gather opinions from a wide spectrum of paediatric rheumatologists and nephrologists; (2) a consensus conference using nominal group technique was held. Ten international experts, all paediatricians, met for the consensus conference. Agreement of at least 80% of the participants was defined as consensus. <b>Results:</b> Consensus was reached to base the general working classification for childhood vasculitides on vessel size. The small vessel disease was further subcategorised into "granulomatous" and "non-granulomatous." Final criteria were developed to classify a child as HSP, KD, childhood PAN, WG, or TA, with changes introduced based on paediatric experience. Mandatory criteria were suggested for all diseases except WG. <b>Conclusions:</b> It is hoped that the suggested criteria will be widely accepted around the world because of the reliable techniques used and the international and multispecialist composition of the expert group involved.
Prediction models in reproductive medicine: a critical appraisal†
Authors: Esther Leushuis, Jan Willem van der Steeg, Pieternel Steures, Patrick M.M. Bossuyt, Marinus J.C. Eijkemans, Fulco van der Veen, Ben W.J. Mol, Peter G.A. Hompes
Journal: Human Reproduction Update (2009)

Prediction models have been developed in reproductive medicine to help assess the chances of a treatment-(in)dependent pregnancy. Careful evaluation is needed before these models can be implemented in clinical practice. We systematically searched the literature for papers reporting prediction models in reproductive medicine for three strategies: expectant management, intrauterine insemination (IUI) or in vitro fertilization (IVF). We evaluated which phases of development these models had passed, distinguishing between (i) model derivation, (ii) internal and/or external validation, and (iii) impact analysis. We summarized their performance at external validation in terms of discrimination and calibration. We identified 36 papers reporting on 29 prediction models. There were 9 models for the prediction of treatment-independent pregnancy, 3 for the prediction of pregnancy after IUI and 17 for the prediction of pregnancy after IVF. All of the models had completed the phase of model derivation. For six models, the validity of the model was assessed only in the population in which it was developed (internal validation). For eight models, the validity was assessed in populations other than the one in which the model was developed (external validation), and only three of these showed good performance. One model had reached the phase of impact analysis. Currently, there are three models with good predictive performance. These models can be used reliably as a guide for making decisions about fertility treatment, in patients similar to the development population. The effects of using these models in patient care have to be further investigated.
Diagnostic Testing of Patients Suspected of Primary Ciliary Dyskinesia
Authors: Wendy A. Stannard, Mark A. Chilvers, Andrew R. Rutman, Chris D. Williams, Chris O'Callaghan
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Electron microscopy (EM) of ciliated epithelium is widely used to diagnose primary ciliary dyskinesia (PCD). Ciliary beat frequency (CBF) has been used to screen samples to determine whether EM is indicated. Beat pattern analysis has been advocated as an additional diagnostic test. Neither has been subject to formal review.To determine the ability of CBF and beat pattern analysis to predict EM-diagnosed PCD.CBF calculation and beat pattern analysis, using high-speed video microscopy, and EM were performed on nasal tissue from 371 patients consecutively referred to the Leicester Royal Infirmary for diagnostic assessment for PCD. With EM as the "gold standard," receiver operating characteristic (ROC) curves were constructed and sensitivity, specificity, and positive (PPV) and negative (NPV) predictive values were calculated for CBF less than 11 Hz, ciliary dyskinesia score equal to or exceeding 2, at least 90% of ciliated edges beating dyskinetically, and an immotility index equal to or exceeding 10%.PCD was excluded in 270 patients and confirmed in 70 by EM. The sensitivity, specificity, PPV, and NPV for CBF less than 11 Hz were 87.1, 77.2, 50.0, and 95.8%, respectively. These values were higher for ciliary dyskinesia scores equal to or exceeding 2 (92.5, 97.6, 91.2, and 98.0%) and when at least 90% of ciliated edges were dyskinetic (97.1, 95.3, 84.6, and 99.2%). ROCs confirmed that the ciliary dyskinesia score and percentage of dyskinetic edges were superior screening indices compared with CBF and the immotility index.The use of CBF alone to screen which biopsies should have EM will result in a significant number of missed diagnoses. Ciliary beat pattern analysis is a more sensitive and specific test for PCD with higher PPV and NPV.
The Effect of Chronic Pain on Diabetes Patients’ Self-Management
Authors: Sarah L. Krein, Michele Heisler, John D. Piette, Fatima Makki, Eve A. Kerr
Journal: Diabetes Care (2005)

OBJECTIVE—Many adults experience chronic pain, yet little is known about the consequences of such pain among individuals with diabetes. The purpose of this study was to examine whether and how chronic pain affects diabetes self-management. RESEARCH DESIGN AND METHODS—This is a cross-sectional study of 993 patients with diabetes receiving care through the Department of Veterans Affairs (VA). Data on chronic pain, defined as pain present most of the time for 6 months or more during the past year, and diabetes self-management were collected through a written survey. Multivariable regression techniques were used to examine the association between the presence and severity of chronic pain and difficulty with diabetes self-management, adjusting for sociodemographic and other health characteristics including depression. RESULTS—Approximately 60% of respondents reported chronic pain. Patients with chronic pain had poorer diabetes self-management overall (P = 0.002) and more difficulty following a recommended exercise plan (adjusted odds ratio [OR] 3.0 [95% CI 2.1–4.1]) and eating plan (1.6 [1.2–2.1]). Individuals with severe or very severe pain, compared with mild or moderate, reported significantly poorer diabetes self-management (P = 0.003), including greater difficulty with taking diabetes medications (2.0 [1.2–3.4]) and exercise (2.5 [1.3–5.0]). CONCLUSIONS—Chronic pain was prevalent in this cohort of patients with diabetes. Even after controlling for general health status and depressive symptoms, chronic pain was a major limiting factor in the performance of self-care behaviors that are important for minimizing diabetes-related complications. Competing demands, such as chronic pain, should be considered when working with patients to develop effective diabetes self-care regimens.
Phase I Clinical and Pharmacology Study of Clofarabine in Patients With Solid and Hematologic Cancers
Authors: Hagop M. Kantarjian, Varsha Gandhi, Peter Kozuch, Stefan Faderl, Francis Giles, Jorge Cortes, Susan O’Brien, Nuhad Ibrahim, Fadlo Khuri, Min Du, Mary Beth Rios, Sima Jeha, Peter McLaughlin, William Plunkett, Michael Keating
Journal: Journal of Clinical Oncology (2003)

To define the maximum-tolerated doses (MTDs) and dose-limiting toxicities (DLTs) of clofarabine, given as a 1-hour infusion daily for 5 days, in patients with solid tumors and with acute leukemia.The initial part of the study defined the MTD and DLT in solid tumors. The second part of the study defined the MTD and DLT in acute leukemia.The starting dose of clofarabine (15 mg/m(2)) was myelosuppressive, requiring several dose de-escalations to 2 mg/m(2), the dose suggested for phase II studies in solid tumors. Dose escalation in acute leukemia started at 7.5 mg/m(2), with several escalations to 55 mg/m(2). The DLT was reversible hepatotoxicity at 55 mg/m(2). The recommended dose for acute leukemia phase II studies was 40 mg/m(2). Among 32 treated patients with acute leukemia, two achieved a complete response and three had a marrow complete response without platelet recovery (hematologic improvement), for an overall response rate of 16%. At 40 mg/m(2), the median plasma clofarabine level was 1.5 micro mol/L (range, 0.42 to 3.2 micro mol/L; n = 7). Cellular and plasma pharmacokinetic studies suggested dose proportionality but showed a wide variation in intracellular concentrations of clofarabine triphosphate.This phase I study defined the following two MTDs for clofarabine given as a 1-hour infusion daily for 5 days: 2 mg/m(2) for solid tumors, the DLT being myelosuppression; and 40 mg/m(2) for acute leukemia, the DLT being hepatotoxicity. Encouraging activity was observed in acute leukemia.
Differential expression of Fas (CD95) and Fas ligand on normal human phagocytes: implications for the regulation of apoptosis in neutrophils.
Authors: W C Liles, P A Kiener, J A Ledbetter, A Aruffo, S J Klebanoff
Journal: The Journal of Experimental Medicine (1996)

Human neutrophils, monocytes, and eosinophils are known to undergo apoptotic cell death. The Fas/Fas ligand pathway has been implicated as an important cellular pathway mediating apoptosis in diverse cell types. We conducted studies to examine the importance of the Fas/FasL system in normal human phagocytes. Although Fas expression was detected on neutrophils, monocytes, and eosinophils, constitutive expression of FasL was restricted to neutrophils. The three types of phagocytes demonstrated differential sensitivity to Fas-induced apoptosis. Only neutrophils were highly susceptible to rapid apoptosis in vitro after stimulation with activating anti-Fas IgM (mAb CH-11). Fas-mediated neutrophil apoptosis was suppressed by incubation with G-CSF, GM-CSF, IFN-gamma, TNF-alpha, or dexamethasone, as well as the selective tyrosine kinase inhibitors, herbimycin A and genistein. Spontaneous neutrophil death in vitro was partially suppressed by Fas-Ig fusion protein or antagonistic anti-Fas IgG1 (mAb ZB4). In coculture experiments, neutrophils released a soluble factor inducing death in Fas-susceptible Jurkat cells via a mechanism sensitive to the presence of Fas-Ig or anti-Fas IgG1. Immunoblot analysis using specific anti-human FasL IgG1 (mAb No. 33) identified a 37-kD protein in lysates of freshly isolated neutrophils and a 30-kD protein in the culture supernatant of neutrophils maintained in vitro. Our results suggest that mature neutrophils may be irrevocably committed to autocrine death by virtue of their constitutive coexpression of cell-surface Fas and FasL via a mechanism that is sensitive to proinflammatory cytokines, glucocorticoids, and inhibitors of tyrosine kinase activity. Furthermore, neutrophils can serve as a source of soluble FasL, which may function in a paracrine pathway to mediate cell death.
Combination Therapy Salmeterol/Fluticasone Versus Doubling Dose of Fluticasone in Children With Asthma
Authors: Anna A. P. H. Vaessen-Verberne, Norbert J. van den Berg, Jan C. van Nierop, Hein J. L. Brackel, Gerardus P. J. M. Gerrits, Wim C. J. Hop, Eric J. Duiverman
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

For children with symptomatic asthma despite low to moderate doses of inhaled corticosteroids, evidence is still lacking whether to add a long-acting bronchodilator or to increase the dose of inhaled corticosteroids.To evaluate whether salmeterol/fluticasone propionate (SFP), 50/100 μg twice a day, is noninferior regarding symptom control compared with fluticasone propionate (FP), 200 μg twice a day Diskus in children with symptomatic asthma.A multicenter, randomized, parallel-group, double-blind study was performed comparing SFP and FP treatment during 26 weeks on asthma control and lung function.A total of 158 children, 6-16 years old, still symptomatic on FP, 100 μg twice a day, during a 4-week run-in period, were included. Percentage of symptom-free days during the last 10 weeks of the treatment period did not differ between treatment groups (per protocol analysis: adjusted mean difference [FP minus SFP] 2.6%; 95% confidence interval, -8.1 to 13.4). Both groups showed substantial improvements of about 25 percent points in symptom-free days (both P < 0.001 from baseline). Lung function measurements (FEV(1), FVC, PEF rate, and maximal expiratory flow) did not differ between groups except for a slight advantage in maximal expiratory flow in the SFP group at 1 week. No differences were found between FP and SFP regarding exacerbation rates, adverse events, or growth.In our study the efficacy on symptom control and lung function of the combination of a long-acting bronchodilator with inhaled corticosteroid is equal to doubling the dose of the inhaled corticosteroid in children still symptomatic on a moderate dose of inhaled corticosteroid.
Evolution of hepatitis B genotype C viral quasi-species during hepatitis B e antigen seroconversion
Authors: Shuang Wu, Fumio Imazeki, Fuat Kurbanov, Kenichi Fukai, Makoto Arai, Tatsuo Kanda, Yutaka Yonemitsu, Yasuhito Tanaka, Masashi Mizokami, Osamu Yokosuka
Journal: Journal of Hepatology (2010)