tbuckley/cabot-search huggingface dataset:
Spontaneous benign prostatic hyperplasia in the beagle. Age-associated changes in serum hormone levels, and the morphology and secretory function of the canine prostate.
Authors: C B Brendler, S J Berry, L L Ewing, A R McCullough, R C Cochran, J D Strandberg, B R Zirkin, D S Coffey, L G Wheaton, M L Hiler, M J Bordy, G D Niswender, W W Scott, P C Walsh
Journal: Journal of Clinical Investigation (1983)

This paper is a cross-sectional study of spontaneous benign prostatic hyperplasia (BPH) in a single canine species. The effects of aging and hormonal changes on the growth, histology, and glandular secretory function of the canine prostate were studied in 42 male beagles ranging in age from 8 mo to 9 yr. The beagle prostate enlarges for at least 6 yr, whether normal or hyperplastic. In contrast, prostatic secretory function, determined by ejaculate volume and total ejaculate protein, declines markedly after 4 yr of age. These reciprocal growth and functional changes in the prostate are closely associated with a progressive increase in the incidence of BPH, which is already apparent in some dogs by age two. With age there is a modest decrease in serum androgen levels with no apparent change in serum 17 beta-estradiol levels. This suggests that the growth and functional changes that are associated with the development of BPH and are initiated very early in life reflect an altered sensitivity of the prostate to serum androgens or a response to the relative decrease in the serum androgen to estrogen ratio.
Performance of the Traditional Age, Sex, and Angina Typicality–Based Approach for Estimating Pretest Probability of Angiographically Significant Coronary Artery Disease in Patients Undergoing Coronary Computed Tomographic Angiography
Authors: Victor Y. Cheng, Daniel S. Berman, Alan Rozanski, Allison M. Dunning, Stephan Achenbach, Mouaz Al-Mallah, Matthew J. Budoff, Filippo Cademartiri, Tracy Q. Callister, Hyuk-Jae Chang, Kavitha Chinnaiyan, Benjamin J.W. Chow, Augustin Delago, Millie Gomez, Martin Hadamitzky, Jörg Hausleiter, Ronald P. Karlsberg, Philipp Kaufmann, Fay Y. Lin, Erica Maffei, Gilbert L. Raff, Todd C. Villines, Leslee J. Shaw, James K. Min
Journal: Circulation (2011)

Background— Guidelines for the management of patients with suspected coronary artery disease (CAD) rely on the age, sex, and angina typicality–based pretest probabilities of angiographically significant CAD derived from invasive coronary angiography (guideline probabilities). Reliability of guideline probabilities has not been investigated in patients referred to noninvasive CAD testing. Methods and Results— We identified 14048 consecutive patients with suspected CAD who underwent coronary computed tomographic angiography. Angina typicality was recorded with the use of accepted criteria. Pretest likelihoods of CAD with ≥50 diameter stenosis (CAD50) and ≥70 diameter stenosis (CAD70) were calculated from guideline probabilities. Computed tomographic angiography images were evaluated by ≥1 expert reader to determine the presence of CAD50 and CAD70. Typical angina was associated with the highest prevalence of CAD50 (40 in men, 19 in women) and CAD70 (27 men, 11 women) compared with other symptom categories ( P &lt;0.001 for all). Observed CAD50 and CAD70 prevalences were substantially lower than those predicted by guideline probabilities in the overall population (18 versus 51 for CAD50, 10 versus 42 for CAD70; P &lt;0.001), driven by pronounced differences in patients with atypical angina (15 versus 47 for CAD50, 7 versus 37 for CAD70) and typical angina (29 versus 86 for CAD50, 19 versus 71 for CAD70). Marked overestimation of disease prevalence by guideline probabilities was found at all participating centers and across all sex and age subgroups. Conclusion— In this multinational study of patients referred for coronary computed tomographic angiography, determination of pretest likelihood of angiographically significant CAD by the invasive angiography-based guideline probabilities greatly overestimates the actual prevalence of disease.
Coronary Bypass Surgery Performed off Pump Does Not Result in Lower In-Hospital Morbidity Than Coronary Artery Bypass Grafting Performed on Pump
Authors: Jean-Francois Légaré, Karen J. Buth, Sharon King, Jeremy Wood, John A. Sullivan, Camille Hancock Friesen, John Lee, Kier Stewart, Gregory M. Hirsch
Journal: Circulation (2004)

There is increasing evidence that cardiopulmonary bypass (CPB) may be responsible for the morbidity associated with coronary artery bypass grafting (CABG) surgery. Recent developments in cardiac stabilization devices have made CABG without CPB feasible. However, there is conflicting evidence to date from published trials comparing outcomes between CABG performed with and without CPB, with some trials indicating an advantage to the avoidance of CPB and others showing little benefit.In a single-center randomized trial, 300 patients requiring CABG surgery at a single institution were prospectively randomized to have the procedure performed with CPB (n=150) or on the beating heart (n=150). Exclusion criteria for the trial included emergency procedure, concomitant major cardiac procedures, ejection fraction <30%, and reoperation. In-hospital outcomes were analyzed on an intention-to-treat basis. A mean of 3.0+/-0.9 grafts were performed in the CPB group compared with 2.8+/-0.9 grafts in the beating-heart group (P=0.06). There were no significant differences between the CPB group and the beating-heart group in mortality (0.7% versus 1.3%; P=1.0), transfusion (8.7% versus 9.3%), perioperative myocardial infarction (0.7% versus 2.7%; P=0.37), permanent stroke (0% versus 1.3%; P=0.50), new atrial fibrillation (32% versus 25%; P=0.20), and deep sternal wound infection (0.7% versus 0%; P=1.0). The mean time to extubation was 4 hours, the mean stay in the intensive care unit was 22 hours, and the median length of hospitalization was 5 days in both groups (P=NS).In contrast to published trials, we were unable to demonstrate any advantage with CABG performed without CPB in terms of patient morbidity. Excellent results can be obtained with either surgical approach.
Hydrogel Doped with Nanoparticles for Local Sustained Release of siRNA in Breast Cancer
Authors: Nathaly Segovia, Maria Pont, Nuria Oliva, Victor Ramos, Salvador Borrós, Natalie Artzi
Journal: Advanced Healthcare Materials (2014)

Of all the much hyped and pricy cancer drugs, the benefits from the promising siRNA small molecule drugs are limited. Lack of efficient delivery vehicles that would release the drug locally, protect it from degradation, and ensure high transfection efficiency, precludes it from fulfilling its full potential. This work presents a novel platform for local and sustained delivery of siRNA with high transfection efficiencies both in vitro and in vivo in a breast cancer mice model. siRNA protection and high transfection efficiency are enabled by their encapsulation in oligopeptide‐terminated poly(β‐aminoester) (pBAE) nanoparticles. Sustained delivery of the siRNA is achieved by the enhanced stability of the nanoparticles when embedded in a hydrogel scaffold based on polyamidoamine (PAMAM) dendrimer cross‐linked with dextran aldehyde. The combination of oligopeptide‐terminated pBAE polymers and biodegradable hydrogels shows improved transfection efficiency in vivo even when compared with the most potent commercially available transfection reagents. These results highlight the advantage of using composite materials for successful delivery of these highly promising small molecules to combat cancer.
Better Performance of CARs Deprived of the PD-1 Brake
Authors: Aizea Morales-Kastresana, Sara Labiano, José I. Quetglas, Ignacio Melero
Journal: Clinical Cancer Research (2013)

Immunotherapies often permit combinations to increase efficacy. Two approaches are currently leading our field: adoptive therapy with T cells transfected with chimeric antigen receptors and monoclonal antibodies blocking the PD-1/PD-L1 (B7-H1) axis. In this issue of Clinical Cancer Research, preclinical evidence for a synergistic combination of such approaches is reported.
<i>Here, There Be Dragons</i>: Charting Autophagy-Related Alterations in Human Tumors
Authors: Chandra B. Lebovitz, Svetlana B. Bortnik, Sharon M. Gorski
Journal: Clinical Cancer Research (2012)

Macroautophagy (or autophagy) is a catabolic cellular process that is both homeostatic and stress adaptive. Normal cells rely on basal levels of autophagy to maintain cellular integrity (via turnover of long-lived proteins and damaged organelles) and increased levels of autophagy to buoy cell survival during various metabolic stresses (via nutrient and energy provision through lysosomal degradation of cytoplasmic components). Autophagy can function in both tumor suppression and tumor progression, and is under investigation in clinical trials as a novel target for anticancer therapy. However, its role in cancer pathogenesis has yet to be fully explored. In particular, it remains unknown whether in vitro observations will be applicable to human cancer patients. Another outstanding question is whether there exists tumor-specific selection for alterations in autophagy function. In this review, we survey reported mutations in autophagy genes and key autophagy regulators identified in human tumor samples and summarize the literature regarding expression levels of autophagy genes and proteins in various cancer tissues. Although it is too early to draw inferences from this collection of in vivo studies of autophagy-related alterations in human cancers, their results highlight the challenges that must be overcome before we can accurately assess the scope of autophagy's predicted role in tumorigenesis.
Accumulation of the Oxidative Base Lesion 8-Hydroxyguanine in DNA of Tumor-Prone Mice Defective in Both the <b> <i>Myh</i> </b> and <b> <i>Ogg1</i> </b> DNA Glycosylases
Authors: Maria Teresa Russo, Gabriele De Luca, Paolo Degan, Eleonora Parlanti, Eugenia Dogliotti, Deborah E. Barnes, Tomas Lindahl, Hanjing Yang, Jeffrey H. Miller, Margherita Bignami
Journal: Cancer Research (2004)

Abstract The OGG1 and MYH DNA glycosylases prevent the accumulation of DNA 8-hydroxyguanine. In Myh−/− mice, there was no time-dependent accumulation of DNA 8-hydroxyguanine in brain, small intestine, lung, spleen, or kidney. Liver was an exception to this general pattern. Inactivation of both MYH and OGG1 caused an age-associated accumulation of DNA 8-hydroxyguanine in lung and small intestine. The effects of abrogated OGG1 and MYH on hepatic DNA 8-hydroxyguanine levels were additive. Because there is an increased incidence of lung and small intestine cancer in Myh−/−/Ogg1−/− mice, these findings support a causal role for unrepaired oxidized DNA bases in cancer development.
BCL2 oncogene translocation is mediated by a chi-like consensus.
Authors: R T Wyatt, R A Rudders, A Zelenetz, R A Delellis, T G Krontiris
Journal: The Journal of Experimental Medicine (1992)

Examination of 64 translocations involving the major breakpoint region (mbr) of the BCL2 oncogene and the immunoglobulin heavy chain locus identified three short (14, 16, and 18 bp) segments within the mbr at which translocations occurred with very high frequency. Each of these clusters was associated with a 15-bp region of sequence homology, the principal one containing an octamer related to chi, the procaryotic activator of recombination. The presence of short deletions and N nucleotide additions at the breakpoints, as well as involvement of JH and DH coding regions, suggested that these sequences served as signals capable of interacting with the VDJ recombinase complex, even though no homology with the traditional heptamer/spacer/nonamer (IgRSS) existed. Furthermore, the BCL2 signal sequences were employed in a bidirectional fashion and could mediate recombination of one mbr region with another. Segments homologous to the BCL2 signal sequences flanked individual members of the XP family of diversity gene segments, which were themselves highly overrepresented in the reciprocal products (18q-) of BCL2 translocation. We propose that the chi-like signal sequences of BCL2 represent a distinct class of recognition sites for the recombinase complex, responsible for initiating interactions between regions of DNA separated by great distances, and that BCL2 translocation begins by a recombination event between mbr and DXP chi signals. Since recombinant joints containing chi, not IgRSS, occur in brain cells expressing RAG-1 (Matsuoka, M., F. Nagawa, K. Okazaki, L. Kingsbury, K. Yoshida, U. Muller, D. T. Larue, J. A. Winer, and H. Sakano. 1991. Science [Wash. DC]. 254:81; reference 1), we further suggest that the product of this gene could mediate both BCL2 translocation and the first step of normal DJ assembly through the creation of chi joints, rather than signal or coding joints.
An increased rate of falling leads to a rise in fracture risk in postmenopausal women with self-reported osteoarthritis: a prospective multinational cohort study (GLOW)
Authors: Daniel Prieto-Alhambra, Xavier Nogues, M Kassim Javaid, Allison Wyman, Nigel K Arden, Rafael Azagra, Cyrus Cooper, Jonathan D Adachi, Steven Boonen, Roland D Chapurlat, Juliet E Compston, Stephen H Gehlbach, Susan L Greenspan, Frederick H Hooven, J Coen Netelenbos, Johannes Pfeilschifter, Maurizio Rossini, Philip N Sambrook, Stuart Silverman, Ethel S Siris, Nelson B Watts, Adolfo Díez-Pérez
Journal: Annals of the Rheumatic Diseases (2012)

Objectives Patients with osteoarthritis have increased bone mass but no decrease in fractures. The association between self-reported osteoarthritis and incident falls and fractures was studied in postmenopausal women. Methods The Global Longitudinal Study of Osteoporosis in Women is a prospective multinational cohort of 60 393 non-institutionalised women aged ≥55 years who had visited primary care practices within the previous 2 years. Questionnaires were mailed at yearly intervals. Patients were classified as having osteoarthritis if they answered yes to the question, ‘Has a doctor or other health provider ever said that you had osteoarthritis or degenerative joint disease?’, and this was validated against primary care records in a subsample. Information on incident falls, fractures and covariates was self-reported. Cox and Poisson models were used for incident fractures and number of falls, respectively, to compute hazard ratios (HRs) and rate ratios (RRs) for baseline osteoarthritis status. Results Of 51 386 women followed for a median of 2.9 years (interquartile range 2.1–3.0), 20 409 (40%) reported osteoarthritis. The adjusted HR for osteoarthritis predicting fracture was 1.21 (95% CI 1.13 to 1.30; p&lt;0.0001) and the adjusted RR for falls was 1.24 (95% CI 1.22 to 1.26; p&lt;0.0001). However, the association between osteoarthritis and fracture was not significant after adjustment for incident falls (HR 1.06 (95% CI 0.98 to 1.15; p=0.13)). Conclusions Postmenopausal women with self-reported osteoarthritis have a 20% increased risk of fracture and experience 25% more falls than those without osteoarthritis. These data suggest that increased falls are the causal pathway of the association between osteoarthritis and fractures.
P207 Does the Nijmegen correlate to the D12 when used as an outcome measure in patients with breathing pattern dysfunction
Authors: R. Johnston, F. Shaw, A. M. Gow, L. Flude
Journal: Thorax (2011)

<h3>Introduction</h3> Breathing pattern dysfunction (BPD) in patients with and without respiratory disease is linked to disproportionate dyspnoea. Asthma patients in particular have a high prevalence of BPD. The Nijmegen questionnaire (NQ) is a validated outcome measure in patients with no underlying respiratory pathophysiology, not in patients with organic disease. There is no validated tool that can be used to assess the effectiveness of breathing retraining in patients with BPD. The Dyspnoea-12 (D12) questionnaire provides a global score of breathlessness severity and is validated in respiratory disease, but not in patients with BPD. The aim was to correlate the D12 to the NQ and assess its use as an outcome measure for patients with BPD. Pre and post scores were compared to assess the effectiveness of Physiotherapy breathing retraining on patients with BPD referred to our tertiary centre. <h3>Method</h3> We included all Physiotherapy referrals to the outpatient department of the Royal Brompton Hospital for BPD between January and July 2011. The D12 and NQ were completed before and after 3 Physiotherapy interventions and respiratory rate was also measured. <h3>Results</h3> Initial data were available for 26 patients: mean (SD) age 47.6 yrs (13), 16 (62%) female, 13 (50%) had a diagnosis of asthma. Post intervention data were available for 17 (65%) patients. Respiratory rate did not correlate with the NQ or D12 in any of the groups. There was a statistically significant correlation between the NQ and D12 both pre (p=0.0017, R=0.59) and post (p=0.0156, R=0.58) intervention. A statistically significant difference pre and post intervention was shown in the NQ (p=0.0242 mean (SD)=7.35 (12.1)) and the D12 (p=0.0127). <h3>Conclusion</h3> The data suggests that breathing retraining provides both a clinically effective and statistically significant improvement in symptoms of patients with BPD. There was a significant correlation between the D12 and NQ scores in patients referred with BPD. This highlights that the D12 may be an appropriate outcome measure in this patient population.
Dependency on mask ventilation after acute respiratory failure in the intermediate care unit
Authors: A. Cuvelier
Journal: European Respiratory Journal (2005)

The predictive factors for long-term dependency (LTD) on noninvasive ventilation (NIV) immediately after acute hypercapnic respiratory failure (AHRF) have not been identified. The present authors studied 42 patients with chronic obstructive pulmonary disease (COPD) and 58 non-COPD patients successfully treated by NIV for an AHRF episode. Parameters at stable state, at admission for AHRF and during a 1-yr follow-up were compared in patients with or without LTD-NIV at discharge. The incidence of LTD-NIV was 39% in non-COPD patients and 19% in COPD patients. Based on multivariate analysis with stepwise logistic regression, lower baseline pH values and noninfectious causes of AHRF were independently associated with LTD-NIV. Mutually adjusted odds ratios were found to be 1.316 (95% confidence interval (CI) = 1.127-1.536) for a 0.01 decrease of baseline pH value and 5.1 (95% CI = 1.8-14.0) for a noninfectious cause of AHRF. Outcome after 1 yr was poor in COPD patients. Long-term dependency on noninvasive ventilation is not an uncommon situation after resolution of an acute hypercapnic respiratory failure episode, especially in patients with non-chronic obstructive pulmonary disease causes of respiratory failure. The present study raises the need for prospective validation of a weaning protocol in patients managed by noninvasive ventilation for an acute hypercapnic respiratory failure episode.
Multiplex target capture with double-stranded DNA probes
Authors: Peidong Shen, Wenyi Wang, Aung-Kyaw Chi, Yu Fan, Ronald W Davis, Curt Scharfe
Journal: Genome Medicine (2013)

Target enrichment technologies utilize single-stranded oligonucleotide probes to capture candidate genomic regions from a DNA sample before sequencing. We describe target capture using double-stranded probes, which consist of single-stranded, complementary long padlock probes (cLPPs), each selectively capturing one strand of a genomic target through circularization. Using two probes per target increases sensitivity for variant detection and cLPPs are easily produced by PCR at low cost. Additionally, we introduce an approach for generating capture libraries with uniformly randomized template orientations. This facilitates bidirectional sequencing of both the sense and antisense template strands during one paired-end read, which maximizes target coverage.
Signal Transduction and Ca <sup>2+</sup> Signaling in Contractile Regulation Induced by Crosstalk Between Endothelin-1 and Norepinephrine in Dog Ventricular Myocardium
Authors: Li Chu, Reiko Takahashi, Ikuo Norota, Takuya Miyamoto, Yasuchika Takeishi, Kuniaki Ishii, Isao Kubota, Masao Endoh
Journal: Circulation Research (2003)

In certain cardiovascular disorders, such as congestive heart failure and ischemic heart disease, several endogenous regulators, including norepinephrine (NE) and endothelin-1 (ET-1), are released from various types of cell. Because plasma levels of these regulators are elevated, it seems likely that cardiac contraction might be regulated by crosstalk among these endogenous regulators. We studied the regulation of cardiac contractile function by crosstalk between ET-1 and NE and its relationship to Ca2+ signaling in canine ventricular myocardium. ET-1 alone did not affect the contractile function. However, in the presence of NE at subthreshold concentrations (0.1 to 1 nmol/L), ET-1 had a positive inotropic effect (PIE). In the presence of NE at higher concentrations (100 to 1000 nmol/L), ET-1 had a negative inotropic effect. ET-1 had a biphasic inotropic effect in the presence of NE at an intermediate concentration (10 nmol/L). The PIE of ET-1 was associated with an increase in myofilament sensitivity to Ca2+ ions and a small increase in Ca2+ transients, which required the simultaneous activation of protein kinase A (PKA) and PKC. ET-1 elicited translocation of PKCepsilon from cytosolic to membranous fraction, which was inhibited by the PKC inhibitor GF 109203X. Whereas the Na+-H+ exchange inhibitor Hoe 642 suppressed partially the PIE of ET-1, detectable alteration of pHi did not occur during application of ET-1 and NE. The negative inotropic effect of ET-1 was associated with a pronounced decrease in Ca2+ transients, which was mediated by pertussis toxin-sensitive G proteins, activation of protein kinase G, and phosphatases. When the inhibitory pathway was suppressed, ET-1 had a PIE even in the absence of NE. Our results indicate that the myocardial contractility is regulated either positively or negatively by crosstalk between ET-1 and NE through different signaling pathways whose activation depends on the concentration of NE in the dog.
Intermediate-dose intramuscular methylprednisolone acetate in the treatment of rheumatic disease.
Authors: J Kovarsky
Journal: Annals of the Rheumatic Diseases (1983)

Treatment with a high-dose, intravenous bolus of methylprednisolone has been reported in numerous cases of rheumatic diseases. The optimal routes of administration, dosage, dosage interval, and other factors are unknown. This report describes uncontrolled clinical observations with a single dose of 320 mg of intramuscular methylprednisolone acetate in patients with rheumatic disease (12 with rheumatoid arthritis, 2 with spondyloarthropathy). This treatment may provide a useful therapeutic adjunct in selected clinical circumstances.
COPD assessment test (CAT) in acute exacerbation of COPD and in the long term follow up of COPD patients
Authors: Nikoletta Rovina, Michail Symiakakis, Anastasia Tsioka, Apostolos Travlos, Konstantinos Vlachos, Antonia Koutsoukou, Nikolaos Koulouris
Journal: European Respiratory Journal (2013)

Aim of this study was to assess the usefulness of the COPD Assessment Test (CAT) to detect changes in health status in patients experiencing COPD exacerbations (ECOPD) and to examine the correlations between CAT scores and disease outcome measures in a one year’s follow up. Sixty seven patients hospitalized for an ECOPD completed the CAT during the first 48 hours of admission, and at 3, 6, and 12 months after their discharge from the hospital.  CAT score in ECOPD was 29.9 ±7.4 (mean ± SD), while it remained stable at 3, 6 and 12m after discharge, time-points with stable COPD (13.9 ± 8.6, 13.6 ± 8.2, and 13.6 ± 7.7, accordingly, p  CAT scores increase at exacerbation, reflect the severity of the ECOPD as well as of stable COPD, and predict the occurrence of at least one exacerbation or hospitalization 3 months following discharge.