tbuckley/cabot-search huggingface dataset:
Multidrug Resistance and the Lung Resistance-Related Protein in Human Colon Carcinoma SW-620 Cells
Authors: M Kitazono, T Sumizawa, Y Takebayashi, Z S Chen, T Furukawa, S Nagayama, A Tani, S Takao, T Aikou, S Akiyama
Journal: JNCI Journal of the National Cancer Institute (1999)

Lung resistance-related protein (LRP), the major vault protein in humans, is sometimes overexpressed in multidrug-resistant cells. Because cells transfected with the LRP gene did not express the multidrug-resistant phenotype, we investigated whether LRP is involved in multidrug resistance.SW-620 cells, a human colon carcinoma cell line, alone or transfected with an expression vector carrying a LRP-specific ribozyme or with an empty vector, were treated with sodium butyrate to induce differentiation. Expression of P-glycoprotein, multidrug resistance protein, and LRP in the cells was examined by northern and western blotting, and the efflux of doxorubicin in the cells or isolated nuclei was examined by fluorescence microscopy.A 2-week treatment with sodium butyrate induced LRP and conferred resistance to doxorubicin, vincristine, etoposide, gramicidin D, and paclitaxel (Taxol) in SW-620 cells. Insertion of either of two LRP-specific ribozymes into SW-620 cells inhibited these activities. Levels of drugs accumulating in the cells were not decreased by sodium butyrate, suggesting that the adenosine triphosphate-binding cassette transporter is not involved in sodium butyrate-induced multidrug resistance. Doxorubicin was mainly located in the nuclei of untreated cells and in the cytoplasm of sodium butyrate-treated cells. Isolated nuclei from untreated cells or sodium butyrate-treated cells incubated with anti-LRP polyclonal antibodies contained more doxorubicin than the nuclei of sodium butyrate-treated cells alone. Efflux of doxorubicin was greater from the nuclei of sodium butyrate-treated cells than the nuclei of untreated cells or of sodium butyrate-treated cells transfected with a LRP-specific ribozyme and was inhibited by an anti-LRP polyclonal antibody.LRP is involved in resistance to doxorubicin, vincristine, etoposide, paclitaxel, and gramicidin D and has an important role in the transport of doxorubicin from the nucleus to the cytoplasm.
Increased tumour necrosis factor‐α plasma levels during moderate-intensity exercise in COPD patients
Authors: R.A. Rabinovich, M. Figueras, E. Ardite, N. Carbó, T. Troosters, X. Filella, J.A. Barberà, J.C. Fernandez-Checa, J.M. Argilés, J. Roca
Journal: European Respiratory Journal (2003)

Post-training downregulation of muscle tumour necrosis factor (TNF)‐α messenger ribonucleic acid (mRNA) expression and decrease in cellular TNF‐α levels have been reported in the elderly. It is hypothesised that chronic obstructive pulmonary disease (COPD) patients may not show these adaptations due to their reduced ability to increase muscle antioxidant capacity with training. Eleven COPD patients (forced expiratory volume in one second 40±4.4% of the predicted value) and six age-matched controls were studied. Pre- and post-training levels of TNF‐α, soluble TNF receptors (sTNFRs: sTNFR55 and sTNFR75) and interleukin (IL)‐6 in plasma at rest and during exercise and vastus lateralis TNF‐α mRNA were examined. Moderate-intensity constant-work-rate exercise (11 min at 40% of pretraining peak work-rate) increased pretraining plasma TNF‐α levels in COPD patients (from 17±3.2 to 23±2.7 pg·mL −1 ; p&lt;0.005) but not in controls (from 19±4.6 to 19±3.2 pg·mL −1 ). No changes were observed in sTNFRs or IL‐6 levels. After 8 weeks' endurance training, moderate-intensity exercise increased plasma TNF‐α levels similarly to pretraining (from 16±3 to 21±4 pg·mL −1 ; p&lt;0.01). Pretraining muscle TNF‐α mRNA expression was significantly higher in COPD patients than in controls (29.3±13.9 versus 5.0±1.5 TNF‐α/18S ribonucleic acid, respectively), but no changes were observed after exercise or training. It is concluded that moderate-intensity exercise abnormally increases plasma tumour necrosis factor‐α levels in chronic obstructive pulmonary disease patients without exercise-induced upregulation of the tumour necrosis factor‐α gene in skeletal muscle.
Impaired Glomerular Maturation and Lack of VEGF165b in Denys-Drash Syndrome
Authors: Valérie Anne Schumacher, Stefanie Jeruschke, Frank Eitner, Jan Ulrich Becker, Gerald Pitschke, Yasemin Ince, Jeffrey H. Miner, Ivo Leuschner, Rainer Engers, Anne Schulze Everding, Monika Bulla, Brigitte Royer-Pokora
Journal: Journal of the American Society of Nephrology (2007)

Individuals with Denys-Drash syndrome (DDS) develop diffuse mesangial sclerosis, ultimately leading to renal failure. The disease is caused by mutations that affect the zinc finger structure of the Wilms’ tumor protein (WT1), but the mechanisms whereby these mutations result in glomerulosclerosis remain largely obscure. How WT1 regulates genes is likely to be complex, because it has multiple splice forms, binds both DNA and RNA, and associates with spliceosomes. Herein is described that in DDS podocytes, the ratio of both WT1 +KTS isoforms C to D differs considerably from that of normal child and adult control podocytes and more closely resembles fetal profiles. Aside from the delay in podocyte maturation, DDS glomeruli show swollen endothelial cells, reminiscent of endotheliosis, together with incompletely fused capillary basement membranes; a dramatic decrease in collagen α4(IV) and laminin β2 chains; and the presence of immature or activated mesangial cells that express α-smooth muscle actin. Because appropriate vascular endothelial growth factor A (VEGF-A) expression is known to be essential for the development and maintenance of glomerular architecture and function, this article addresses the question of whether VEGF-A expression is deregulated in DDS. The data presented here show that DDS podocytes express high levels of the proangiogenic isoform VEGF165, but completely lack the inhibitory isoform VEGF165b. The VEGF165/VEGF165b ratio in DDS resembles that of fetal S-shaped bodies, rather than that of normal child or adult control subjects. The alteration in VEGF-A expression presented here may provide a mechanistic insight into the pathogenesis of DDS.
Doxorubicin Disaccharide Analogue: Apoptosis-Related Improvement of Efficacy In Vivo
Authors: F Arcamone, F Animati, M Berettoni, M Bigioni, G Capranico, A M Casazza, C Caserini, A Cipollone, M De Cesare, M Franciotti, P Lombardi, A Madami, S Manzini, E Monteagudo, D Polizzi, G Pratesi, S C Righetti, C Salvatore, R Supino, F Zunino
Journal: JNCI Journal of the National Cancer Institute (1997)

Background: Although doxorubicin remains one of the most effective agents for the treatment of solid tumors, there is an intensive effort to synthesize doxorubicin analogues (compounds with similar chemical structures) that may have improved antitumor properties. We have synthesized a novel doxorubicin disaccharide analogue (MEN 10755) and have characterized some of its relevant biochemical, biologic, and pharmacologic properties. Methods: The antitumor activity of this compound (MEN 10755) was studied in a panel of human tumor xenografts, including xenografts of A2780 ovarian tumor cells, MX-1 breast carcinoma cells, and POVD small-cell lung cancer cells. MEN 10755 was compared with doxorubicin according to the optimal dose and schedule for each drug. The drug's cytotoxic effects, induction of DNA damage, and intracellular accumulation were studied in A2780 cells. DNA cleavage mediated by the enzyme topoisomerase II was investigated in vitro by incubating fragments of simian virus 40 DNA with the purified enzyme at various drug concentrations and analyzing the DNA cleavage-intensity patterns. Drug-induced apoptosis (programmed cell death) in tumors was determined with the use of MX-1 and POVD tumor-bearing athymic Swiss nude mice. Results: MEN 10755 was more effective than doxorubicin as a topoisomerase II poison and stimulated DNA fragmentation at lower intracellular concentrations. In addition, MEN 10755 exhibited striking antitumor activity in the treatment of human tumor xenografts, including those of the doxorubicin-resistant breast carcinoma cell line MX-1. Conclusions: The high antitumor activity of MEN 10755 in human tumor xenografts, including doxorubicin-resistant xenografts, and its unique pharmacologic and biologic properties make this disaccharide analogue a promising candidate for clinical evaluation.
Totally epicardial cardiac resynchronization therapy system implantation in patients with heart failure undergoing CABG
Authors: Kinga Goscinska‐Bis, Jaroslaw Bis, Michal Krejca, Rafal Ulczok, Przemyslaw Szmagala, Andrzej Bochenek, Wlodzimierz Kargul
Journal: European Journal of Heart Failure (2008)
Direct in vivo gene transfer into the coronary and peripheral vasculatures of the intact dog.
Authors: C S Lim, G D Chapman, R S Gammon, J B Muhlestein, R P Bauman, R S Stack, J L Swain
Journal: Circulation (1991)

Gene therapy approaches have been suggested for the treatment of cardiovascular disease. Recently, direct transfer of the gene encoding beta-galactosidase into peripheral arteries of the pig has been demonstrated. To determine whether this approach is applicable to other arterial beds and to other species, we first evaluated the use of beta-galactosidase as a marker protein in the canine model. We demonstrate that variable but substantial endogenous beta-galactosidase-like activity is induced by manipulation of canine peripheral arteries, which precludes the use of this marker protein in evaluating the efficiency of gene transfer in this model. A marker gene encoding firefly luciferase was then evaluated, and background luciferase activity was found to be low in the dog even after arterial manipulation. Using the luciferase gene, we then demonstrated lipid-mediated gene transfer directly into both coronary and peripheral arteries of the intact dog. These results indicate the feasibility of in vivo gene transfer into coronary arteries and demonstrate the use of the luciferase marker protein in quantifying recombinant protein expression following gene transfer in canine models. This simple and effective method for direct in vivo gene transfer into coronary and peripheral arteries may be applicable to the localized production of therapeutically important proteins for the treatment of cardiovascular diseases.
Risk of atrial fibrillation and stroke in rheumatoid arthritis: Danish nationwide cohort study
Authors: J. Lindhardsen, O. Ahlehoff, G. H. Gislason, O. R. Madsen, J. B. Olesen, J. H. Svendsen, C. Torp-Pedersen, P. R. Hansen
Journal: BMJ (2012)

To determine if patients with rheumatoid arthritis have increased risk of atrial fibrillation and stroke.Longitudinal nationwide register based cohort study.Inpatient and outpatient hospital care in Denmark from 1997 to 2009.Entire Danish population aged over 15 years without rheumatoid arthritis, atrial fibrillation, or stroke before 1997. Participants with rheumatoid arthritis were identified by individual level linkage of diagnoses and rheumatoid arthritis treatment.Rates of atrial fibrillation and stroke.Of 4,182,335 participants included in the cohort, 18,247 were identified as having rheumatoid arthritis during follow-up, with a mean age at disease onset of 59.2 years and a median follow-up of 4.8 years. A total of 156,484 people, including 774 with rheumatoid arthritis, were diagnosed as having atrial fibrillation (age and sex matched event rates of 8.2 per 1000 person years in rheumatoid arthritis patients and 6.0 per 1000 person years in the general population), with an adjusted incidence rate ratio of 1.41 (95% confidence interval 1.31 to 1.51). In addition, 165,343 people, including 718 with rheumatoid arthritis, had a stroke (7.6 per 1000 person years in rheumatoid arthritis and 5.7 per 1000 person years in the general population), with a resultant rate ratio of 1.32 (1.22 to 1.42). For both atrial fibrillation and stroke, relative risks were increased in all strata based on thirds of sex and age, with higher relative risks in younger patients but higher absolute risk differences in older patients.Rheumatoid arthritis was associated with an increased incidence of atrial fibrillation and stroke. The novel finding of increased risk of atrial fibrillation in rheumatoid arthritis suggests that this arrhythmia is relevant in cardiovascular risk assessment of these patients.
A Hidden Solution
Authors: Pornpoj Pramyothin, Angela M. Leung, Elizabeth N. Pearce, Alan O. Malabanan, Lewis E. Braverman
Journal: New England Journal of Medicine (2011)

A 51-year-old woman presented to the ER with a 6-month history of intermittent palpitations, which had worsened that day. She described her pulse as fast but regular. She also reported worsening fatigue, heat intolerance, and an 18-kg (40-lb) weight loss.
Prospective, Multicenter, Randomized Phase II Trial of the Herbal Supplement, PC-SPES, and Diethylstilbestrol in Patients With Androgen-Independent Prostate Cancer
Authors: William K. Oh, Philip W. Kantoff, Vivian Weinberg, Graham Jones, Brian I. Rini, Mika K. Derynck, Robert Bok, Matthew R. Smith, Glenn J. Bubley, Robert T. Rosen, Robert S. DiPaola, Eric J. Small
Journal: Journal of Clinical Oncology (2004)

To evaluate the herbal combination, PC-SPES, and diethylstilbestrol (DES) in patients with androgen independent prostate cancer (AIPC).A randomized phase II study was conducted with cross-over design. Patients were randomly assigned to receive either three PC-SPES capsules orally three times a day or DES 3 mg orally once a day. Prophylactic warfarin was administered. At clinical or prostate-specific antigen progression, patients received the other therapy. The study closed prematurely after PC-SPES was withdrawn from the market. Chemical analyses were performed on multiple lots of PC-SPES.Ninety patients were enrolled, of whom 85 were assessable for response. Prostate-specific antigen declines > or = 50% were noted in 40% (95% CI, 25% to 56%) with PC-SPES, and 24% (95% CI, 12% to 39%) with DES. Median response duration was not reached with PC-SPES, and was 3.8 months with DES. Median time to progression for randomly assigned patients was 5.5 months for PC-SPES and 2.9 months for DES. Common toxicities included mild fatigue, gynecomastia, and mastodynia. Five thromboembolic events occurred (one PC-SPES, four DES). Responses in the cross-over phase were inconclusive. Four lots of PC-SPES had measurable quantities of DES, ranging from 0.01% to 3.1% of the dose used in the DES arm. Ethinyl estradiol was also detected in PC-SPES lots.PC-SPES and DES demonstrate activity in AIPC and are well tolerated. However, the synthetic estrogens, DES and ethinyl estradiol, were detected in various lots of PC-SPES, including those used in this trial. Clinical trials that utilize herbal therapies must account for issues of purity and consistency.
Coronary Heart Disease Risk Factors in Men and Women Aged 60 Years and Older
Authors: Philip H. Frost, Barry R. Davis, Alfredo J. Burlando, J. David Curb, Gordon P. Guthrie, Jonathan L. Isaacsohn, Sylvia Wassertheil-Smoller, Alan C. Wilson, Jeremiah Stamler
Journal: Circulation (1996)

Background Coronary heart disease (CHD) is the most common cause of death in men and women aged 60 years and older. Although a number of studies support the concept that CHD risk factors that have been defined in younger adults are significantly associated with CHD events in older adults, others do not support this thesis, and further definition of the risk-factor concept in older adults is required. Methods and Results The Systolic Hypertension in the Elderly Program recruited 4736 persons (mean age, 72 years); 14% were black, and 43% were men. Mean systolic and diastolic blood pressures were 170 and 77 mm Hg, respectively. About 13% of participants were current smokers; 10% had a history of diabetes; 5%, a prior myocardial infarction; 5%, angina pectoris; 2.3%, intermittent claudication; and 7%, a carotid bruit. Mean total cholesterol value was 6.11 mmol/L. Mean follow-up was 4.5 years. In multivariate Cox regression analyses for CHD, variables that were significant were baseline total cholesterol value, smoking, history of diabetes, presence of carotid bruit, and treatment group in the trial. Active treatment yielded a 27% reduction in CHD risk. For each 1.03 mmol/L increase in total cholesterol value, there was an increase in risk of about 20%. Current smokers had a 73% increase, diabetics a 121% increase, and those with carotid bruit a 113% increase in CHD risk. Conclusions The results of this study support the concept that CHD risk factors are important in older men and women with isolated systolic hypertension.
Protective and Harmful Effects of Viral Infections in Childhood on Wheezing Disorders and Asthma
Authors: PETER J. M. OPENSHAW, COLIN HEWITT
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

It seems certain that environmental (not genetic) factors are responsible for the remarkable increase in prevalence of allergic respiratory diseases over the last 20 yr (1). One such factor might be improved hygiene, which has led to fewer childhood infections. However, it is well established that respiratory syncytial virus (RSV) infections cause many exacerbations in older children with asthma. In addition, many studies show that children with bronchiolitis are much more likely to suffer recurrent wheezing during the first 7-10 yr of life. It is not clear whether bronchiolitis reveals a preexisting weakness in the lungs, which later manifests as recurrent wheeze, or whether bronchiolitis itself causes persistent effects that could be avoided if RSV infections could be prevented (Figure 1). This is currently one of the most important unanswered questions in RSV research (2, 3). It seems that viral infections have both positive and negative influences on the development of airway inflammation, wheezing, and asthma. In this review, we summarize the evidence that viral infections influence the development of persistent airway inflammation, discuss some of the ways in which viral infections might affect the establishment of asthma, identify areas in which more information is needed, and try to define how this information could be obtained.
Prognostic Impact of 18FDG-PET-CT Findings in Clinical Stage III and IIB Breast Cancer
Authors: D. Groheux, E. Hindie, M. Delord, S. Giacchetti, A.-s. Hamy, C. de Bazelaire, A. de Roquancourt, L. Vercellino, M.-E. Toubert, P. Merlet, M. Espie
Journal: JNCI Journal of the National Cancer Institute (2012)

This study prospectively evaluated the yield of fluorodeoxyglucose positron emission tomography/computed tomography ((18)FDG-PET-CT) in patients with clinical stages II and III breast cancer and the impact of PET-CT results on prognosis.In the course of 71 months, 254 consecutive patients with clinical stages II and III breast cancer (based on clinical examination, mammography, breast magnetic resonance imaging, and locoregional ultrasonography) underwent (18)FDG-PET-CT. The yield was assessed in the whole population and for each American Joint Committee on Cancer subgroup. The prognostic impact of PET-CT findings was analyzed. Tests of statistical significance were two-sided.(18)FDG-PET-CT changed the clinical stage in 77 of 254 patients (30.3%; 95% confidence interval [CI] = 25.0% to 36.2%). It showed unsuspected N3 disease (infraclavicular, supraclavicular, or internal mammary nodes) in 40 patients and distant metastases in 53. PET-CT revealed distant metastases in 2.3% (1 of 44) of clinical stage IIA, 10.7% (6 of 56) of stage IIB, 17.5% (11 of 63) of stage IIIA, 36.5% (27 of 74) of stage IIIB, and 47.1% (8 of 17) of stage IIIC patients. Among 189 patients with clinical stage IIB or higher disease and adequate follow-up, disease-specific survival was statistically significantly shorter in the 47 patients scored M1 on (18)FDG-PET-CT in comparison with those scored M0, with a three-year disease-specific survival of 57% vs 88% (P < .001). In multivariable analysis, only distant disease on PET-CT and triple-negative phenotype were statistically significant prognostic factors. The relative risk of death was 26.60 (95% CI = 6.60 to 102.62) for M1 vs M0 patients.The yield of (18)FDG-PET-CT appeared substantial in patients with clinical stage IIB or higher breast cancer. In these patients, (18)FDG-PET-CT provided powerful prognostic stratification.
Early Detection of Anthracycline Cardiotoxicity and Improvement With Heart Failure Therapy
Authors: Daniela Cardinale, Alessandro Colombo, Giulia Bacchiani, Ines Tedeschi, Carlo A. Meroni, Fabrizio Veglia, Maurizio Civelli, Giuseppina Lamantia, Nicola Colombo, Giuseppe Curigliano, Cesare Fiorentini, Carlo M. Cipolla
Journal: Circulation (2015)

Background— Three types of anthracycline-induced cardiotoxicities are currently recognized: acute, early-onset chronic, and late-onset chronic. However, data supporting this classification are lacking. We prospectively evaluated incidence, time of occurrence, clinical correlates, and response to heart failure therapy of cardiotoxicity. Methods and Results— We assessed left ventricular ejection fraction (LVEF), at baseline, every 3 months during chemotherapy and for the following year, every 6 months over the following 4 years, and yearly afterward in a heterogeneous cohort of 2625 patients receiving anthracycline-containing therapy. In case of cardiotoxicity (LVEF decrease &gt;10 absolute points, and &lt;50%), heart failure therapy was initiated. Recovery from cardiotoxicity was defined as partial (LVEF increase &gt;5 absolute points and &gt;50%) or full (LVEF increase to the baseline value). The median follow-up was 5.2 (quartile 1 to quartile 3, 2.6–8.0) years. The overall incidence of cardiotoxicity was 9% (n=226). The median time elapsed between the end of chemotherapy and cardiotoxicity development was 3.5 (quartile 1 to quartile 3, 3–6) months. In 98% of cases (n=221), cardiotoxicity occurred within the first year. Twenty-five (11%) patients had full recovery, and 160 (71%) patients had partial recovery. At multivariable analysis, end-chemotherapy LVEF (hazard ratio, 1.37; 95% confidence interval, 1.33–1.42 for each percent unit decrement) and cumulative doxorubicin dose (hazard ratio, 1.09; 95% confidence interval, 1.04–1.15 for each 50 mg/m 2 increment) were independent correlates of cardiotoxicity. Conclusions— Most cardiotoxicity after anthracycline-containing therapy occurs within the first year and is associated with anthracycline dose and LVEF at the end of treatment. Early detection and prompt therapy of cardiotoxicity appear crucial for substantial recovery of cardiac function.