tbuckley/cabot-search huggingface dataset:
A Lung Computed Tomographic Assessment of Positive End-Expiratory Pressure–induced Lung Overdistension
Authors: SILVIA R. R. VIEIRA, LOUIS PUYBASSET, JACK RICHECOEUR, QIN LU, PHILIPPE CLUZEL, PABLO B. GUSMAN, PIERRE CORIAT, JEAN-JACQUES ROUBY
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

The aim of this study was to assess positive end-expiratory pressure (PEEP)-induced lung overdistension and alveolar recruitment in six patients with acute lung injury (ALI) using a computed tomographic (CT) scan method. Lung overdistension was first determined in six healthy volunteers in whom CT sections were obtained at FRC and at TLC with a positive airway pressure of 30 cm H2O. In patients, lung volumes were quantified by the analysis of the frequency distribution of CT numbers on the entire lung at zero end-expiratory pressure (ZEEP) and PEEP. In healthy volunteers at FRC, the distribution of the density histograms was monophasic with a peak at − 791 ± 12 Hounsfield units (HU). The lowest CT number observed was − 912 HU. At TLC, lung volume increased by 79 ± 35% and the peak CT number decreased to − 886 ± 26 HU. More than 70% of the increase in lung volume was located below − 900 HU, suggesting that this value can be considered as the threshold separating normal aeration from overdistension. In patients with ALI, at ZEEP the distribution of density histograms was either monophasic (n = 3) or biphasic (n = 3). The mean CT number was − 319 ± 34 HU. At PEEP 13 ± 3 cm H2O, lung volume increased by 47 ± 19% whereas mean CT number decreased to − 538 ± 171 HU. PEEP induced a mean alveolar recruitment of 320 ± 160 ml and a mean lung overdistension of 238 ± 320 ml. In conclusion, overdistended lung parenchyma of healthy volunteers is characterized by a CT number below − 900 HU. This threshold can be used in patients with ALI for differentiating PEEP-induced alveolar recruitment from lung overdistension.
Use of anti-asthma drugs in New Zealand.
Authors: B L Sinclair, D W Clark, M R Sears
Journal: Thorax (1987)

Increased sales of anti-asthma drugs, and a second "epidemic" of asthma mortality, raised concerns about the management of asthma in New Zealand. To study this, prescriptions were obtained from randomly selected pharmacies to identify 235 patients receiving one common anti-asthma drug, 175 of whom were willing to be interviewed. The authors considered that 80% had asthma, and only 20% suffered primarily from chronic bronchitis or emphysema. The increased sales of anti-asthma drugs could not therefore be explained by their increasing use in treatment of other respiratory disorders. One third of the identified asthmatic subjects experienced daily symptoms despite regular drug treatment. Inhaled corticosteroids were used by only 42% of this group with persistent symptoms. Regular or short course oral corticosteroids, with or without inhaled steroids, had been required by 49%. All patients with domiciliary nebulisers appeared to use these appropriately, and most had peak expiratory flow meters. Despite the increased sales of anti-asthma drugs, corticosteroids appear to be as much underused in patients with chronic asthma in the community as in those who die of their disease.
Identification of Inherited Genetic Variations Influencing Prognosis in Early-Onset Breast Cancer
Authors: Sajjad Rafiq, William Tapper, Andrew Collins, Sofia Khan, Ioannis Politopoulos, Sue Gerty, Carl Blomqvist, Fergus J. Couch, Heli Nevanlinna, Jianjun Liu, Diana Eccles
Journal: Cancer Research (2013)

Abstract Genome-Wide Association Studies (GWAS) have begun to investigate associations between inherited genetic variations and breast cancer prognosis. Here, we report our findings from a GWAS conducted in 536 patients with early-onset breast cancer aged 40 or less at diagnosis and with a mean follow-up period of 4.1 years (SD = 1.96). Patients were selected from the Prospective Study of Outcomes in Sporadic versus Hereditary breast cancer. A Bonferroni correction for multiple testing determined that a P value of 1.0 × 10−7 was a statistically significant association signal. Following quality control, we identified 487,496 single nucleotide polymorphisms (SNP) for association tests in stage 1. In stage 2, 35 SNPs with the most significant associations were genotyped in 1,516 independent cases from the same early-onset cohort. In stage 2, 11 SNPs remained associated in the same direction (P ≤ 0.05). Fixed effects meta-analysis models identified one SNP associated at close to genome wide level of significance 556 kb upstream of the ARRDC3 locus [HR = 1.61; 95% confidence interval (CI), 1.33–1.96; P = 9.5 × 10−7]. Four further associations at or close to the PBX1, RORα, NTN1, and SYT6 loci also came close to genome-wide significance levels (P = 10−6). In the first ever GWAS for the identification of SNPs associated with prognosis in patients with early-onset breast cancer, we report a SNP upstream of the ARRDC3 locus as potentially associated with prognosis (median follow-up time for genotypes: CC = 4 years, CT = 3 years, and TT = 2.7 years; Wilcoxon rank-sum test CC vs. CT, P = 4 × 10−4 and CT vs. TT, P = 0.76). Four further loci may also be associated with prognosis. Cancer Res; 73(6); 1883–91. ©2012 AACR.
Cardiac-Specific Deletion of <i>Gata4</i> Reveals Its Requirement for Hypertrophy, Compensation, and Myocyte Viability
Authors: Toru Oka, Marjorie Maillet, Alistair J. Watt, Robert J. Schwartz, Bruce J. Aronow, Stephen A. Duncan, Jeffery D. Molkentin
Journal: Circulation Research (2006)

The transcription factor GATA4 is a critical regulator of cardiac gene expression where it controls embryonic development, cardiomyocyte differentiation, and stress responsiveness of the adult heart. Traditional deletion of Gata4 caused embryonic lethality associated with endoderm defects and cardiac malformations, precluding an analysis of the role of GATA4 in the adult myocardium. To address the function of GATA4 in the adult heart, Gata4-loxP-targeted mice (Gata4fl/fl) were crossed with mice containing a beta-myosin heavy chain (beta-MHC) or alpha-MHC promoter-driven Cre transgene, which produced viable mice that survived into adulthood despite a 95% and 70% loss of GATA4 protein, respectively. However, cardiac-specific deletion of Gata4 resulted in a progressive and dosage-dependent deterioration in cardiac function and dilation in adulthood. Moreover, pressure overload stimulation induced rapid decompensation and heart failure in cardiac-specific Gata4-deleted mice. More provocatively, Gata4-deleted mice were compromised in their ability to hypertrophy following pressure overload or exercise stimulation. Mechanistically, cardiac-specific deletion of Gata4 increased cardiomyocyte TUNEL at baseline in embryos and adults as they aged, as well as dramatically increased TUNEL following pressure overload stimulation. Examination of gene expression profiles in the heart revealed a number of profound alterations in known GATA4-regulated structural genes as well as genes with apoptotic implications. Thus, GATA4 is a necessary regulator of cardiac gene expression, hypertrophy, stress-compensation, and myocyte viability.
Polypeptide‐Based “Smart” Micelles for Dual‐Drug Delivery: A Combination Study of Experiments and Simulations
Authors: Lili Chen, Tao Jiang, Chunhua Cai, Liquan Wang, Jiaping Lin, Xuguang Cao
Journal: Advanced Healthcare Materials (2014)

A dual‐drug‐loaded micelle is designed and constructed from a mixture of poly(propylene oxide)‐ b ‐poly(γ‐benzyl‐ l ‐glutamate)‐ b ‐poly(ethylene glycol) (PPO‐ b ‐PBLG‐ b ‐PEG) triblock terpolymers and two model drugs, doxorubicin (DOX) and naproxen (Nap). In the micelles, the DOX is chemically linked to the PBLG backbones through an acid‐cleavable hydrazone bond, whereas the Nap is physically encapsulated in the cores. The drug loading and releasing behaviors of the dual‐drug‐loaded micelles as well as single drug‐loaded micelles (DOX‐conjugated or Nap‐loaded micelles) are studied. The structures of micelles are characterized by means of microscopies and dynamic light scattering, and further examined by dissipative particle dynamics (DPD) simulations. It is revealed that the micelles possess a core–shell–corona structure in which the PPO/Nap, PBLG/DOX, and PEG aggregate to form the core, shell, and corona, respectively. In vitro studies reveal that the release of DOX and Nap is pH‐ and thermosensitive. Such drug releasing behaviors are also examined by DPD simulations, and more information regarding the mechanism is obtained. In addition, the bio‐related properties such as cellular uptake of the micelles and biocompatibility of the deliveries are evaluated. The results show that the dual‐drug‐loaded micelles are biocompatible at normal physiological conditions and retain the anti‐cancer efficiency.
Changes in Serum and Urinary Calcium during Treatment with Hydrochlorothiazide: Studies on Mechanisms
Authors: Arnold S. Brickman, Shaul G. Massry, Jack W. Coburn
Journal: Journal of Clinical Investigation (1972)

Studies were undertaken in man to evaluate the roles of volume depletion and of the parathyroid glands in mediating the changes in serum and urinary calcium which follow the administration of hydrochlorothiazide, 100 mg twice daily, for 4 days, 42 studies were carried out in 16 normal subjects, 9 patients with hyperparathyroidism, and 7 vitamin D-treated subjects with hypoparathyroidism. In six studies in normal subjects, daily sodium losses during thiazide administration were quantitatively replaced, and in six other studies the effect of equivalent sodium losses produced by furosemide was evaluated.
l-Arginine enriched biscuits improve endothelial function and glucose metabolism: A pilot study in healthy subjects and a cross-over study in subjects with impaired glucose tolerance and metabolic syndrome
Authors: Lucilla D. Monti, Maria C. Casiraghi, Emanuela Setola, Elena Galluccio, Maria A. Pagani, Lucio Quaglia, Emanuele Bosi, PierMarco Piatti
Journal: Metabolism (2012)
Inflammatory Biomarkers Improve Clinical Prediction of Mortality in Chronic Obstructive Pulmonary Disease
Authors: Bartolome R. Celli, Nicholas Locantore, Julie Yates, Ruth Tal-Singer, Bruce E. Miller, Per Bakke, Peter Calverley, Harvey Coxson, Courtney Crim, Lisa D. Edwards, David A. Lomas, Annelyse Duvoix, William MacNee, Stephen Rennard, Edwin Silverman, Jørgen Vestbo, Emiel Wouters, Alvar Agustí
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Rationale: Accurate prediction of mortality helps select patients for interventions aimed at improving outcome.Objectives: Because chronic obstructive pulmonary disease is characterized by low-grade systemic inflammation, we hypothesized that addition of inflammatory biomarkers to established predictive factors will improve accuracy.Methods: A total of 1,843 patients enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints study were followed for 3 years. Kaplan-Meier curves, log-rank analysis, and Cox proportional hazards analyses determined the predictive value for mortality of clinical variables, while C statistics assessed the added discriminative power offered by addition of biomarkers.Measurements and Main Results: At recruitment we measured anthropometrics, spirometry, 6-minute walk distance, dyspnea, BODE index, history of hospitalization, comorbidities, and computed tomography scan emphysema. White blood cell and neutrophil counts, serum or plasma levels of fibrinogen, chemokine ligand 18, surfactant protein D, C-reactive protein, Clara cell secretory protein-16, IL-6 and -8, and tumor necrosis factor-α were determined at recruitment and subsequent visits. A total of 168 of the 1,843 patients (9.1%) died. Nonsurvivors were older and had more severe airflow limitation, increased dyspnea, higher BODE score, more emphysema, and higher rates of comorbidities and history of hospitalizations. The best predictive model for mortality using clinical variables included age, BODE, and hospitalization history (C statistic of 0.686; P < 0.001). One single biomarker (IL-6) significantly improved the C statistic to 0.708, but this was further improved to 0.726 (P = 0.003) by the addition of all biomarkers.Conclusions: The addition of a panel of selected biomarkers improves the ability of established clinical variables to predict mortality in chronic obstructive pulmonary disease.Clinical trial registered with www.clinicaltrials.gov (NCT00292552).
Thanks be to Zebrafish
Authors: Ruth Williams
Journal: Circulation Research (2010)

D uring the last 10 -15 years, the tiny, tropical, fresh- water zebrafish has become one of the most powerful and versatile models for studying vertebrate heart development.Three recent reports in Nature remind us of just how much we owe to this fishy friend of research.The zebrafish was first developed for use as a model organism by George Streisinger at the University of Oregon in the 1970s.A common resident of household tropical aquariums, the fish soon became a common laboratory resident thanks to its hardiness and many other researchfriendly characteristics.The zebrafish is small, easy to keep, and produces large numbers of offspring on a regular basis-female zebrafish can produce up to 200 eggs per week.Such features make it perfect for genetic analysis.Its genome has been fully sequenced, large-scale mutation screenings have been carried out, and countless transgenic strains and human disease models are available.In addition, the zebrafish embryo is transparent, develops rapidly, and grows externally from the mother, allowing for easy experimental manipulation and observation.The zebrafish is, thus, close to being the ideal model organism for studying vertebrate development.In the field of cardiovascular biology, studies of zebrafish heart development have revealed a large number of genes and pathways that are conserved with higher vertebrates and mammals.Thus, although the zebrafish is coldblooded and its heart has just a single ventricle, it serves as a great tool and starting point for comparative analysis.One feature of the zebrafish heart that differs dramatically from that of mammals is the capacity for regeneration.In 2002, Kenneth Poss (Duke University, Durham, NC) and colleagues reported in the journal Science that after removing up to 20% of the fish's ventricle, the heart could regrow fully. 1 This led to the exciting idea that if scientists could discover how the fish did it, maybe they could use the same tools to mend injuries in human hearts.In that study, Poss et al also observed that cardiomyocyte proliferation was necessary for the regenerative process.The origin of those cardiomyocytes was unknown, however."What we didn't know was whether those cardiomyocytes that divide are those that existed in the uninjured heart or that maybe there's a progenitor cell that creates them," Poss explains."It's a bit of a subtle distinction."Initial findings from the team hinted that progenitor cells might be the starting material, 2 but their new study in Nature, 3 together with an accompanying report by Chris
Combined intense lifestyle and pharmacologic lipid treatment further reduce coronary events and myocardial perfusion abnormalities compared with usual-care cholesterol-lowering drugs in coronary artery disease
Authors: Stefano Sdringola, Keiichi Nakagawa, Yuko Nakagawa, S.Wamique Yusuf, Fernando Boccalandro, Nizar Mullani, Mary Haynie, Mary Jane Hess, K.Lance Gould
Journal: Journal of the American College of Cardiology (2003)
Presence of PAF-Acether in Human Breast Carcinoma: Relation to Axillary Lymph Node Metastasis
Authors: C. Pitton, M. Lanson, P. Besson, F. Fetissoff, J. Lansac, J. Benveniste, P. Bougnoux
Journal: JNCI Journal of the National Cancer Institute (1989)

PAF-acether (PAF; formerly platelet-activating factor), a potent lipid mediator of inflammation, is involved in multiple cellular functions. To evaluate the role of PAF in human cancer, we obtained specimens from patients with localized breast carcinoma and assayed them for PAF. PAF was found in almost all carcinoma, although it was not detected in most of the matched, nontumor breast tissue samples. Intratumor PAF level was elevated when axillary lymph node involvement was low. Greater axillary extension (two or more positive lymph nodes) was associated with a decreased intratumor PAF level. These findings, along with the independence of other prognostic factors, indicate that PAF is a tumor marker of axillary lymph node involvement. [J Natl Cancer Inst 81:1298–1302, 1989]
Targeting CD24 for Treatment of Colorectal and Pancreatic Cancer by Monoclonal Antibodies or Small Interfering RNA
Authors: Eyal Sagiv, Alex Starr, Uri Rozovski, Rami Khosravi, Peter Altevogt, Timothy Wang, Nadir Arber
Journal: Cancer Research (2008)

CD24 is a potential oncogene reported to be overexpressed in a large variety of human malignancies. We have shown that CD24 is overexpressed in 90% of colorectal tumors at a fairly early stage in the multistep process of carcinogenesis. Anti-CD24 monoclonal antibodies (mAb) induce a significant growth inhibition in colorectal and pancreatic cancer cell lines that express the protein. This study is designed to investigate further the effects of CD24 down-regulation using mAb or small interfering RNA in vitro and in vivo. Western blot analysis showed that anti-CD24 mAb induced CD24 protein down-regulation through lysosomal degradation. mAb augmented growth inhibition in combination with five classic chemotherapies. Xenograft models in vivo showed that tumor growth was significantly reduced in mAb-treated mice. Similarly, stable growth inhibition of cancer cell lines was achieved by down-regulation of CD24 expression using short hairpin RNA (shRNA). The produced clones proliferated more slowly, reached lower saturation densities, and showed impaired motility. Most importantly, down-regulation of CD24 retarded tumorigenicity of human cancer cell lines in nude mice. Microarray analysis revealed a similar pattern of gene expression alterations when cells were subjected to anti-CD24 mAb or shRNA. Genes in the Ras pathway, mitogen-activated protein kinase, or BCL-2 family and others of oncogenic association were frequently down-regulated. As a putative new oncogene that is overexpressed in gastrointestinal malignancies early in the carcinogenesis process, CD24 is a potential target for early intervention in the prevention and treatment of cancer.
PIK3CA-mediated PI3-kinase signalling is essential for HPV-induced transformation in vitro
Authors: Florianne E Henken, N Sanjib Banerjee, Peter JF Snijders, Chris JLM Meijer, Johanna De-Castro Arce, Frank Rösl, Thomas R Broker, Louise T Chow, Renske DM Steenbergen
Journal: Molecular Cancer (2011)

Abstract Background High-risk human papillomavirus (hrHPV) infections are causally related to cervical cancer development. The additional (epi)genetic alterations driving malignant transformation of hrHPV-infected cells however, are not yet fully elucidated. In this study we experimentally assessed the role of the PI3-kinase pathway and its regulator PIK3CA, which is frequently altered in cervical cancer, in HPV-induced transformation. Methods Cervical carcinomas and ectocervical controls were assessed for PIK3CA mRNA and protein expression by quantitative RT-PCR and immunohistochemical staining, respectively. A longitudinal in vitro model system of hrHPV-transfected keratinocytes, representing the immortal and anchorage independent phenotype, was assayed for PI3-kinase activation and function using chemical pathway inhibition i.e. LY294002 treatment, and PIK3CA RNA interference. Phenotypes examined included cellular viability, migration, anchorage independent growth and differentiation. mRNA expression of hTERT and HPV16 E6E7 were studied using quantitative RT-PCR and Northern blotting. Results Cervical carcinomas showed significant overexpression of PIK3CA compared to controls. During HPV-induced transformation in vitro , expression of the catalytic subunit PIK3CA as well as activation of downstream effector PKB/AKT progressively increased in parallel. Inhibition of PI3-kinase signalling in HPV16-transfected keratinocytes by chemical interference or siRNA-mediated silencing of PIK3CA resulted in a decreased phosphorylation of PKB/AKT. Moreover, blockage of PI3-kinase resulted in reduced cellular viability, migration, and anchorage independent growth. These properties were accompanied with a downregulation of HPV16E7 and hTERT mRNA expression. In organotypic raft cultures of HPV16- and HPV18-immortalized cells, phosphorylated PKB/AKT was primarily seen in differentiated cells staining positive for cytokeratin 10 (CK10). Upon PI3-kinase signalling inhibition, there was a severe impairment in epithelial tissue development as well as a dramatic reduction in p-PKB/AKT and CK10. Conclusion The present data indicate that activation of the PI3-kinase/PKB/AKT pathway through PIK3CA regulates various transformed phenotypes as well as growth and differentiation of HPV-immortalized cells and may therefore play a pivotal role in HPV-induced carcinogenesis.
Role of 1,25-Dihydroxyvitamin D3 on Intestinal Phosphate Absorption in Rats with a Normal Vitamin D Supply
Authors: R. Rizzoli, H. Fleisch, J-P. Bonjour
Journal: Journal of Clinical Investigation (1977)

In vitamin D-deficient rats, impaired intestinal phosphorus (P) absorption can be corrected by 1,25-dihydroxyvitamin D3[1,25-(OH)2D3]. In the present study, it was investigated whether changes in 1,25-(OH)2D3 production can influence intestinal P transport also in animals with a normal supply of vitamin D. The intestinal P absorption was evaluated in rats using both the in situ duodenal loop technique and the determination of the overall gastrointestinal absorption under three conditions known to influence the production of 1,25-(OH)2D3: (a) variation in dietary P, (b) thyroparathyroidectomy (TPTX) with or without administration of parathyroid hormone (PTH), and (c) treatment with disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP). In all circumstances changes in duodenal absorption paralleled the changes in the overall fractional absorption. (a) Lowering dietary P stimulated P absorption. (b) TPTX decreased P absorption. This effect was corrected either by the administration of PTH or by the administration of 1,25-(OH)2D3. (c) EHDP, when given at a dose known to inhibit 1,25-(OH)2D3 formation, decreased the duodenal P absorption in both intact and TPTX animals. This effect was corrected by 1,25-(OH)2D3. In the TPTX-EHDP-treated animals, the administration of PTH did not rectify the low duodenal P absorption. These results support the thesis that, in rats with normal vitamin D supply, variations in the endogenous production of 1,25-(OH)2D3 change the rate of P absorption. However, these changes are in such magnitude that they are of relatively small importance when compared to the effect of variation in the dietary intake of P. These results also strongly suggest that the action of PTH on duodenal P transport is mediated by its effect on 1,25-(OH)2D3 production, inasmuch as the effect of the hormone is abolished after blocking the renal 1-hydroxylation with EHDP.