tbuckley/cabot-search huggingface dataset:
Non–Polymer-Based Paclitaxel-Coated Coronary Stents for the Treatment of Patients With De Novo Coronary Lesions
Authors: Alexandra J. Lansky, Ricardo A. Costa, Gary S. Mintz, Yoshihiro Tsuchiya, Mark Midei, David A. Cox, Charles O’Shaughnessy, Robert A. Applegate, Louis A. Cannon, Michael Mooney, Anthony Farah, Mark A. Tannenbaum, Steven Yakubov, Dean J. Kereiakes, S. Chiu Wong, Barry Kaplan, Ecaterina Cristea, Gregg W. Stone, Martin B. Leon, William D. Knopf, William W. O’Neill
Journal: Circulation (2004)

Paclitaxel, a microtubule-stabilizing compound with potent antitumor activity, has been shown to inhibit smooth muscle cell proliferation and migration. The DELIVER trial was a prospective, randomized, blinded, multicenter clinical evaluation of the non-polymer-based paclitaxel-coated ACHIEVE stent compared with the stainless steel Multi-Link (ML) PENTA stent.A total of 1043 patients with focal de novo coronary lesions, <25 mm in length, in 2.5- to 4.0-mm vessels were randomized (ACHIEVE n=524; ML PENTA n=519). Angiographic follow-up was performed in a subset of 442 patients (ACHIEVE n=228; ML PENTA n=214). Prespecified end points were a 40% reduction in target-vessel failure at 9 months (primary clinical end point) and a 50% reduction in binary restenosis at 8 months (major secondary end point). Baseline clinical characteristics were comparable between the groups. Patients in ACHIEVE had more type C lesions and a larger reference diameter. At follow-up, stent late loss was 0.81 versus 0.98 mm (P=0.003), stent binary restenosis was 14.9% versus 20.6% (P=0.076), and target-vessel failure was 11.9% versus 14.5% (P=0.12) for ACHIEVE and ML PENTA, respectively.The ACHIEVE paclitaxel-coated stent decreased neointimal proliferation compared with the bare-metal PENTA stent; however, this reduction was insufficient to meet the prespecified primary end point of target-vessel failure and the secondary end point of binary restenosis.
Sex steroid hormone regulation of follicle-stimulating hormone subunit messenger ribonucleic acid (mRNA) levels in the rat.
Authors: S D Gharib, M E Wierman, T M Badger, W W Chin
Journal: Journal of Clinical Investigation (1987)

Follicle-stimulating hormone (FSH) beta, luteinizing hormone (LH) beta, and alpha subunit messenger RNA (mRNA) levels were examined in rats after castration and sex-steroid replacement. Subunit mRNAs were determined by blot hybridization using rat FSH beta genomic DNA, and alpha and LH beta complementary DNA (cDNA). Rat FSH beta mRNA is 1.7 kilobase in size. After ovariectomy, female FSH beta mRNA levels increased fourfold, whereas those of LH beta and alpha increased twenty- and eightfold, respectively. With estradiol, all subunits returned toward normal levels. Male LH beta and alpha mRNA levels rose eight- and fourfold, respectively, 40 d postcastration, but FSH beta mRNA levels increased minimally. After 7 d of testosterone propionate, LH beta and alpha mRNAs declined to normal levels, whereas FSH beta mRNA increased slightly. We conclude that in female rats FSH beta is negatively regulated by gonadal steroids, but to a lesser extent than LH beta or alpha mRNAs, and there is a differential regulation of FSH beta mRNA levels in males as compared with females at the time points examined.
Spectral analysis of wakefulness and REM sleep EEG in patients with sleep apnoea syndrome
Authors: F Morisson, G Lavigne, D Petit, T Nielsen, J Malo, J Montplaisir
Journal: European Respiratory Journal (1998)

Neuropsychological investigations of patients with obstructive sleep apnoea syndrome (OSAS) have shown impairments in such basic functions as memory, attention and executive control. Since executive functions are known to be dependent on the integrity of the frontal lobe, it was hypothesized that OSAS may be associated with hypoxaemic frontal lobe dysfunction. To test this hypothesis, 21 apnoeic patients and 10 normal controls were studied with quantitative electroencephalographic (EEG) methods during rapid eye movement (REM) sleep, when most apnoeic events occur and during wakefulness. In apnoeic patients, EEG slowing in REM sleep was observed over frontal, central and parietal regions, while EEG slowing during wakefulness was observed over all cortical regions examined. A positive correlation was found between EEG slowing during wakefulness and oxygen desaturation during the night. Contrary to the hypothesis, these electroencephalographic changes were not localized only to the frontal region. This result may explain the wide range of neuropsychological deficits noted in patients with obstructive sleep apnoea syndrome, in addition to their poor performance in tasks of executive functioning.
Comparison of childhood wheezing phenotypes in 2 birth cohorts: ALSPAC and PIAMA
Authors: Olga E. Savenije, Raquel Granell, Daan Caudri, Gerard H. Koppelman, Henriëtte A. Smit, Alet Wijga, Johan C. de Jongste, Bert Brunekreef, Jonathan A. Sterne, Dirkje S. Postma, John Henderson, Marjan Kerkhof
Journal: Journal of Allergy and Clinical Immunology (2011)
Detection and Characterization of a Novel Subset of CD8+CD57+ T Cells in Metastatic Melanoma with an Incompletely Differentiated Phenotype
Authors: Richard C. Wu, Shujuan Liu, Jessica A. Chacon, Sheng Wu, Yufeng Li, Pariya Sukhumalchandra, James L. Murray, Jeffrey J. Molldrem, Patrick Hwu, Hanspeter Pircher, Gregory Lizée, Laszlo G. Radvanyi
Journal: Clinical Cancer Research (2012)

Tumor-specific T cells are frequently induced naturally in melanoma patients and infiltrate tumors. It is enigmatic why these patients fail to experience tumor regression. Given that CD8(+) T cells mediate antigen-specific killing of tumor cells, the focus of this study was to identify alterations in the differentiation of CD8(+) residing at the tumor site, with emphasis on a population expressing CD57, a marker for terminal differentiation.We conducted flow cytometric analysis of CD8(+) tumor-infiltrating lymphocytes (TIL) isolated from 44 resected melanoma metastases with known T-cell differentiation markers. For comparison, peripheral blood mononuclear cells were isolated from matched melanoma patients. We sorted different CD8(+) subsets found in TIL and determined their effector functions. In addition, we carried out Vβ clonotype expression analysis of T-cell receptors to determine lineage relationship between the CD8(+) TIL subsets.The majority of CD8(+) TIL was in the early-effector memory stage of differentiation. A significant population consisted of an oligoclonal subset of cells coexpressing CD27, CD28, CD57, and Granzyme B, with little or no perforin. These cells could be induced to proliferate, produce a high level of IFN-γ, and differentiate into CD27(-)CD57(+), perforin(high) mature CTL in vitro. Addition of TGF-β1 prevented further differentiation.Our studies identified a novel subset of incompletely differentiated CD8(+) CTL coexpressing early effector memory and late CTL markers. This population resembles that found in patients with uncontrolled chronic viral infections. TGF-β1, frequently produced by melanoma tumors, may be a key cytokine inhibiting further maturation of this subset.
Progression-free Survival Following Stereotactic Body Radiotherapy for Oligometastatic Prostate Cancer Treatment-naive Recurrence: A Multi-institutional Analysis
Authors: Piet Ost, Barbara Alicja Jereczek-Fossa, Nicholas Van As, Thomas Zilli, Alexander Muacevic, Kenneth Olivier, Daniel Henderson, Franco Casamassima, Roberto Orecchia, Alessia Surgo, Lindsay Brown, Alison Tree, Raymond Miralbell, Gert De Meerleer
Journal: European Urology (2015)
The Tissue Engineering Puzzle: A Molecular Perspective
Authors: Viola Vogel, Gretchen Baneyx
Journal: Annual Review of Biomedical Engineering (2003)

▪ Abstract The inability of biomaterial scaffolds to functionally integrate into surrounding tissue is one of the major roadblocks to developing new biomaterials and tissue-engineering scaffolds. Despite considerable advances, current approaches to engineering cell-surface interactions fall short in mimicking the complexity of signals through which surrounding tissue regulates cell behavior. Cells adhere and interact with their extracellular environment via integrins, and their ability to activate associated downstream signaling pathways depends on the character of adhesion complexes formed between cells and their extracellular matrix. In particular, α 5 β 1 and α v β 3 integrins are central to regulating downstream events, including cell survival and cell-cycle progression. In contrast to previous findings that α v β 3 integrins promote angiogenesis, recent evidence argues that α v β 3 integrins may act as negative regulators of proangiogenic integrins such as α 5 β 1 . This suggests that fibronectin is critical for scaffold vascularization because it is the only mammalian adhesion protein that binds and activates α 5 β 1 integrins. Cells are furthermore capable of stretching fibronectin matrices such that the protein partially unfolds, and recent computational simulations provide structural models of how mechanical stretching affects fibronectin function. We propose a model whereby excessive tension generated by cells in contact to biomaterials may in fact render fibronectin fibrils nonangiogenic and potentially inhibit vascularization. The model could explain why current biomaterials independent of their surface chemistries and textures fail to vascularize.
Atrial effects of the novel K+-channel-blocker AVE0118 in anesthetized pigs
Authors: K Wirth
Journal: Cardiovascular Research (2003)

Objectives: AVE0118 is a novel blocker of the K+ channels Kv1.5 and Kv4.3 which are the molecular basis for the human cardiac ultrarapid delayed rectifier potassium current (IKur) and the transient outward current (Ito). The objective of this study was to investigate the effect of AVE0118 on atrial refractoriness (ERP), left atrial vulnerability (LAV) and on left atrial monophasic action potentials (MAP) in pentobarbital anesthetized pigs in comparison to the selective IKr blocker dofetilide in order to assess the therapeutic potential of the novel K+ channel blocker for atrial fibrillation. Methods: Atrial ERP was determined with the S1–S2-stimulus method in the free walls of left and right atrium at 240, 300 and 400 ms basic cycle length (BCL). The inducibility of mostly nonsustained atrial tachyarrhythmias by the premature S2 extrastimulus, which is very high in the left pig atrium and referred to as LAV, was evaluated before and after drugs. Left atrial epicardial MAP was recorded to study the influence of the potassium channel blockers on the time course of repolarization. Left ventricular epicardial MAP, ERP and QT interval were measured to investigate a possible effect of AVE0118 on ventricular repolarization. Results: ERPs determined at 240, 300 and 400 ms BCL were significantly shorter in the left vs. right atrium (99±3, 106±4 and 113±3 ms vs. 133±4 ms, 142±4 and 149±5, respectively; p<0.001; n = 21). AVE0118 administered i.v. dose-dependently prolonged the atrial ERP independent from rate and inhibited LAV (100% at 0.5 and 1 mg/kg) while having no effect at all on the corrected QT (QTc) interval. At 1 mg/kg (n = 5) AVE0118 prolonged left vs. right atrial ERP by 49.6±4.1 ms vs. 37.7±9.7 ms (means±SEM of changes at 240, 300, and 400 ms BCL), respectively, corresponding to a relative increase of 53.2±6.2% vs. 27.6±6.8% (p<0.05 for percent increase of left vs. right atrial ERP). In a separate group of pigs (n = 5) AVE0118 had no effect on left ventricular ERP at 333, 400 and 500 ms BCL and no effect on MAP duration and QT at 600 ms BCL. After 1 mg/kg of AVE0118 the atrial MAP was significantly prolonged already at 10% repolarization (P<0.05; n = 7) reaching the maximum at 40% repolarization. In contrast to AVE0118 the effect of dofetilide (10 μg/kg) on atrial MAP started to become significant only at 60% repolarization (n = 6) with a maximum increase at 90%. Dofetilide, which prolonged the QTc interval by 16.9% (P<0.001), had a significantly stronger effect on right (34.7±5 ms) vs. left atrial ERP (23.5±7 ms) at 300 ms BCL, respectively, but did not significantly inhibit LAV (14%; n = 6). Conclusion: The novel K+ channel blocker AVE0118 prolonged atrial ERP and showed strong atrial antiarrhythmic efficacy with no apparent effect on ventricular repolarization in pigs in vivo.
Chemosensitivity and Stratification by a Five Monoclonal Antibody Immunohistochemistry Test in the NSABP B14 and B20 Trials
Authors: Douglas T. Ross, Chung-yeul Kim, Gong Tang, Olga L. Bohn, Rodney A. Beck, Brian Z. Ring, Robert S. Seitz, Soonmyung Paik, Joseph P. Costantino, Norman Wolmark
Journal: Clinical Cancer Research (2008)

Abstract Purpose: To test the association between risk stratification and outcome in a prospectively designed, blinded retrospective study using tissue arrays of available paraffin blocks from the estrogen receptor–expressing, node-negative samples from the National Surgical Adjuvant Breast and Bowel Project B14 and B20 tamoxifen and chemotherapy trials. Experimental Design: Tissue arrays were stained by immunohistochemistry targeting p53, NDRG1, SLC7A5, CEACAM5, and HTF9C. Risk stratification was done using predefined scoring rules, algorithm for combining scores, and cutoff points for low-risk, moderate-risk, and high-risk patient strata. Results: In a univariate Cox model, this test was significantly associated with recurrence-free interval [HR, 1.3 (95% confidence interval, 1.1-1.6); P = 0.006]. In a multivariate model it contributed information independent of age, tumor size, and menopausal status (P = 0.007). The Kaplan-Meier estimates of the proportion of recurrence-free after 10 years were 73%, 86%, and 85% for the high-risk, moderate-risk, and low-risk groups (P = 0.001). The Kaplan-Meier estimates of the breast-cancer-specific-death rate were 23%, 10%, and 9% (P &amp;lt; 0.0001). Exploratory analysis in patients ≥60 years old showed Kaplan-Meier estimates of the proportion of recurrence-free of 78%, 89%, and 92%. Both high-risk and low-risk groups showed significant improvement on treatment with cytotoxic chemotherapy. Conclusions: Immunohistochemistry using five monoclonal antibodies assigns breast cancer patients to a risk index that was significantly associated with clinical outcome among the estrogen receptor–expressing, node-negative tamoxifen-treated patients. It seems that the test may be able to identify patients who have greater absolute benefit from adjuvant chemotherapy compared with unstratified patient populations. Exploratory analysis suggests that this test will be most useful in clinical decision making for postmenopausal patients.
High PSA anxiety and low health literacy skills: drivers of early use of salvage ADT among men with biochemically recurrent prostate cancer after radiotherapy?
Authors: B.A. Mahal, M.-H. Chen, C.L. Bennett, M.W. Kattan, O. Sartor, K. Stein, A.V. D'Amico, P.L. Nguyen
Journal: Annals of Oncology (2015)
GP earnings hit a five year low as practice expenses rise
Authors: A. O'Dowd
Journal: BMJ (2012)

The growing costs of running a general practice mean that GPs’ income has fallen to a five year low—declining £6000 since 2005-6.

Figures from the NHS Health and Social Care Information Centre show that the average income for contract holding GPs before tax was £104 100 in 2010-11—a fall of 1.5% on the previous year and almost £6000 (€7500; $9700) lower than in 2005-6.1

The BMA said that GPs were providing an “exceptional value for money service” and were effectively accepting a pay cut so that they could maintain a high level of service to patients.

The report took into consideration the earnings and expenses of full and part time GPs and covered …
Cathepsins in bleomycin-induced lung injury in rat
Authors: R. Koslowski, K. Knoch, E. Kuhlisch, D. Seidel, M. Kasper
Journal: European Respiratory Journal (2003)

Endogenous inhibitors tightly control the activity of proteinases in the extracellular space. Proteinase/antiproteinase imbalance may be caused by predominance of proteinases, resulting in severe tissue damage or abundance of proteinase inhibitors, leading to a shift in the balance of synthesis and degradation of extracellular matrix proteins and accumulation of these matrix components. Lung fibrosis is characterised by accumulation of fibrous matrix proteins in the alveolar interstitium. The activity of cathepsin D and amounts of cathepsins D and B in bleomycin-injured rat lung tissue and alveolar macrophages were examined. In addition, the activities of cathepsins and cysteine proteinase inhibitors (CPIs) in bronchoalveolar lavage fluid (BALF) were determined. No cathepsin but high CPI activity and large amounts of procathepsin B were detected in the BALF. In the alveolar lumen, the disturbed proteinase/antiproteinase balance for cysteine proteinases was clearly dominated by CPIs. In alveolar macrophages, the main source of increased cathepsin levels, large changes in cathepsin B and D content were observed during the inflammatory phase, corresponding to the occurrence of procathepsin B in BALF. With the end of the phase of tissue remodelling, imbalances in cathepsin and CPI activities were largely eliminated. Immunoblot data, revealing an increase in cathepsin D levels in myofibroblast-like cells compared to fibroblasts and in resting fibroblasts compared to proliferating cells, implicate this proteinase in the differentiation and conversion processes occurring at the beginning of the fibrotic phase of lung injury. The results show that cathepsin amounts and activities are increased transiently in lung tissue during regeneration processes in bleomycin-induced lung injury. Imbalances of cathepsin and cysteine proteinase inhibitors activities are also a phenomenon of the phase of tissue remodelling initiated by lung injury.
Rotating Night Shifts and Risk of Skin Cancer in the Nurses’ Health Study
Authors: Eva S. Schernhammer, Pedram Razavi, Tricia Y. Li, Abrar A. Qureshi, Jiali Han
Journal: JNCI Journal of the National Cancer Institute (2011)

Night shift work is associated with increased risk of several cancers, but the risk of skin cancer among night shift workers is unknown. We documented 10 799 incident skin cancers in 68 336 women in the Nurses' Health Study from June 1988 to June 2006 and examined the relationship between rotating night shifts and skin cancer. We used Cox proportional hazard models, adjusted for confounding variables (phenotypic and established risk factors of skin cancer), and performed stratified analysis to explore the modifying effect of hair color. Working 10 years or more on rotating night shifts was associated with a 14% decreased risk of skin cancer compared with never working night shifts (age-standardized incidence rate: 976 per 100 000 person-years (PY) vs 1070 per 100 000 PY, respectively; adjusted hazard ratios = 0.86, 95% confidence interval = 0.81 to 0.92, Ptrend < .001). This association was strongest for cutaneous melanoma; working 10 years or more of rotating night shifts was associated with 44% decreased risk of melanoma, after adjustment for melanoma risk factors (age-standardized incidence rate: 20 per 100 000 PY vs 35 per 100 000 PY, respectively; adjusted hazard ratios = 0.56, 95% confidence interval = 0.36 to 0.87, Ptrend = .005). Hair color, a surrogate for an individual's susceptibility to skin cancer, was a statistically significant effect modifier for the observed associations; darker-haired women had the lowest risk ( Pinteraction = .02).
Time constant of isovolumic pressure fall in the intact canine left ventricle
Authors: R. KETTUNEN, J. TIMISJARVI, P. RAMO, E. KOUVALAINEN, J. HEIKKILA, L. HIRVONEN
Journal: Cardiovascular Research (1986)

The two standard methods of computation of the time constant of the isovolumic single exponential decay of the left ventricular pressure were compared in anaesthetised, artificially ventilated, closed chest dogs in 87 experiments. In 23 additional experiments, carried out under basal steady state conditions, the time constant attained a mean (SD) value of 32(5) ms when computed according to the method with zero pressure asymptote assumption (Tz) and 39(7) ms when estimated according to a fit with variable pressure asymptote (Tv). Phenylephrine infusion significantly prolonged Tz from 31(6) to 46(12) and Tv from 39(7) to 92(52) ms. The increase in Tv was significantly greater than that in Tz. Propranolol increased Tv by 50% but Tz remained unaltered. Isoproterenol significantly decreased Tz from 33(2) to 18(3) and Tv from 38(3) to 29(3) ms. The decrease in Tz was significantly greater than that in Tv. Calcium chloride and atrial pacing decreased time constants, but volume loading by dextran infusion did not affect them. With regard to the whole material, the linear regression analysis yielded 0.776 as the coefficient of correlation between Tz and Tv. The two methods of time constant calculation appeared to diverge significantly always when changes in afterload or sympathetic activity were involved. These results indicate the dependence of relaxation on afterload but the independence on preload or ejection timing. In the light of these results the zero pressure asymptote method is recommended for the time constant computation as the practical choice when relaxation of the intact left ventricle is assessed.
Whole-Genome Resequencing of Experimental Populations Reveals Polygenic Basis of Egg-Size Variation in<i>Drosophila melanogaster</i>
Authors: Aashish R. Jha, Cecelia M. Miles, Nodia R. Lippert, Christopher D. Brown, Kevin P. White, Martin Kreitman
Journal: Molecular Biology and Evolution (2015)

Complete genome resequencing of populations holds great promise in deconstructing complex polygenic traits to elucidate molecular and developmental mechanisms of adaptation. Egg size is a classic adaptive trait in insects, birds, and other taxa, but its highly polygenic architecture has prevented high-resolution genetic analysis. We used replicated experimental evolution in Drosophila melanogaster and whole-genome sequencing to identify consistent signatures of polygenic egg-size adaptation. A generalized linear-mixed model revealed reproducible allele frequency differences between replicated experimental populations selected for large and small egg volumes at approximately 4,000 single nucleotide polymorphisms (SNPs). Several hundred distinct genomic regions contain clusters of these SNPs and have lower heterozygosity than the genomic background, consistent with selection acting on polymorphisms in these regions. These SNPs are also enriched among genes expressed in Drosophila ovaries and many of these genes have well-defined functions in Drosophila oogenesis. Additional genes regulating egg development, growth, and cell size show evidence of directional selection as genes regulating these biological processes are enriched for highly differentiated SNPs. Genetic crosses performed with a subset of candidate genes demonstrated that these genes influence egg size, at least in the large genetic background. These findings confirm the highly polygenic architecture of this adaptive trait, and suggest the involvement of many novel candidate genes in regulating egg size.