tbuckley/cabot-search huggingface dataset:
A Systems Perspective of Ras Signaling in Cancer
Authors: Edward C. Stites, Kodi S. Ravichandran
Journal: Clinical Cancer Research (2009)

The development of cancer reflects the complex interactions and properties of many proteins functioning as part of large biochemical networks within the cancer cell. Although traditional experimental models have provided us with wonderful insights on the behavior of individual proteins within a cancer cell, they have been deficient in simultaneously keeping track of many proteins and their interactions in large networks. Computational models have emerged as a powerful tool for investigating biochemical networks due to their ability to meaningfully assimilate numerous network properties. Using the well-studied Ras oncogene as an example, we discuss the use of models to investigate pathologic Ras signaling and describe how these models could play a role in the development of new cancer drugs and the design of individualized treatment regimens.
Inhibition of Allogeneic T Cell Proliferation by Indoleamine 2,3-Dioxygenase–expressing Dendritic Cells
Authors: Peter Terness, Thomas M. Bauer, Lars Röse, Christoph Dufter, Andrea Watzlik, Helmut Simon, Gerhard Opelz
Journal: The Journal of Experimental Medicine (2002)

Indoleamine 2,3-dioxygenase (IDO), an enzyme involved in the catabolism of tryptophan, is expressed in certain cells and tissues, particularly in antigen-presenting cells of lymphoid organs and in the placenta. It was shown that IDO prevents rejection of the fetus during pregnancy, probably by inhibiting alloreactive T cells, and it was suggested that IDO-expression in antigen-presenting cells may control autoreactive immune responses. Degradation of tryptophan, an essential amino acid required for cell proliferation, was reported to be the mechanism of IDO-induced T cell suppression. Because we wanted to study the action of IDO-expressing dendritic cells (DCs) on allogeneic T cells, the human IDO gene was inserted into an adenoviral vector and expressed in DCs. Transgenic DCs decreased the concentration of tryptophan, increased the concentration of kynurenine, the main tryptophan metabolite, and suppressed allogeneic T cell proliferation in vitro. Kynurenine, 3-hydroxykynurenine, and 3-hydroxyanthranilic acid, but no other IDO-induced tryptophan metabolites, suppressed the T cell response, the suppressive effects being additive. T cells, once stopped in their proliferation, could not be restimulated. Inhibition of proliferation was likely due to T cell death because suppressive tryptophan catabolites exerted a cytotoxic action on CD3+ cells. This action preferentially affected activated T cells and increased gradually with exposure time. In addition to T cells, B and natural killer (NK) cells were also killed, whereas DCs were not affected. Our findings shed light on suppressive mechanisms mediated by DCs and provide an explanation for important biological processes in which IDO activity apparently is increased, such as protection of the fetus from rejection during pregnancy and possibly T cell death in HIV-infected patients.
Role of ultrasound guided fine needle aspiration biopsy in the diagnosis of hepatocellular carcinoma.
Authors: G Sbolli, F Fornari, G Civardi, M Di Stasi, L Cavanna, E Buscarini, L Buscarini
Journal: Gut (1990)

In 170 cases of hepatocellular carcinoma, ultrasound showed a high sensitivity in identifying focal liver lesions. Fine needle aspiration biopsy guided by ultrasound yielded a pathological diagnosis in the majority of cases. The advantages of this technique, its high diagnostic yield and low cost, render the older technique of blind percutaneous biopsy using a coarse needle obsolete. Laparoscopy retains its essential role in selected cases. Complementary use of fine needle aspiration biopsy under ultrasound guidance and laparoscopy assures the highest rate of diagnostic accuracy in hepatocellular carcinoma. We confirm the poor sensitivity of alpha fetoprotein.
Impaired left ventricular relaxation in type 2 diabetic rats is related to myocardial accumulation of N<sup>ɛ</sup>‐(carboxymethyl) lysine
Authors: Stefan Schäfer, Jochen Huber, Cornelia Wihler, Hartmut Rütten, Andreas E. Busch, Wolfgang Linz
Journal: European Journal of Heart Failure (2005)
Transcriptional Profiling Identifies Altered Intracellular Labile Iron Homeostasis as a Contributing Factor to the Toxicity of Adaphostin: Decreased Vascular Endothelial Growth Factor Secretion Is Independent of Hypoxia-Inducible Factor-1 Regulation
Authors: Curtis Hose, Gurmeet Kaur, Edward A. Sausville, Anne Monks
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Adaphostin was developed as an inhibitor of the p210bcr-abl tyrosine kinase, but as its activity is not limited to tumor cell lines containing this translocation, transcriptional profiling was used as a tool to elucidate additional mechanisms responsible for adaphostin cytotoxicity. Experimental design: Profiles of drug-induced transcriptional changes were measured in three hematopoietic cell lines following 1 and 10 μmol/L adaphostin for 2 to 6 hours and then confirmed with real-time reverse transcription-PCR (2-24 hours). These data indicated altered iron homeostasis, and this was confirmed experimentally. Alteration of vascular endothelial growth factor (VEGF) secretion through hypoxia-inducible factor-1 (HIF-1) regulation was also investigated. Results: Drug-induced genes included heat shock proteins and ubiquitins, but an intriguing response was the induction of ferritins. Measurement of the labile iron pool showed release of chelatable iron immediately after treatment with adaphostin and was quenched with the addition of an iron chelator. Pretreatment of cells with desferrioxamine and N-acetyl-cysteine reduced but did not ablate the sensitivity of the cells to adaphostin, and desferrioxamine was able to modulate adaphostin-induced activation of p38 and inactivation of AKT. VEGF secretion was shown to be reduced in cell lines after the addition of adaphostin but was not dependent on HIF-1. Conclusions: Adaphostin-induced cytotoxicity is caused in part by a rapid release of free iron, leading to redox perturbations and cell death. Despite this, reduced VEGF secretion was found to be independent of regulation by the redox responsive transcription factor HIF-1. Thus, adaphostin remains an interesting agent with the ability to kill tumor cells directly and modulate angiogenesis.
Diaphragm Activation during Exercise in Chronic Obstructive Pulmonary Disease
Authors: CHRISTER SINDERBY, JADRANKA SPAHIJA, JENNIFER BECK, DAREK KAMINSKI, SHENG YAN, NORMAN COMTOIS, PAWEL SLIWINSKI
Journal: American Journal of Respiratory and Critical Care Medicine (2001)

Although it has been postulated that central inhibition of respiratory drive may prevent development of diaphragm fatigue in patients with chronic obstructive pulmonary disease (COPD) during exercise, this premise has not been validated. We evaluated diaphragm electrical activation (EAdi) relative to maximum in 10 patients with moderately severe COPD at rest and during incremental exhaustive bicycle exercise. Flow was measured with a pneumotachograph and volume by integration of flow. EAdi and transdiaphragmatic pressures (Pdi) were measured using an esophageal catheter. End-expiratory lung volume (EELV) was assessed by inspiratory capacity (IC) maneuvers, and maximal voluntary EAdi was obtained during these maneuvers. Minute ventilation (V˙ e) was 12.2 ± 1.9 L/min (mean ± SD) at rest, and increased progressively (p < 0.001) to 31.0 ± 7.8 L/min at end-exercise. EELV increased during exercise (p < 0.001) causing end-inspiratory lung volume to attain 97 ± 3% of TLC at end-exercise. Pdi at rest was 9.4 ± 3.2 cm H2O and increased during the first two thirds of exercise (p < 0.001) to plateau at about 13 cm H2O. EAdi was 24 ± 6% of voluntary maximal at rest and increased progressively during exercise (p < 0.001) to reach 81 ± 7% at end-exercise. In conclusion, dynamic hyperinflation during exhaustive exercise in patients with COPD reduces diaphragm pressure-generating capacity, promoting high levels of diaphragm activation.
Subjective sensation of dyspnea relates to physical inactivity in COPD
Authors: Milla Katajisto, Henna Kupiainen, Piritta Rantanen, Ari Lindqvist, Heikki Tikkanen, Maritta Kilpeläinen, Tarja Laitinen
Journal: European Respiratory Journal (2012)

Background:  The importance of physical activity in COPD has been recognised. Physical inactivity relates to exacerbations, hospitalisations and mortality. We dont know why significant proportion of patients who have severe disease can maintain physical activity, while others turn inactive at early stages of the disease. More information is needed about the factors behind physical activity.   Aim of the study:  The aim was to study physical activity in well defined COPD patient cohort. We asked about daily life activity, history in sports and barriers for exercising.   Methods:  The study was postal survey of the COPD cohort (N=719) recruited in Helsinki and Turku University Central Hospitals and followed since 2005. Validated questions were chosen to evaluate physical activity, dyspnea, and quality of life.   Results:  Fifty percent of the participants exercised >2 times a week throughout the year. Participants showed great variation in activity and sport choices. Active patients did not differ from inactive by gender, age, smoking status, somatic co-morbidities, or BMI. Activity correlated significantly with patients9 reported dyspnea (r=0.32, p   Conclusion : Co-morbidities did not explain physical inactivity. Even though proportion of inactive patients increased with disease progression, many patients with severe disease exercised. Dyspnea related to physical inactivity. When COPD patient suffers from dyspnea, actions should be taken to promote physical activity.
Is shared care with annual hospital review better value for money than predominantly hospital-based care in patients with established stable rheumatoid arthritis?
Authors: L. Mary Davies, E. Anne Fargher, K. Tricker, P. Dawes, D. L Scott, D. Symmons
Journal: Annals of the Rheumatic Diseases (2006)

To assess the cost effectiveness and cost effectiveness acceptability of symptom control delivered by shared care (SCSC) and aggressive treatment delivered in hospital (ATH) for established rheumatoid arthritis (RA).Economic data were collected within the British Rheumatoid Outcome Study Group randomised controlled trial of SCSC and ATH. A broad perspective was used (UK National Health Service, social support services and patients). Cost per quality adjusted life year (QALY) gained, net benefit statistics and cost effectiveness acceptability curves were estimated. Costs and outcomes were discounted at 3.5%. Sensitivity analysis tested the robustness of the results to analytical assumptions.The mean (SD) cost per person was 4540 pounds (4700) in the SCSC group and 4440 pounds (4900) in the ATH group. The mean (SD) QALYs per person for 3 years were 1.67 (0.56) in the SCSC group and 1.60 (0.60) in the ATH group. If decision makers are prepared to pay > or = 2000 pounds to gain 1 QALY, SCSC is likely to be cost effective in 60-90% of cases.The primary economic analysis and sensitivity analyses indicate that SCSC is likely to be more cost effective than ATH in 60-90% of cases. This result seems to be robust to assumptions required by the analysis. This study is one of a limited number of randomised controlled trials to collect detailed resource use and health status data and estimate the costs and QALYs of treatment for established RA. This trial is one of the largest RA studies to use the EuroQol.
Problem drug use
Authors: Nigel Williams
Journal: BMJ (2006)

A 24 year old man asks you for help with his heroin problem.He has been taking the drug for about a year and is spending at least £60 (€90; $110) a day on it. What issues you should coverYou should do a full assessment before deciding on any action; this is likely to take more than one consultation.An empathic and non-judgmental approach will engage him and help him to begin the process of change.You need to clarify why he has come to you now and what he wants-often, but not always, this is a prescription.All GPs should be able to gather the information they need for an appropriate referral and to provide general care.Current drug use-Ask about all illicit drugs he has taken in the past month (including cannabis).Record quantity and frequency of use, together with route of administration.Also note his smoking and drinking habits.Past drug history and treatment experience-Ask about onset of drug use and when it first became a problem.What do drugs do for him?Has he tried stopping previously?Injecting history-Has he ever injected, and if so how recently?Past injectors have a high incidence of hepatitis C infection.Ask about his needle supply and history of sharing equipment.Unprotected sex may also be relevant.Medical history-Review his virology test results and immunisation history, if known.Ask about prescribed drugs.(In women patients cover contraception and cervical screening.)Psychiatric history-Mental health problems are common among drug users.He may have a history of overdose or contact with psychiatric services.Questioning may elicit ongoing symptoms of anxiety or depression.Forensic history-Include contact with the criminal justice system and any offending he does to fund his habit.Social situation-Ask about personal relationships.Who is available to support him?Does he have a drug using partner?Also ask about his employment history and current accommodation.(Is he homeless?)Child protection-Identify any children he may care for and consider the possible effects of his drug use on their wellbeing.
Autologous fascia lata for heart valve replacement
Authors: M. I. Ionescu, D. N. Ross, R. Deac, V. A. Grimshaw, S. H. Taylor, W. Whitaker, G. H. Wooler
Journal: Thorax (1970)

To obviate the drawbacks of prosthetic devices and in search of a better substitute for diseased heart valves a technique of using autologous fascia lata grafts attached to a support frame was developed. The technique of preparing mounted fascia lata grafts is briefly outlined and their surgical implantation into the mitral, tricuspid, and aortic areas is described. Since April 1969, 83 fascial grafts have been inserted into 76 patients with very good immediate and short-term results. Ten patients succumbed within the operative period. None of these deaths was due to failure of the graft <i>per se.</i> Thromboembolic manifestations have been completely absent although anticoagulants were not used. All sixty-six survivors are very much improved. Data concerning the structure and function of fascia are presented and the experimental and clinical use of fascia lata in extracardiac and cardiac surgery is reviewed. The use of autologous, living, fascia lata valves is considered to be a better approach for heart valve replacement because autologous fascia maintains its structure unchanged after transplantation and, being under mechanical stimulation, it retains its functional properties.
The Impact of Smoking on Inhaled Insulin
Authors: Anders Himmelmann, Johan Jendle, Anders Mellén, Astrid H. Petersen, Ulf L. Dahl, Per Wollmer
Journal: Diabetes Care (2003)

This study, one of the first to address issues of pulmonary insulin delivery in smokers, compared pharmacokinetics of inhaled insulin delivered via the AERx insulin Diabetes Management System (iDMS) in nondiabetic cigarette smokers and nonsmokers.In this randomized two-period crossover efficacy and safety trial in 27 nondiabetic smokers and 16 nonsmokers (18 men/25 women, mean age 28 years, mean BMI 23.0 kg/m(2)), subjects received single doses of inhaled insulin (33.8 IU) following overnight fasting on consecutive dosing days. On one dosing day, smokers smoked three cigarettes immediately before insulin administration ("acute smoking"); on the other dosing day, smokers had not smoked since midnight ("nonacute smoking"). After inhalation, 6-h serum insulin and serum glucose profiles were determined.Pharmacokinetic results for evaluable subjects were derived from serum insulin profiles. The amount of insulin absorbed during the first 6 h after dosing (area under the exogenous serum insulin curve from 0 to 6 h [AUC((0-6 h))]) was significantly greater in smokers (63.2 vs. 40.0 mU l(-1) x h(-1), P = 0.0017); peak concentration was both higher and earlier in the smokers (maximal serum concentration of insulin [C(max)] 42.0 vs. 13.9 mU/l, P < 0.0001; time to maximal serum concentration of insulin [t(max)] 31.5 vs. 53.9 min, P = 0.0003). The estimated intrasubject variability of AUC((0-6 h)) was 13.7 and 16.5% for nonsmokers and smokers, respectively. No safety issues arose.Absorption of inhaled insulin via the AERx iDMS was significantly greater in smokers, with a higher AUC((0-6 h)) and C(max) and a shorter t(max). Intrasubject variability of AUC((0-6 h)) was low and similar in nonsmokers and smokers. These data prompt more extensive investigation of inhaled insulin in diabetic smokers.
Molecular Evidence for the Same Clonal Origin of Multifocal Papillary Thyroid Carcinomas
Authors: Ryan P. McCarthy, Mingsheng Wang, Timothy D. Jones, Randall W. Strate, Liang Cheng
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Patients with papillary thyroid carcinoma often have two or more distinct papillary tumors at thyroidectomy. Whether these multifocal papillary lesions are clonally related or whether they arise independently is unknown as previous studies have shown conflicting results. Molecular analysis of microsatellite alterations and X-chromosome inactivation status in separate tumors from the same patient can be used to define the genetic relationships among the multiple coexisting tumors. Experimental Design: We examined 64 separate tumors from 22 female patients who underwent thyroidectomy for thyroid carcinoma. All patients had multiple and separate papillary carcinomas (range, two to six). Genomic DNA samples were prepared from formalin-fixed, paraffin-embedded tissue sections using laser-capture microdissection. Loss of heterozygosity assays for three microsatellite polymorphic markers for putative tumor suppressor genes on chromosomes 3p25 (D3S1597), 9p21 (D9S161), and 18p11.22-p11 (D18S53) were done. In addition, X-chromosome inactivation analysis was done on the tumors from all patients. Results: Twenty of 22 (91%) cases showed allelic loss in one or more of the papillary lesions in at least one of the three polymorphic markers analyzed. Concordant allelic loss patterns between coexisting papillary tumors were seen in 20 of 23 (87%) cases. A concordant pattern of nonrandom X-chromosome inactivation in the multiple coexisting papillary lesions was seen in all informative cases. Conclusion: Our data suggest that the multifocal tumors in patients with papillary thyroid carcinoma often arise from the same clone. Thus, intrathryoid metastasis may play an important role in the spread of papillary thyroid carcinoma, a finding that has important therapeutic, diagnostic, and prognostic implications.
The Wnt-5a–Derived Hexapeptide Foxy-5 Inhibits Breast Cancer Metastasis<i>In vivo</i>by Targeting Cell Motility
Authors: Annette Säfholm, Johanna Tuomela, Jeanette Rosenkvist, Janna Dejmek, Pirkko Härkönen, Tommy Andersson
Journal: Clinical Cancer Research (2008)

Abstract Purpose: An inherent problem in breast cancer treatment is that current therapeutic approaches fail to specifically target the dissemination of breast cancer cells from the primary tumor. Clinical findings show that the loss of Wnt-5a protein expression in the primary breast tumor predicts a faster tumor spread, and in vitro analyses reveal that it does so by inhibiting tumor cell migration. Therefore, we hypothesized that the reconstitution of Wnt-5a signaling could be a novel therapeutic strategy to inhibit breast cancer metastasis. Experimental Design: We used in vitro techniques to show that 4T1 mouse breast cancer cells responded to the reconstitution of Wnt-5a signaling using our novel Wnt-5a mimicking hexapeptide, Foxy-5, in the same way as human breast cancer cells. Therefore, we could subsequently study its effect in vivo on the metastatic spread of cancer following the inoculation of 4T1 cells into mice. Results: In vitro analyses revealed that both recombinant Wnt-5a and the Wnt-5a–derived Foxy-5 peptide impaired migration and invasion without affecting apoptosis or proliferation of 4T1 breast cancer cells. The in vivo experiments show that i.p. injections of Foxy-5 inhibited metastasis of inoculated 4T1 breast cancer cells from the mammary fat pad to the lungs and liver by 70% to 90%. Conclusions: These data provide proof of principle that the reconstitution of Wnt-5a signaling in breast cancer cells is a novel approach to impair breast tumor metastasis by targeting cell motility. In combination with existing therapies, this approach represents a potential novel therapeutic strategy for the treatment of breast cancer patients.
Cross-cultural comparison of the sleep-disordered breathing prevalence among Americans and Japanese
Authors: K. Yamagishi, T. Ohira, H. Nakano, S.J. Bielinski, S. Sakurai, H. Imano, M. Kiyama, A. Kitamura, S. Sato, M. Konishi, E. Shahar, A.R. Folsom, H. Iso, T. Tanigawa
Journal: European Respiratory Journal (2010)

The aim of the present study was to compare the prevalence of sleep-disordered breathing among Hispanic and white Americans and Japanese. A 1-night sleep study using a single-channel airflow monitor was performed on 211 Hispanics and 246 Whites from the Minnesota field centre (St Paul, MN, USA) of the Multi-Ethnic Study of Atherosclerosis (MESA), and 978 Japanese from three community-based cohorts of the Circulatory Risk in Communities Study (CIRCS) in Japan. The respiratory disturbance index and sleep-disordered breathing, defined as a respiratory disturbance index of ≥15 events·h −1 , were estimated. The prevalence of sleep-disordered breathing was higher in males (34.2%) than females (14.7%), and among Hispanics (36.5%) and Whites (33.3%) than among Japanese (18.4%), corresponding to differences in body mass index. Within body mass index strata, the race difference in sleep-disordered breathing was attenuated. This was also true when body mass index was adjusted for instead of stratification. The strong association between body mass index and sleep-disordered breathing was similar in Japanese and Americans. The prevalence of sleep-disordered breathing was lower among Japanese than among Americans. However, the association of body mass index with sleep-disordered breathing was strong, and similar among the race/ethnic groups studied. The majority of the race/ethnic difference in sleep-disordered breathing prevalence was explained by a difference in body mass index distribution.