tbuckley/cabot-search huggingface dataset:
An Adenoviral Vaccine Encoding Full-Length Inactivated Human Her2 Exhibits Potent Immunogenicty and Enhanced Therapeutic Efficacy without Oncogenicity
Authors: Zachary C. Hartman, Junping Wei, Takuya Osada, Oliver Glass, Gangjun Lei, Xiao-Yi Yang, Sharon Peplinski, Dong-Wan Kim, Wenle Xia, Neil Spector, Jeffrey Marks, William Barry, Amy Hobeika, Gayathri Devi, Andrea Amalfitano, Michael A. Morse, H. Kim Lyerly, Timothy M. Clay
Journal: Clinical Cancer Research (2010)

Abstract Purpose: Overexpression of the breast cancer oncogene HER2 correlates with poor survival. Current HER2-directed therapies confer limited clinical benefits and most patients experience progressive disease. Because refractory tumors remain strongly HER2+, vaccine approaches targeting HER2 have therapeutic potential, but wild type (wt) HER2 cannot safely be delivered in imunogenic viral vectors because it is a potent oncogene. We designed and tested several HER2 vaccines devoid of oncogenic activity to develop a safe vaccine for clinical use. Experimental Design: We created recombinant adenoviral vectors expressing the extracellular domain of HER2 (Ad-HER2-ECD), ECD plus the transmembrane domain (Ad-HER2-ECD-TM), and full-length HER2 inactivated for kinase function (Ad-HER2-ki), and determined their immunogenicity and antitumor effect in wild type (WT) and HER2-tolerant mice. To assess their safety, we compared their effect on the cellular transcriptome, cell proliferation, anchorage-dependent growth, and transformation potential in vivo. Results: Ad-HER2-ki was the most immunogenic vector in WT animals, retained immunogenicity in HER2-transgenic tolerant animals, and showed strong therapeutic efficacy in treatment models. Despite being highly expressed, HER2-ki protein was not phosphorylated and did not produce an oncogenic gene signature in primary human cells. Moreover, in contrast to HER2-wt, cells overexpressing HER2-ki were less proliferative, displayed less anchorage-independent growth, and were not transformed in vivo. Conclusions: Vaccination with mutationally inactivated, nononcogenic Ad-HER2-ki results in robust polyclonal immune responses to HER2 in tolerant models, which translates into strong and effective antitumor responses in vivo. Ad-HER2-ki is thus a safe and promising vaccine for evaluation in clinical trials. Clin Cancer Res; 16(5); 1466–77
Potassium-induced release of endothelium-derived relaxing factor from canine femoral arteries.
Authors: G M Rubanyi, P M Vanhoutte
Journal: Circulation Research (1988)

Experiments were designed in a bioassay system to analyze the effect of elevated (from 5.9 mM to 7.5-45.9 mM) extracellular K+ concentration on the release of endothelium-derived relaxing factor. Segments of canine femoral artery with endothelium (donor segment) were mounted in an organ bath and perfused with modified Krebs-Ringer bicarbonate solution; the effluent from the donor segment was used to superfuse a canine coronary artery ring without endothelium (bioassay tissue). Elevation of perfusate K+ concentration by 1.6-15 mM by intraluminal infusion of potassium chloride upstream of the donor segment evoked further contractions of bioassay rings contracted with prostaglandin F2 alpha. In contrast, the bioassay rings progressively relaxed when increasing concentrations of potassium chloride (10-40 mM) were added extraluminally to the organ bath where the perfused segment was mounted. Extraluminal application of phenylephrine or prostaglandin F2 alpha did not evoke relaxations in the bioassay ring. Removal of the endothelium from the donor segment or selective exposure of the segment (but not the bioassay ring) to Ca2+-deficient solution prevented the K+-induced relaxations. Treatment of the donor segment and the bioassay ring with inhibitors of known endogenous vasoactive substances (acetylcholine, norepinephrine, adenine nucleotides, and prostanoids) had no significant effect on the relaxation of the bioassay ring evoked by extraluminal application of potassium chloride. Simultaneous measurements of changes in isometric force in the donor segment and bioassay ring revealed that extraluminal elevation of K+ concentration relaxed the segments as well and that the relaxations could not be prevented by simultaneous intraluminal infusion of potassium chloride.(ABSTRACT TRUNCATED AT 250 WORDS)
Morphological characteristics of P waves during selective pulmonary vein pacing
Authors: Teiichi Yamane, Dipen C Shah, Jing-Tian Peng, Pierre Jaı̈s, Mélèze Hocini, Isabel Deisenhofer, Kee-Joon Choi, Laurent Macle, Jacques Clémenty, Michel Haı̈ssaguerre
Journal: Journal of the American College of Cardiology (2001)
Community-acquired pneumonia in five European countries: Usage patterns and real-life effectiveness of antibiotics (REACH study)
Authors: Francesco Blasi, Javier Garau, Jesús Medina, Marco Ávila, Kyle McBride, Helmut Ostermann
Journal: European Respiratory Journal (2012)

Background  Comprehensive, current data on the burden of hospitalized community-acquired pneumonia (CAP) in Europe are scarce.  Aims  To describe the hospitalized CAP population in Europe and to review current clinical practice and its impact.  Methods  REACH (NCT01293435) was a retrospective (2010–2011), observational study in ten EU countries. Patients were ≥ 18 years old, hospitalized with CAP and requiring IV antibiotics. Data were collected via an electronic Case Report Form. We present data from five countries selected as representative of the full sample: Italy (IT), the Netherlands (NL), Spain (ES), Turkey (TR) and the UK.  Results  Patient characteristics were similar in the five countries. Rates of initial treatment modification (due to treatment failure or other reasons) were 33.0% (TR), 36.7% (IT), 42.3% (ES), 50.0% (UK) and 51.7% (NL) (overall population: 37.1%).  Conclusions  Antibiotic use differed somewhat between countries. Modification of initial treatment was common with many frequently used therapies, with variability among countries, suggesting that initial treatment choices may not always be optimal.
Predictive implications of ventricular premature contractions associated with treadmill stress testing.
Authors: J A Udall, M H Ellestad
Journal: Circulation (1977)

Follow-up data on future coronary events was collected on 6,500 patients who had undergone stress testing; 1,327 of these exhibited ventricular premature contractions (VPCs) associated with one or more phases of treadmill stress testing (TSTs). Eighty-three percent of all patients tested had known or suspected cardiovascular disease. The annual incidence of new coronary events (myocardial infarction, angina, cardiac death) during a five year follow-up was 1.7% among 1,067 patients without VPCs or ischemic ST changes, 6.4% in 758 patients with VPCs alone, 9.5% among 609 patients with ischemic ST changes alone and 11.4% in 569 patients with VPCs plus ischemic ST changes. The significance of VPCs associated with the TSTs rests largely upon the clinical status of the persons tested. VPCs observed among patients referred for TSTs for the evaluation of known or suspected cardiovascular disease, with or without ischemic ST abnormalities, represent a definite risk factor for future coronary events.
Cardiovascular risk stratification in rheumatic diseases: carotid ultrasound is more sensitive than Coronary Artery Calcification Score to detect subclinical atherosclerosis in patients with rheumatoid arthritis
Authors: Alfonso Corrales, José A Parra, Carlos González-Juanatey, Javier Rueda-Gotor, Ricardo Blanco, Javier Llorca, Miguel A González-Gay
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objective</h3> To determine the ability of Coronary Artery Calcification Score (CACS) and carotid ultrasonography in detecting subclinical atherosclerosis in rheumatoid arthritis (RA). <h3>Methods</h3> A set of 104 consecutive RA patients without history of cardiovascular (CV) events were studied to determine CACS, carotid intima-media thickness (cIMT) and plaques. Systematic Coronary Risk Evaluation (SCORE) modified according to the EULAR recommendations (mSCORE) was also assessed. <h3>Results</h3> The mean disease duration was 10.8 years, 72.1% had rheumatoid factor and/or anti-CCP positivity and 16.4% extra-articular manifestations. Nine were excluded because they had type 2 diabetes mellitus or chronic kidney disease. CV risk was categorised in the remaining 95 RA patients according to the mSCORE as follows: low (n=21), moderate (n=60) and high/very high risk (n=14). Most patients with low mSCORE (16/21; 76.2%) had normal CACS (zero), and none of them CACS&gt;100. However, a high number of patients with carotid plaques was disclosed in the groups with CACS 0 (23/40; 57.5%) or CACS 1–100 (29/38; 76.3%). 72 (75.8%) of the 95 patients fulfilled definitions for high/very high CV as they had an mSCORE ≥5% or mSCORE &lt;5% plus one of the following findings: severe carotid ultrasonography findings (cIMT&gt;0.9 mm and/or plaques) or CACS&gt;100. A CACS&gt;100 showed sensitivity similar to mSCORE (23.6% vs 19.4%). In contrast, the presence of severe carotid ultrasonography findings allowed identifying most patients who met definitions for high/very high CV risk (70/72; sensitivity 97.2% (95% CI 90.3 to 99.7)). <h3>Conclusions</h3> Carotid ultrasonography is more sensitive than CACS for the detection of subclinical atherosclerosis in RA.
Angiotensin II stimulates interleukin-6 release from cultured mouse mesangial cells.
Authors: T Moriyama, M Fujibayashi, Y Fujiwara, T Kaneko, C Xia, E Imai, T Kamada, A Ando, N Ueda
Journal: Journal of the American Society of Nephrology (1995)

Interleukin-6 (IL-6) is a multifunctional cytokine exerting a wide variety of biologic responses, including cell proliferation. Recently, IL-6 has been known to play a role in the pathogenesis of mesangial proliferative glomerulonephritis. IL-6 is now recognized as an autocrine growth factor for glomerular mesangial cells, and various inflammatory mediators have been shown to promote IL-6 release from mesangial cells. However, little is known about the noninflammatory stimuli of IL-6 release from mesangial cells. In this study, it was hypothesized that angiotensin II (AngII) is one of the noninflammatory mediators of IL-6 release in mesangial cells, and the effects of AngII on IL-6 release and mRNA expression in cultured mouse mesangial cells (CMMC) were investigated. It was demonstrated that AngII (10(-7) M or higher) caused IL-6 release and mRNA accumulation in CMMC. IL-6 release was detected at 4 h and reached a plateau at 8 h after the addition of AngII, whereas IL-6 mRNA expression peaked at 4 h. The effects of AngII on IL-6 release and gene expression were completely blocked by the AngII receptor type 1 (AT1 receptor) antagonist CV-11974. AngII and IL-6 were both shown to stimulate DNA synthesis in CMMC, and the blockade of IL-6 signaling with anti-IL-6 receptor antibody abolished the enhanced DNA synthesis induced by AngII. These results raise a possibility that the growth-promoting effect of AngII on mesangial cells is at least partially mediated by IL-6 released from mesangial cells.
Phase I Pharmacokinetic/Pharmacodynamic Study of MLN8237, an Investigational, Oral, Selective Aurora A Kinase Inhibitor, in Patients with Advanced Solid Tumors
Authors: Andres Cervantes, Elena Elez, Desamparados Roda, Jeffrey Ecsedy, Teresa Macarulla, Karthik Venkatakrishnan, Susana Roselló, Jordi Andreu, JungAh Jung, Juan Manuel Sanchis-Garcia, Adelaida Piera, Inma Blasco, Laura Maños, José-Alejandro Pérez-Fidalgo, Howard Fingert, Jose Baselga, Josep Tabernero
Journal: Clinical Cancer Research (2012)

Aurora A kinase (AAK) is a key regulator of mitosis and a target for anticancer drug development. This phase I study investigated the safety, pharmacokinetics, and pharmacodynamics of MLN8237 (alisertib), an investigational, oral, selective AAK inhibitor, in 59 adults with advanced solid tumors.Patients received MLN8237 once daily or twice daily for 7, 14, or 21 consecutive days, followed by 14 days recovery, in 21-, 28-, or 35-day cycles. Dose-limiting toxicities (DLT) and the maximum-tolerated dose (MTD) for the 7- and 21-day schedules were determined. Pharmacokinetic parameters were derived from plasma concentration-time profiles. AAK inhibition in skin and tumor biopsies was evaluated and antitumor activity assessed.Neutropenia and stomatitis were the most common DLTs. The MTD for the 7- and 21-day schedules was 50 mg twice daily and 50 mg once daily, respectively. MLN8237 absorption was fast (median time to maximum concentration, 2 hours). Mean terminal half-life was approximately 19 hours. At steady state, pharmacodynamic effects were shown by accumulation of mitotic and apoptotic cells in skin, and exposure-related increases in numbers of mitotic cells with characteristic spindle and chromosomal abnormalities in tumor specimens, supporting AAK inhibition by MLN8237. Stable disease was observed and was durable with repeat treatment cycles, administered over 6 months, in 6 patients, without notable cumulative toxicity.The recommended phase II dose of MLN8237 is 50 mg twice daily on the 7-day schedule, which is being evaluated further in a variety of malignancies, including in a phase III trial in peripheral T-cell lymphoma.
Laboratory diagnosis of paraneoplastic pemphigus
Authors: A.M. Poot, G.F.H. Diercks, D. Kramer, I. Schepens, G. Klunder, T. Hashimoto, L. Borradori, M.F. Jonkman, H.H. Pas
Journal: British Journal of Dermatology (2013)

Background Paraneoplastic pemphigus (PNP) is a multiorgan disease characterized by antibodies against plakins, desmogleins and the α2-macroglobulin-like-1 (A2ML1) protein, in association with an underlying neoplasm. Accurate diagnosis relies on the demonstration of these autoantibodies in serum. Objectives To evaluate the value of different laboratory techniques in the serological diagnosis of PNP. Methods We performed immunoblotting, envoplakin (EP) enzyme-linked immunosorbent assay (ELISA), indirect immunofluorescence (IIF) on rat bladder, radioactive immunoprecipitation and a nonradioactive combined immunoprecipitation-immunoblot assay. Additional assays included BP180 ELISA and BP230 ELISA. We included the sera of 19 patients with PNP and 40 control subjects. Results The sensitivities were 63% for anti-EP ELISA, 74% for rat bladder IIF, 89% for immunoblotting, 95% for radioactive immunoprecipitation and 100% for nonradioactive immunoprecipitation. Specificities ranged from 86% to 100%. The BP180 and BP230 ELISAs had low sensitivity and specificity for PNP. The combination of rat bladder IIF and immunoblot showed 100% sensitivity and specificity. The analysis of sequential PNP sera showed that antibody titres may decrease over time, possibly resulting in negative outcomes for EP ELISA and rat bladder IIF studies. Conclusions The detection of autoantibodies against EP and periplakin, or A2ML1 by immunoprecipitation is most sensitive for PNP. The combination of rat bladder IIF and immunoblotting is equally sensitive and highly specific, and represents an alternative valuable and relatively easy approach for the serological diagnosis of PNP.
Normalization of coronary vasomotion after percutaneous transluminal coronary angioplasty?
Authors: T M Suter, M Buechi, O M Hess, C Haemmerli-Saner, A Gaglione, H P Krayenbuehl
Journal: Circulation (1992)

BACKGROUND Coronary vasomotion was evaluated at rest and during bicycle exercise in 33 patients (age, 53 +/- 7 years) with coronary artery disease. In a first group of patients (n = 15), vasomotion was studied before and 4.3 +/- 2.3 months (early) after percutaneous transluminal coronary angioplasty (PTCA), whereas in a second group (n = 18), exercise coronary arteriography was performed 30 +/- 11 months (late) after successful PTCA. Patients with restenosis (percent area stenosis greater than or equal to 75% or percent diameter stenosis greater than or equal to 50%) were excluded. METHODS AND RESULTS Luminal areas of a normal segment and the stenotic segment were determined at rest, during supine bicycle exercise, and 5 minutes after sublingual nitrate administration by using biplane quantitative coronary arteriography. Work loads before and early after PTCA were identical in group 1 and similar late after PTCA in group 2. Percent area stenosis decreased from 86% to 36% (p less than 0.001) in group 1 and from 93% to 46% (p less than 0.001) in group 2. Normal coronary arteries showed mild vasodilation during exercise before (+3%, NS versus rest), early (+7%, NS versus rest), and late after (+10%, p less than 0.05 versus rest) PTCA. Administration of sublingual nitrate was associated with significant vasodilation of the normal vessel segment before (+27%, p less than 0.001 versus rest), early (+31%, p less than 0.001 versus rest), and late (+21%, p less than 0.001 versus rest) after PTCA. In contrast, the stenotic vessel segments showed coronary vasoconstriction during exercise before PTCA (-25%, p less than 0.001 versus rest), whereas minimal vasomotion was observed early (+2%; NS versus rest) as well as late (+5%; NS versus rest) after PTCA. Individual post-PTCA (early and late) exercise data elicited vasodilation in 19, no vasomotion in four, and vasoconstriction in 10 instances. Sublingual administration of nitrate was associated with a significant increase in minimal luminal area before (+18%, p less than 0.05 versus rest), early (+24%, p less than 0.01 versus rest), and late (+16%, p less than 0.001 versus rest) after PTCA. An inverse linear correlation was found between the percent change in minimal luminal area during peak exercise and percent area stenosis at rest (r = 0.77, p less than 0.001). CONCLUSIONS Exercise-induced stenosis narrowing is observed before PTCA but normal vasomotion is reestablished in two thirds of all patients early and late after PTCA. In one third, an abnormal reaction to exercise (i.e., vasoconstriction) persisted after PTCA, mainly in those patients with a residual area stenosis of 50% (percent diameter stenosis of 30%) or more. Thus, PTCA appears to have a salutary effect on coronary vasomotion during exercise, which, however, remains dependent on the severity of the residual stenosis.
Does Adjuvant Chemotherapy in Elderly Patients With Stage III Colon Cancer Really Save Lives?
Authors: Hui-li Wong, Peter Gibbs
Journal: Journal of Clinical Oncology (2012)

as the response rate), and Wieand et al 5 proposed multistage designs for the comparison of a time to event end point (such as progression-free survival and overall survival) between randomly assigned arms.The strength of clinical trials is well-controlled and unbiased study results.However, this is true only when clinical trials satisfy the conditions of prospective studies (ie, they are conducted and the final data analyses are performed as planned by the study protocols).
Changes in Weight and Glucose Tolerance During Treatment With Mirtazapine
Authors: H. Himmerich
Journal: Diabetes Care (2006)

Weight gain is a serious problem with numerous psychotropic drugs (1), and drug-induced weight gain may be associated with health risks typically linked to obesity such as type 2 diabetes. Some second generation antipsychotics are known to lead to weight gain and to impair glucose tolerance (2), but little is known about the influence of weight gain–inducing novel antidepressants such as mirtazapine on glucose tolerance.

In a naturalistic study, we assessed weight, glucose tolerance, and plasma levels of insulin and cortisol, which are major players regarding glucose metabolism (3), in 11 inpatients (7 males and 4 females; age [mean ± SD]: 46.7 ± 20.5 years; weight: 73.3 ± 5.5 kg) with major depression according to the ICD-10 and Diagnostic and Statistical Manual …
Changes in recruitment of transversus abdominis correlate with disability in people with chronic low back pain
Authors: P H Ferreira, M L Ferreira, C G Maher, K Refshauge, R D Herbert, P W Hodges
Journal: British Journal of Sports Medicine (2009)

Objectives Although motor control exercises have been shown to be effective in the management of low back pain (LBP) the mechanism of action is unclear. The current study investigated the relationship between the ability to recruit transversus abdominis and clinical outcomes of participants in a clinical trial. Methods Ultrasonography was used to assess the ability to recruit transversus abdominis in a nested design: a sample of 34 participants with chronic LBP was recruited from participants in a randomised controlled trial comparing the efficacy of motor control exercise, general exercise and spinal manipulative therapy. Perceived recovery, function, disability and pain were also assessed. Results Participants with chronic LBP receiving motor control exercise had a greater improvement in recruitment of transversus abdominis (7.8%) than participants receiving general exercise (4.9% reduction) or spinal manipulative therapy (3.7% reduction). The effect of motor control exercise on pain reduction was greater in participants who had a poor ability to recruit transversus abdominis at baseline. There was a significant, moderate correlation between improved recruitment of transversus abdominis and a reduction in disability (r = −0.35; 95% CI 0.02 to 0.62). Conclusion These data provide some support for the hypothesised mechanism of action of motor control exercise and suggest that the treatment may be more effective in those with a poor ability to recruit transversus abdominis.
Factors that influence cancer patients' anxiety following a medical consultation: impact of a communication skills training programme for physicians
Authors: A. Liénard, I. Merckaert, Y. Libert, N. Delvaux, S. Marchal, J. Boniver, A.-M. Etienne, J. Klastersky, C. Reynaert, P. Scalliet, J.-L. Slachmuylder, D. Razavi
Journal: Annals of Oncology (2006)
Macrophage-Restricted Interleukin-10 Receptor Deficiency, but Not IL-10 Deficiency, Causes Severe Spontaneous Colitis
Authors: Ehud Zigmond, Biana Bernshtein, Gilgi Friedlander, Catherine R. Walker, Simon Yona, Ki-Wook Kim, Ori Brenner, Rita Krauthgamer, Chen Varol, Werner Müller, Steffen Jung
Journal: Immunity (2014)
Mycophenolate Mofetil Dose Reduction and the Risk of Acute Rejection after Renal Transplantation
Authors: Greg A Knoll, Ian MacDonald, Asmat Khan, Carl Van Walraven
Journal: Journal of the American Society of Nephrology (2003)

Mycophenolate mofetil (MMF) significantly decreases acute rejection rates after renal transplantation, but intolerance often occurs, leading to dose reduction. The clinical effect of MMF dose reduction has not been clearly established. This study determined whether MMF dose reduction after renal transplantation was associated with subsequent risk of acute rejection. This retrospective cohort study assessed 213 renal transplant recipients. Cox regression was used to model MMF dose as a time-dependent variable, with time to first acute rejection as the primary outcome. One hundred twenty-six patients (59%) had a total of 176 MMF dose reductions during the study. MMF dose was reduced because of leukopenia (55.1%), gastrointestinal symptoms (22.2%), infection (7.4%), malignancy (1.1%), and unknown reasons (14.2%). The cumulative number of days with the MMF dose reduced below full dose was an independent predictor of acute rejection. The relative risk of rejection increased by 4% for every week that the MMF dose was reduced below full dose. No significant association was observed between the number of days with MMF dropped below full dose and allograft failure. The cumulative number of days with the MMF dose dropped below full dose is a significant predictor of acute rejection after renal transplantation. Clinicians need to be aware of the rejection risk when the MMF dose is reduced and maintain close surveillance on such patients.