tbuckley/cabot-search huggingface dataset:
Identification of Genes Upregulated in <i>ALK</i>-Positive and <i>EGFR/KRAS/ALK</i>-Negative Lung Adenocarcinomas
Authors: Hirokazu Okayama, Takashi Kohno, Yuko Ishii, Yoko Shimada, Kouya Shiraishi, Reika Iwakawa, Koh Furuta, Koji Tsuta, Tatsuhiro Shibata, Seiichiro Yamamoto, Shun-ichi Watanabe, Hiromi Sakamoto, Kensuke Kumamoto, Seiichi Takenoshita, Noriko Gotoh, Hideaki Mizuno, Akinori Sarai, Shuichi Kawano, Rui Yamaguchi, Satoru Miyano, Jun Yokota
Journal: Cancer Research (2011)

Abstract Activation of the EGFR, KRAS, and ALK oncogenes defines 3 different pathways of molecular pathogenesis in lung adenocarcinoma. However, many tumors lack activation of any pathway (triple-negative lung adenocarcinomas) posing a challenge for prognosis and treatment. Here, we report an extensive genome-wide expression profiling of 226 primary human stage I–II lung adenocarcinomas that elucidates molecular characteristics of tumors that harbor ALK mutations or that lack EGFR, KRAS, and ALK mutations, that is, triple-negative adenocarcinomas. One hundred and seventy-four genes were selected as being upregulated specifically in 79 lung adenocarcinomas without EGFR and KRAS mutations. Unsupervised clustering using a 174-gene signature, including ALK itself, classified these 2 groups of tumors into ALK-positive cases and 2 distinct groups of triple-negative cases (groups A and B). Notably, group A triple-negative cases had a worse prognosis for relapse and death, compared with cases with EGFR, KRAS, or ALK mutations or group B triple-negative cases. In ALK-positive tumors, 30 genes, including ALK and GRIN2A, were commonly overexpressed, whereas in group A triple-negative cases, 9 genes were commonly overexpressed, including a candidate diagnostic/therapeutic target DEPDC1, that were determined to be critical for predicting a worse prognosis. Our findings are important because they provide a molecular basis of ALK-positive lung adenocarcinomas and triple-negative lung adenocarcinomas and further stratify more or less aggressive subgroups of triple-negative lung ADC, possibly helping identify patients who may gain the most benefit from adjuvant chemotherapy after surgical resection. Cancer Res; 72(1); 100–11. ©2011 AACR.
Quality of colonoscopy in an organised colorectal cancer screening programme with immunochemical faecal occult blood test: the EQuIPE study (Evaluating Quality Indicators of the Performance of Endoscopy)
Authors: Manuel Zorzi, Carlo Senore, Filippo Da Re, Alessandra Barca, Luigina Ada Bonelli, Renato Cannizzaro, Renato Fasoli, Lucia Di Furia, Emilio Di Giulio, Paola Mantellini, Carlo Naldoni, Romano Sassatelli, Douglas Rex, Cesare Hassan, Marco Zappa
Journal: Gut (2014)

<h3>Objectives</h3> To assess variation in the main colonoscopy quality indicators in organised colorectal cancer (CRC) screening programmes based on faecal immunochemical test (FIT). <h3>Design</h3> Data from a case-series of colonoscopies of FIT-positive subjects were provided by 44 Italian CRC screening programmes. Data on screening history, endoscopic procedure and histology results, and additional information on the endoscopy centre and the endoscopists were collected. The adenoma detection rate (ADR) and caecal intubation rate (CIR) were assessed for the whole population and the individual endoscopists. To explore variation in the quality indicators, multilevel analyses were performed according to patient/centre/endoscopist characteristics. <h3>Results</h3> We analysed 75 569 (mean age: 61.3 years; men: 57%) colonoscopies for positive FIT performed by 479 endoscopists in 79 centres. ADR ranged from 13.5% to 75% among endoscopists (mean: 44.8%). ADR was associated with gastroenterology specialty (OR: 0.87 for others, 95% CI 0.76 to 0.96) and, at the endoscopy centre level, with the routine use of sedation (OR: 0.80 if occasional (&lt;33%); 95% CI 0.64 to 1.00) and availability of screening-dedicated sessions (OR: 1.35; 95% CI 1.11 to 1.66). CIR ranged between 58.8% and 100% (mean: 93.1%). Independent predictors of CIR at the endoscopist level were the yearly number of screening colonoscopies performed (OR: 1.51 for endoscopists with &gt;600 colonoscopies; 95% CI 1.11 to 2.04) and, at the endoscopy centre level, screening-dedicated sessions (OR: 2.18; 95% CI 1.24 to 3.83) and higher rates of sedation (OR: 0.47 if occasional; 95% CI 0.24 to 0.92). <h3>Conclusions</h3> The quality of colonoscopy was affected by patient-related, endoscopist-related and centre-related characteristics. Policies addressing organisational issues should improve the quality of colonoscopy in our programme and similar programmes.
Jaundice During Treatment With Oral Contraceptive Agents
Authors: Ulf Larsson-Cohn
Journal: JAMA (1965)

Two patients had jaundice during treatment with oral contraceptives. One of them had a history of idiopathic jaundice of pregnancy. The laboratory data included elevated levels of serum transaminase and alkaline phosphatase, and increased sulfobromophthalein (Bromsulphthalein) retention. Optical microscopy of the livers revealed intrahepatic cholestasis and slight hepatocellular damage. Electron microscopy showed cholestasis and hepato-cellular damage. Similar cases have been reported in the literature.
Regulation of T cell receptor signaling by activation-induced zinc influx
Authors: Mingcan Yu, Won-Woo Lee, Deepak Tomar, Sergey Pryshchep, Marta Czesnikiewicz-Guzik, David L. Lamar, Guangjin Li, Karnail Singh, Lu Tian, Cornelia M. Weyand, Jörg J. Goronzy
Journal: The Journal of Experimental Medicine (2011)

Zinc is a trace element that is essential for innate and adaptive immune responses. In addition to being a structural element of many proteins, zinc also functions as a neurotransmitter and an intracellular messenger. Temporal or spatial changes in bioavailable zinc may influence the activity of several enzymes, including kinases and phosphatases. We provide evidence that zinc functions as an ionic signaling molecule after T cell activation. Cytoplasmic zinc concentrations increased within 1 min after T cell receptor (TCR) triggering, in particular in the subsynaptic compartment. The increase depended on the extracellular zinc concentrations and was inhibited by silencing zinc transporter Zip6. Increased zinc influx reduced the recruitment of SHP-1 to the TCR activation complex, augmented ZAP70 phosphorylation and sustained calcium influx. By calibrating TCR activation thresholds, increased extracellular zinc bioavailability facilitated the induction of T cell proliferative responses to suboptimal stimuli.
Antiretroviral therapy, interferon sensitivity, and virologic setpoint in human immunodeficiency virus/hepatitis C virus coinfected patients
Authors: Ashwin Balagopal, Abraham J. Kandathil, Yvonne H. Higgins, Jonathan Wood, Justin Richer, Jeffrey Quinn, Lois Eldred, Zhiping Li, Stuart C. Ray, Mark S. Sulkowski, David L. Thomas
Journal: Hepatology (2014)

Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) cause substantial mortality, especially in persons chronically infected with both viruses. HIV infection raises plasma HCV RNA levels and diminishes the response to exogenous alpha interferon (IFN). The degree to which antiretroviral therapy (ART) control of infection overcomes these HIV effects is unknown. Participants with HIV-HCV coinfection were enrolled in a trial to measure HCV viral kinetics after IFN administration (ΔHCV IFN ) twice: initially before (pre-ART) and then after (post-ART) HIV RNA suppression. Liver tissue was obtained 2-4 hours before each IFN injection to measure interferon stimulated genes (ISGs). Following ART, the ΔHCV IFN at 72 hours (ΔHCV IFN,72 ) increased in 15/19 (78.9%) participants by a median (interquartile range [IQR]) of 0.11 log 10 IU/mL (0.00-0.40; P &lt; 0.05). Increases in ΔHCV IFN,72 post-ART were associated with decreased hepatic expression of several ISGs ( r = −0.68; P = 0.001); a 2-fold reduction in a four-gene ISG signature predicted an increase in ΔHCV IFN,72 of 0.78 log 10 IU/mL (95% confidence interval [CI] 0.36,1.20). Pre- and post-ART ΔHCV IFN,72 were closely associated ( r = 0.87; P &lt; 0.001). HCV virologic setpoint also changed after ART (ΔHCV ART ): transient median increases of 0.28 log 10 IU/mL were followed by eventual median decreases from baseline of 0.21 log 10 IU/mL ( P = 0.002). A bivariate model of HIV RNA control ( P &lt; 0.05) and increased expression of a nine-gene ISG signature ( P &lt; 0.001) predicted the eventual decreased ΔHCV ART . Conclusion : ART is associated with lower post-IFN HCV RNA levels and that change is linked to reduced hepatic ISG expression. These data support recommendations to provide ART prior to IFN-based treatment of HCV and may provide insights into the pathogenesis of HIV-HCV coinfection. (Hepatology 2014;60:477–486)
Sputum and ciliary inhibition in asthma.
Authors: M J Dulfano, C K Luk
Journal: Thorax (1982)

Twenty-eight sputum samples collected from 20 patients with chronic bronchial asthma of atopic and intrinsic clinical types were incubated with human bronchial explants to study their influence on ciliary motility. Of these, 19 (68%) of the sputa exerted a ciliary inhibitory effect of varying degree in a two-hour period. Analysis of the data indicates that (1) the ciliary inhibitory effect was invariably present when patients produced a distinctive slurry sputum; (2) this occurred more frequently during clinical exacerbations; (3) the induced ciliary inhibition was reversible on removal of the sputum; (4) the intensity of the ciliary inhibitory effect decreased with clinical improvement of the patient; (5) the inhibitory effect was unrelated to the medications used; (6) it was equally common in the atopic and the intrinsic types of asthmatic patients; (7) the effect was not pH dependent or related to the degree of eosinophilia. The ciliary inhibitory factor in sputum was identified as having a molecular weight of 6000-8000. It may play a part in the pathogenesis of asthma and recognition of sputum containing it carries implications for treatment.
Longitudinal associations of socioeconomic position in childhood and adulthood with decline in lung function over 20 years: results from a population-based cohort of British men
Authors: S. E. Ramsay, P. H. Whincup, L. T. Lennon, R. W. Morris, S. G. Wannamethee
Journal: Thorax (2011)

<h3>Background</h3> Associations of socioeconomic position with lung function are reported mostly from cross-sectional studies. The aim of this study was to investigate the associations between socioeconomic position both in adulthood and childhood with changes in lung function over a 20-year period. <h3>Methods</h3> A socioeconomically representative cohort of 7735 British men aged 40–59 years was followed-up from 1978–1980 to 1998–2000. Lung function (height-standardised forced expiratory volume in 1 s (FEV<sub>1</sub>) and forced vital capacity (FVC)) was assessed at both time points in 4252 survivors. Adult socioeconomic position was derived from longest-held occupation in middle age and childhood socioeconomic position from father9s longest-held occupation. <h3>Results</h3> Both FEV<sub>1</sub> and FVC declined over time; the decline increased progressively from social class I (highest) to V (lowest); p for trend ≤0.0001. The mean difference in decline comparing manual versus non-manual groups was −0.13 litres (95% CI −0.16 to −0.10) for FEV<sub>1</sub> and −0.09 litres (95% CI −0.13 to −0.05) for FVC. These differences remained after adjustment for age, cigarette smoking, body mass index, physical activity and history of bronchitis. Similar differences in lung function decline were observed comparing manual with non-manual childhood social classes, although the differences were reduced by adjustment for adult social class and risk factors. Men in manual social classes in both childhood and adulthood had the greatest decline in lung function compared to those in non-manual groups in childhood and adulthood. <h3>Conclusions</h3> Socioeconomic position across the life course could have a significant impact on decline in lung function in later life. The role of environmental factors associated with socioeconomic position merits further exploration.
Lower extremity performance following ACL rehabilitation in the KANON-trial: impact of reconstruction and predictive value at 2 and 5 years
Authors: Ylva B Ericsson, Ewa M Roos, Richard B Frobell
Journal: British Journal of Sports Medicine (2013)

Background The additional effect of anterior cruciate ligament (ACL) reconstruction on muscle strength and physical performance after a structured exercise programme is not well understood. Objectives To investigate and compare muscle strength and physical performance test results after a structured exercise programme, in young active adults with acute ACL injury, between those treated with and without ACL reconstruction (ACLR) and to evaluate these test results as predictors of clinical outcomes 2 and 5 years after injury. Study design Prospective cohort study. Methods In a treatment randomised controlled trial of acute ACL injury (the KANON-study), 87/121 young active adults underwent two muscle strength tests and five physical performance tests after a structured exercise programme (median 37 (IQR 24) weeks after injury). Results were presented and compared as limb symmetry indices (LSI); endpoints in predictive analyses were having a delayed ACLR over the first 5 years and self-reported knee function (Knee injury and Osteoarthritis Outcome Score; KOOS 4 ) at 2 and 5 years. Results Overall, 74–95% of patients had LSI≥90% in the individual tests, with no difference between treatment groups (p=0.08–0.92). Results of the one-leg rise tests predicted KOOS 4 at 2 and 5 years (R 2 =0.25 and 0.24, p=0.001 and 0.002) and vertical hop results predicted having a delayed ACLR over a 5-year course after injury (p=0.048) in those starting with exercise alone (n=21). Conclusions After an acute ACL tear, the majority of young active adults regain physical performance and muscle strength after a structured exercise programme, with or without surgical reconstruction. Poor physical performance at the end of rehabilitation predicted worse patient-reported outcomes at 2 and 5 years regardless of treatment. Registration number: ISRCTN84752559.
T Cell Responses to Pre-Erythrocytic Stages of Malaria: Role in Protection and Vaccine Development Against Pre-Erythrocytic Stages
Authors: E H Nardin, R S Nussenzweig
Journal: Annual Review of Immunology (1993)

Malaria remains a leading cause of human morbidity and mortality due to the inability of insecticides and chemotherapy/chemoprophylaxis to eliminate the vectors or disease caused by this protozoan parasite. In an effort to develop new methods of control, vaccines targeted to the various stages of the complex life cycle of Plasmodium have been developed. This review describes recent advances in the elucidation of cell-mediated immune mechanisms directed against sporozoites and liver stages of malaria parasites, their role in protection, and their relation to vaccine development. Recent data on the molecular basis of sporozoite-liver cell interaction are presented, and these may provide new approaches for chemoprophylaxis and immunoprophylaxis. We describe the role of the circumsporozoite protein, the major sporozoite surface antigen, in sporozoite movement and as a target of humoral immunity. The recognition of the circumsporozoite protein by human T cells is reviewed with emphasis on cytotoxic T cells and immune resistance against the exo-erythrocytic stage of the parasite. Earlier concepts regarding the polymorphisms of the circumsporozoite protein, the immunological relevance of this polymorphism, and predictions regarding vaccine development are reevaluated on the basis of recent data from different malaria endemic areas. Non-CS sporozoite antigens and liver stage antigens are discussed as potential targets for immune intervention. Recent experimental approaches such as multiple antigen peptides, recombinant live vectors, and new more potent adjuvants are considered for the development of more effective malaria vaccine formulations.
5,6-Dimethylxanthenone-4-Acetic Acid in the Treatment of Refractory Tumors: a Phase I Safety Study of a Vascular Disrupting Agent
Authors: Mark J. McKeage, Peter Fong, Mark Jeffery, Bruce C. Baguley, Phil Kestell, Miroslav Ravic, Michael B. Jameson
Journal: Clinical Cancer Research (2006)

Abstract This phase I safety study aimed to identify the optimal dose of the vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) for combination studies. Using a crossover design, 15 patients with refractory tumors were allocated randomly to receive six sequential doses of DMXAA (300, 600, 1,200, 1,800, 2,400, and 3,000 mg m−2), each given once-weekly as a 20-minute i.v. infusion. The drug was generally well tolerated. Transient, moderate increases in the heart rate–corrected cardiac QT interval occurred at the two highest doses. DMXAA produced transient dose-dependent increases in blood pressure. Transient, dose-related visual disturbances occurred at the two highest doses. No significant changes in Ktrans and kep were observed but Ve, a secondary dynamic contrast–enhanced magnetic resonance imaging variable, increased significantly after giving DMXAA. At 1,200 mg m−2, the Cmax and the area under the concentration-time curve over 24 hours for total and free DMXAA plasma concentrations were 315 ± 25.8 μg/mL, 29 ± 6.4 μg/mL·d, 8.0 ± 1.77 μg/mL, and 0.43 ± 0.07 μg/mL·d, respectively. Plasma levels of the vascular damage biomarker 5-hydroxyindoleacetic acid increased in the 4 hours after treatment in a dose-dependent fashion up to 1,200 mg m−2, with a plateau thereafter. Doses in the range of 1,200 mg m−2 have been selected for further studies (phase II combination studies with taxanes and platins are under way) because this dose produced no significant effect on heart rate–corrected cardiac QT interval, produced near maximum levels of 5-hydroxyindoleacetic acid, achieved DMXAA plasma concentrations within the preclinical therapeutic range, and was well tolerated.
Transcutaneous Ultrasound Augments Lysis of Arterial Thrombi In Vivo
Authors: Huai Luo, Toshihiko Nishioka, Michael C. Fishbein, Bojan Cercek, James S. Forrester, Chong-Jin Kim, Hans Berglund, Robert J. Siegel
Journal: Circulation (1996)

External ultrasound has a synergistic effect on thrombus disruption with thrombolytic agents in vitro. We hypothesized that transcutaneous ultrasound could augment thrombolysis in vivo.Thrombus formation was induced electrically in 48 pairs of iliofemoral arteries of 24 rabbits; arterial occlusions were documented angiographically. In 17 of 24 rabbits, 25000 units/kg streptokinase was then administered intravenously. The pairs of iliofemoral arteries were randomized to receive ultrasound treatment or no ultrasound treatment. Low-frequency (26 kHz) ultrasound (continuous wave, 18 W/cm2) was applied transcutaneously over the area of occlusion. In 7 of 24 rabbits, 14 thrombotically occluded iliofemoral arteries were exposed to ultrasound alone without streptokinase. The results were evaluated through the use of angiography (TIMI grade flow) and histopathology. After 30 +/- 10 minutes of activated sonication combined with intravenous streptokinase, 10 of 17 iliofemoral arteries (59%) treated with transcutaneous ultrasound were widely patent angiographically, with TIMI grade 3 flow. Histologically, the patent arteries had only minimal focal moral thrombus. The angiographic patency rate was significantly lower in the control groups: 1 of 17 arteries (6%) treated with streptokinase alone (P = .0012) and 1 of 14 arteries (7%) treated with ultrasound alone (P = .0036).In vivo transcutaneous ultrasound significantly augments lysis of thrombi with streptokinase in rabbit iliofemoral arteries.
Why so complex? Emotional mediation of revenge, forgiveness, and reconciliation
Authors: Filippo Aureli, Colleen M. Schaffner
Journal: Behavioral and Brain Sciences (2012)

Abstract Humans have the cognitive abilities to implement the revenge and forgiveness systems hypothesized by McCullough et al., but the evidence suggests that simpler processes may underlie most revenge cases in humans and other animals. The mediating role of emotions can be at the basis of the flexibility needed in the hypothesized systems and the associated assessment of social relationships.
Responses of Individual Cardiac Chambers to Stimulation of the Cervical Vagosympathetic Trunk in Atropinized Dogs
Authors: WALTER C. RANDALL, DONALD V. PRIOLA, J. B. PACE, David C. Randall, David C. Harold Spurgeon
Journal: Circulation Research (1967)

Employing multiple chamber pressure recording techniques, the presence of fibers within the right and left cervical vagosympathetic trunks which innervate both right and left ventricles has been demonstrated. Electrical excitation of the cervical vagosympathetic in the atropinized dog elicited a distinct increase in both rate of rise and in maximal systolic intraventricular pressures, with or without cardiac acceleration. It persisted during electrical pacing of the right ventricle. In many animals, the a-wave of the atrial pressure traces also showed augmentation, but this was not consistent or essential for the ventricular response. Although pulmonary vasoconstriction was not ruled out as a concurrent event, its contribution to right ventricular augmentation was not essential as demonstrated in bilateral, isovolumetric ventricular preparations. The evidence indicates the presence of adrenergic fibers in the cervical vagosympathetic trunk which are distributed to all four cardiac chambers. Their effects on the heart are abolished by the β-blocking agent, propranolol, and are unaffected by eserine administration.
Synovial immunopathological changes associated with successful abatacept therapy in a case of severe refractory psoriatic arthritis
Authors: J. D. Canete, R. Celis, V. Hernandez, J. L. Pablos, R. Sanmarti
Journal: Annals of the Rheumatic Diseases (2009)

The overlapping characteristics of rheumatoid arthritis and psoriatic arthritis (PsA) in terms of T-cell and macrophage infiltration and cytokine patterns suggest that targeted therapies could have a similar effect in both diseases.1 Tumour necrosis factor alpha (TNFα) blockers have shown efficacy in PsA, but a significant proportion of patients do not respond or are intolerant to these drugs.2 In these patients, agents blocking T-cell activation are a potential therapeutic option. Preliminary data have shown efficacy of abatacept in psoriasis vulgaris3 and spondyloarthropathy.4 However, data on the effects of abatacept in PsA are lacking. We describe the clinical and immunopathological effects of abatacept in a patient with PsA refractory to TNFα therapy.

A …
The Use of Dorzolamide and Pilocarpine as Adjunctive Therapy to Timolol in Patients with Elevated Intraocular Pressure
Authors: Ellen R. Strahlman, Roger Vogel, Robert Tipping, Coleen M. Clineschmidt, Richard Lewis, Edwin Keates, Harry Quigley, Thomas Zimmerman, Mark B. Abelson, Robert C. Allen, Reay H. Brown, Leonard R. Cacioppo, Marshall N. Cyrlin, David K. Gieser, Kevin C. Greenidge, Ronald L. Gross, David W. Karp, Melvyn M. Koby, Michael Kass, Robert Laibovitz, Charles D. McMahon, Charles S. Ostrov, Thomas Walters, Robert Ritch, John R. Samples, Joel S. Schuman, Janet Serle, M. Angela Vela-Thomas, Jacob Wilensky, Janet Boyle, Erik Lippa, Scott Reines, Kim Strohmaier
Journal: Ophthalmology (1996)