tbuckley/cabot-search huggingface dataset:
A 48-yr-old female with headache and dyspnoea
Authors: S.M. Studer, P.B. Terry
Journal: European Respiratory Journal (2001)

Azelastine, an antiallergy and antiasthmatic drug, has been reported to be metabolized mainly to desmethylazelastine and 6-hydroxyazelastine in mammals. In the present study, the inhibitory effects of azelastine and its two metabolites on human cytochrome P-450 (CYP) isoform-dependent reactions were investigated to predict the drug interactions of azelastine using microsomes from human B-lymphoblast cells expressing CYP. The specific activities for human CYP isoforms included: 7-ethoxyresorufin <i>O</i>-deethylation (CYP1A1), phenacetin <i>O</i>-deethylation (CYP1A2), coumarin 7-hydroxylation (CYP2A6), 7-benzyloxyresorufin<i>O</i>-dealkylation (CYP2B6), <i>S</i>-warfarin 7-hydroxylation (CYP2C9), <i>S</i>-mephenytoin 4′-hydroxylation (CYP2C19), bufuralol 1′-hydroxylation (CYP2D6), chlorzoxazone 6-hydroxylation (CYP2E1), and testosterone 6β-hydroxylation (CYP3A4). In almost all the activities, desmethylazelastine exhibited stronger inhibition than azelastine and 6-hydroxyazelastine. Desmethylazelastine, but not azelastine and 6-hydroxyazelastine, uncompetitively inhibited CYP2B6 activity (<i>K</i><sub>i</sub> = 32.6 ± 4.8 μM). Azelastine, desmethylazelastine, and 6-hydroxyazelastine competitively inhibited CYP2C9 activity (<i>K</i><sub>i</sub> = 13.9 ± 1.8, 15.0 ± 3.1, and 17.0 ± 4.1 μM, respectively), CYP2C19 activity (<i>K</i><sub>i</sub> = 21.9 ± 2.2, 7.3 ± 1.6, and 9.3 ± 1.6 μM, respectively), and CYP2D6 activity (<i>K</i><sub>i</sub>= 1.2 ± 0.1, 1.5 ± 0.2, and 3.0 ± 0.5 μM, respectively). Azelastine and desmethylazelastine competitively inhibited CYP3A4 activity (<i>K</i><sub>i</sub> = 23.7 ± 4.6 and 13.2 ± 2.3 μM). 6-Hydroxyazelastine interfered with the determination of testosterone 6β-hydroxylation by HPLC. CYP1A2, CYP2A6, and CYP2E1 activities were not significantly inhibited by azelastine and the two metabolites. Among the human CYPs tested, the inhibitory effects of azelastine and its two metabolites were the most potent on human CYP2D6. In consideration of the<i>K</i><sub>i</sub> values and the concentration of azelastine and desmethylazelastine in human livers after chronic oral administration of azelastine, the possibility of in vivo drug interaction of azelastine and other drugs that are mainly metabolized by CYP2D6 was suggested although it might not cause critical side effects. The inhibition of CYP2C9, CYP2C19, and CYP3A4 activity by azelastine and its two metabolites might be clinically insignificant.
Assignment of isochores for all completely sequenced vertebrate genomes using a consensus
Authors: Thorsten Schmidt, Dmitrij Frishman
Journal: Genome biology (2008)

Abstract We show that although the currently available isochore mapping methods agree on the isochore classification of about two-thirds of the human DNA, they produce significantly different results with regard to the location of isochore boundaries and isochore length distribution. We present a new consensus isochore assignment method based on majority voting and provide IsoBase, a comprehensive on-line database of isochore maps for all completely sequenced vertebrate genomes.
SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver
Authors: Jay D. Horton, Joseph L. Goldstein, Michael S. Brown
Journal: Journal of Clinical Investigation (2002)

Lipid homeostasis in vertebrate cells is regulated by a family of membrane-bound transcription factors designated sterol regulatory element-binding proteins (SREBPs).SREBPs directly activate the expression of more than 30 genes dedicated to the synthesis and uptake of cholesterol, fatty acids, triglycerides, and phospholipids, as well as the NADPH cofactor required to synthesize these molecules (1-4).In the liver, three SREBPs regulate the production of lipids for export into the plasma as lipoproteins and into the bile as micelles.The complex, interdigitated roles of these three SREBPs have been dissected through the study of ten different lines of gene-manipulated mice.These studies form the subject of this review.
The Affordable Care Act and the Future of Clinical Medicine: The Opportunities and Challenges
Authors: Robert Kocher, Ezekiel J. Emanuel, Nancy-Ann M. DeParle
Journal: Annals of Internal Medicine (2010)

The Affordable Care Act is a once-in-a-generation change to the U.S. health system. It guarantees access to health care for all Americans, creates new incentives to change clinical practice to foster better coordination and quality, gives physicians more information to make them better clinicians and patients more information to make them more value-conscious consumers, and changes the payment system to reward value. The Act and the health information technology provisions in the American Recovery and Reinvestment Act remove many barriers to delivering high-quality care, such as unnecessary administrative complexity, inaccessible clinical data, and insufficient access to primary care and allied health providers. We hope that physicians will embrace the opportunities created by the Affordable Care Act that will enable them to provide better care for their patients and lead the U.S. health system in a more positive direction. To fully realize the benefits of the Affordable Care Act for their practices and their patients, physicians will design their offices for seamless care, employing new practice models and using technology to integrate patient information with professional society guidelines to keep patients with chronic conditions healthy and out of the hospital. Under the Affordable Care Act, physicians who effectively collaborate with other providers to improve patient outcomes, the value of medical services, and patient experiences will thrive and be the leaders of the health care system.
In Vivo And Electron Microscopic Observations of the Hepatic Micro Vasculature in the Rat Following Portacaval Anastomosis
Authors: Robert S. Mccuskey, Franz J. Vonnahme, Martin Grun
Journal: Hepatology (1983)

The livers of rats subjected to end-to-side portacaval anastomoses were studied 3 to 5 months postoperatively by in vivo and electron microscopy. Compared with sham-operated controls, the livers of portacaval anastomoses animals contained dilated, tortuous networks of sinusoids. The velocity of blood flow in these vessels tended to be slower and more variable than controls, but always progressed toward the hepatic venules. Blood entered the sinusoids from portal venules and from arteriosinus twigs which terminated in the initial segments of some of the sinusoids at the periphery of the lobule. Together, the arteriosinus twigs and the short, initial segments of these sinusoids formed functional arterioportal anastomoses. These, in combination with the lack of portal venous flow, resulted in retrograde blood flow in portal venules. Nevertheless, blood still flowed from these portal venules into the sinusoids unless the sinusoid was fed by an arteriosinus twig. In addition to these microcirculatory alterations, the number of Kupffer cells that phagocytized latex particles was less in the animals with portacaval anastomoses, as was the number of particles ingested by these cells. Scanning and transmission electron microscopy confirmed the paucity of Kupffer cells. Those seen appeared inactive since they were flattened, exhibited few microplicae and filopodia and contained few latex particles. The endothelial cells of the sinusoid lining were perforated by increased numbers of large fenestrate which may be a reflection of elevated intrasinusoid pressures generated by the expanded arterialization of the sinusoid bed. The observed dilated sinusoid network interspersed by narrowed plates of hepatocytes is also consistent with this hypothesis. Finally, scattered nodular foci were observed which contained enlarged hepatocytes, narrow sinusoids, active Kupffer cells, and more normal rates of blood flow. Such sites may represent attempts by the liver to regenerate its normal architecture.
Two Drugs Versus One Drug in Non–Small-Cell Lung Cancer: Are We Asking the Right Questions?
Authors: Nasser H. Hanna
Journal: Journal of Clinical Oncology (2012)

The treatment of oncologic diseases has evolved after decades of exhaustive, time-consuming, expensive, and frequently inefficient trial and error. With a limited arsenal of therapeutics, basic questions regarding the dose, schedule, and optimal combination of therapeutics dominated the research landscape for many years. Throughout the 20th century, cancer-drug discovery had largely occurred through serendipitous events; chief among these events included the observations of the effects of mustard gas on soldiers during World War I, the effects of folate and plant products on the growth of leukemic cells, and the death of bacterial cells in a water basin exposed to electrodes made of platinum. These observations were followed years later by a greater understanding of the mechanisms that caused this cancer-kill effect. Several key principles of treatment emerged from the successful treatment of acute leukemia that would be tested over and over again for the next four decades, namely, the most effective treatment for cancer would come from the combination of drugs that had a singleagent activity, differing mechanisms of action, nonoverlapping toxic
Chest computed tomography: a validated surrogate endpoint of cystic fibrosis lung disease?
Authors: Martine Loeve, Gabriel P. Krestin, Margaret Rosenfeld, Marleen de Bruijne, Stephen M. Stick, Harm A. Tiddens
Journal: European Respiratory Journal (2012)

Clinical trials for the treatment of cystic fibrosis (CF) lung disease are important to test and optimise new therapeutic interventions. To evaluate the effect of these interventions, sensitive and accurate outcome measures are needed. The most commonly used endpoints are spirometric variables such as the forced expiratory volume in 1 s and respiratory tract exacerbations. Unfortunately, these endpoints are relatively insensitive for monitoring progression of CF lung disease, and thus require a large number of patients when used in clinical studies. In addition, these endpoints are not suitable to study CF lung disease in young children. Chest computed tomography (CT) holds great promise for use as a sensitive surrogate endpoint in CF. A large body of evidence has been produced to validate the use of chest CT as a primary endpoint to study CF lung disease. However, before chest CT can be used in clinical trials, it has to be recognised as a validated surrogate endpoint by regulatory agencies. The aim of this review is to summarise what is currently known about the use of chest CT as surrogate endpoint in clinical trials in CF.
Pharmacological Actions of Statins: A Critical Appraisal in the Management of Cancer
Authors: Patrizia Gazzerro, Maria Chiara Proto, Giuseppina Gangemi, Anna Maria Malfitano, Elena Ciaglia, Simona Pisanti, Antonietta Santoro, Chiara Laezza, Maurizio Bifulco
Journal: Pharmacological Reviews (2011)

Statins, among the most commonly prescribed drugs worldwide, are cholesterol-lowering agents used to manage and prevent cardiovascular and coronary heart diseases. Recently, a multifaceted action in different physiological and pathological conditions has been also proposed for statins, beyond anti-inflammation and neuroprotection. Statins have been shown to act through cholesterol-dependent and -independent mechanisms and are able to affect several tissue functions and modulate specific signal transduction pathways that could account for statin pleiotropic effects. Typically, statins are prescribed in middle-aged or elderly patients in a therapeutic regimen covering a long life span during which metabolic processes, aging, and concomitant novel diseases, including cancer, could occur. In this context, safety, toxicity, interaction with other drugs, and the state of health have to be taken into account in subjects treated with statins. Some evidence has shown a dichotomous effect of statins with either cancer-inhibiting or -promoting effects. To date, clinical trials failed to demonstrate a reduced cancer occurrence in statin users and no sufficient data are available to define the long-term effects of statin use over a period of 10 years. Moreover, results from clinical trials performed to evaluate the therapeutic efficacy of statins in cancer did not suggest statin use as chemotherapeutic or adjuvant agents. Here, we reviewed the pharmacology of the statins, providing a comprehensive update of the current knowledge of their effects on tissues, biological processes, and pathological conditions, and we dissected the disappointing evidence on the possible future use of statin-based drugs in cancer therapy.
Proteogenomic characterization and mapping of nucleosomes decoded by Brd and HP1 proteins
Authors: Gary LeRoy, Iouri Chepelev, Peter A DiMaggio, Mario A Blanco, Barry M Zee, Keji Zhao, Benjamin A Garcia
Journal: Genome biology (2012)

Abstract Background Histone post-translational modifications (PTMs) constitute a branch of epigenetic mechanisms that can control the expression of eukaryotic genes in a heritable manner. Recent studies have identified several PTM-binding proteins containing diverse specialized domains whose recognition of specific PTM sites leads to gene activation or repression. Here, we present a high-throughput proteogenomic platform designed to characterize the nucleosomal make-up of chromatin enriched with a set of histone PTM binding proteins known as histone PTM readers. We support our findings with gene expression data correlating to PTM distribution. Results We isolated human mononucleosomes bound by the bromodomain-containing proteins Brd2, Brd3 and Brd4, and by the chromodomain-containing heterochromatin proteins HP1β and HP1α. Histone PTMs were quantified by mass spectrometry (ChIP-qMS), and their associated DNAs were mapped using deep sequencing. Our results reveal that Brd- and HP1-bound nucleosomes are enriched in histone PTMs consistent with actively transcribed euchromatin and silent heterochromatin, respectively. Data collected using RNA-Seq show that Brd-bound sites correlate with highly expressed genes. In particular, Brd3 and Brd4 are most enriched on nucleosomes located within HOX gene clusters, whose expression is reduced upon Brd4 depletion by short hairpin RNA. Conclusions Proteogenomic mapping of histone PTM readers, alongside the characterization of their local chromatin environments and transcriptional information, should prove useful for determining how histone PTMs are bound by these readers and how they contribute to distinct transcriptional states.
Genome-wide analysis of mono-, di- and trimethylation of histone H3 lysine 4 in Arabidopsis thaliana
Authors: Xiaoyu Zhang, Yana V Bernatavichute, Shawn Cokus, Matteo Pellegrini, Steven E Jacobsen
Journal: Genome biology (2009)

Abstract Background Post-translational modifications of histones play important roles in maintaining normal transcription patterns by directly or indirectly affecting the structural properties of the chromatin. In plants, methylation of histone H3 lysine 4 (H3K4me) is associated with genes and required for normal plant development. Results We have characterized the genome-wide distribution patterns of mono-, di- and trimethylation of H3K4 (H3K4me1, H3K4me2 and H3K4me3, respectively) in Arabidopsis thaliana seedlings using chromatin immunoprecipitation and high-resolution whole-genome tiling microarrays (ChIP-chip). All three types of H3K4me are found to be almost exclusively genic, and two-thirds of Arabidopsis genes contain at least one type of H3K4me. H3K4me2 and H3K4me3 accumulate predominantly in promoters and 5' genic regions, whereas H3K4me1 is distributed within transcribed regions. In addition, H3K4me3-containing genes are highly expressed with low levels of tissue specificity, but H3K4me1 or H3K4me2 may not be directly involved in transcriptional activation. Furthermore, the preferential co-localization of H3K4me3 and H3K27me3 found in mammals does not appear to occur in plants at a genome-wide level, but H3K4me2 and H3K27me3 co-localize at a higher-than-expected frequency. Finally, we found that H3K4me2/3 and DNA methylation appear to be mutually exclusive, but surprisingly, H3K4me1 is highly correlated with CG DNA methylation in the transcribed regions of genes. Conclusions H3K4me plays widespread roles in regulating gene expression in plants. Although many aspects of the mechanisms and functions of H3K4me appear to be conserved among all three kingdoms, we observed significant differences in the relationship between H3K4me and transcription or other epigenetic pathways in plants and mammals.
Epithelial Barriers in Homeostasis and Disease
Authors: Amanda M. Marchiando, W. Vallen Graham, Jerrold R. Turner
Journal: Annual Review of Pathology Mechanisms of Disease (2010)

Epithelia form barriers that are essential to life. This is particularly true in the intestine, where the epithelial barrier supports nutrient and water transport while preventing microbial contamination of the interstitial tissues. Along with plasma membranes, the intercellular tight junction is the primary cellular determinant of epithelial barrier function. Disruption of tight junction structure, as a result of specific protein mutations or aberrant regulatory signals, can be both a cause and an effect of disease. Recent advances have provided new insights into the extracellular signals and intracellular mediators of tight junction regulation in disease states as well as into the interactions of intestinal barrier function with mucosal immune cells and luminal microbiota. In this review, we discuss the critical roles of the tight junction in health and explore the contributions of barrier dysfunction to disease pathogenesis.
Association of the macrophage migration inhibitory factor gene polymorphisms with inflammatory bowel disease
Authors: J Oliver, A Marquez, M Gomez-Garcia, A Martinez, J L Mendoza, J R Vilchez, M A Lopez-Nevot, A Pinero, E G de la Concha, A Nieto, E Urcelay, D. J Martin
Journal: Gut (2006)

Macrophage migration inhibitory factor (MIF), an immunoregulatory cytokine that has pro-inflammatory, hormonal and enzymatic activities, has been found to be markedly increased in the serum of patients with inflammatory bowel disease (IBD).1,2 MIF-deficient mice failed to develop disease1 and blockage with anti-MIF antibody reduced disease activity.1,2 Finally, functional polymorphisms of the human MIF gene have been associated with increased susceptibility to inflammatory and autoimmune diseases.3 These findings prompted us to investigate the potential association of the functional MIF −173G/C and −794 (CATT)n gene variants with the susceptibility and clinical expression of IBD.

We studied a case–control cohort (cohort 1) comprising 336 patients with Crohn’s disease and 287 patients with ulcerative colitis from south Spain and 361 controls from the same area. An additional cohort (cohort 2) was analysed, comprising 325 patients with Crohn’s disease, 347 patients with ulcerative colitis and 526 controls from Madrid. Table 1 shows the clinical characteristics …
Prognostic Significance of Nuclear Receptor Coactivator-3 Overexpression in Primary Cutaneous Melanoma
Authors: Javier Rangel, Sima Torabian, Ladan Shaikh, Mehdi Nosrati, Frederick L. Baehner, Chris Haqq, Stanley P.L. Leong, James R. Miller, Richard W. Sagebiel, Mohammed Kashani-Sabet
Journal: Journal of Clinical Oncology (2006)

To assess the prognostic significance of nuclear receptor coactivator-3 (NCOA3) overexpression in primary cutaneous melanoma.NCOA3 expression was assessed using immunohistochemical analysis of a melanoma tissue microarray (TMA) containing primary melanomas from 343 patients with defined histology and follow-up. The impact of the presence or absence of various prognostic factors on relapse-free survival (RFS) and disease-specific survival (DSS) of melanoma patients was assessed using Cox regression and Kaplan-Meier analysis. The impact of presence or absence of various factors on sentinel lymph node (SLN) metastasis was assessed using logistic regression analysis.Increasing degree of NCOA3 expression was significantly predictive of SLN metastasis (P = .013) and the mean number of SLN metastases (P = .031). Kaplan-Meier analysis demonstrated a significant association between NCOA3 overexpression and reduced RFS (P = .021) and DSS (P = .030). Logistic regression analysis revealed increasing degree of NCOA3 expression to be an independent predictor of SLN status (P = .017). Multivariate Cox regression analysis showed the independent impact of NCOA3 expression on RFS (P = .0095) and DSS (P = .021). NCOA3 was the most powerful factor predicting DSS, outperforming tumor thickness and ulceration.These results identify NCOA3 as a novel, independent marker of melanoma outcome, with a significant impact on SLN metastasis, RFS, and DSS.
Colorectal cancer (CRC) screening using sigmoidoscopy followed by colonoscopy: a feasibility and efficacy study on a cancer institute based population
Authors: H. Bleiberg, P. Autier, F. Huet, A.M. Schrauwen, E. Staquet, T. Delaunoit, A. Hendlisz, C. Wyns, J.M. Panzer, B. Caucheteur, P. Eisendrath, A. Grivegnée
Journal: Annals of Oncology (2006)
Exploring dynamic stability in a group of intercollegiate athletes
Authors: K Liu, G Gustavsen, T W Kaminski
Journal: British Journal of Sports Medicine (2011)

Background Deficits in postural stability have been linked to an increased risk of ankle sprain. Repeated ankle sprains can lead to ankle instability. Time to stabilisation (TTS) has been used to measure dynamic stability. Objective To determine if differences exist in TTS between stable and unstable ankles. Design Controlled, cross-sectional. Setting Biomechanics Laboratory. Participants 64 Division I collegiate athletes (25 females and 39 males, age=18±0.9, height=180.5±10.3 cm, mass=82.5±18.9 kg). Interventions Group status (stable vs unstable) was determined by the Cumberland Ankle Instability Tool (CAIT). Each participant completed hops onto a force plate from four different directions (forward, backward, medial, lateral) and were instructed to land in the middle of the force plate on a single leg, stabilise as quickly as possible, and remain motionless for 5 sec. Three trials were collected for each of the four directions. TTS was quantified as the time it takes the vertical component of the ground reaction force to reach and stay within ±5% of the participant's body mass after landing. Main outcome measurements TTS (sec) data were analyzed using an independent t-test (p≤0.05) comparing the stable and unstable groups for each of the jump directions. Results There were no significant differences in TTS (sec) between stable and unstable ankles. Jump Direction mean±SD, stable mean±SD, unstable p-value t Backward 1.04±0.55 1.22±0.51 0.152 −1.442 Forward 1.17±0.51 1.20±0.62 0.792 −0.265 Lateral 1.15±0.56 1.09±0.50 0.626 0.488 Medial 1.12±0.50 1.14±0.64 0.884 −0.146 Conclusion Contrast to other reports, our results indicate no difference in TTS between subjects that are classified as functionally stable and unstable. The CAIT determines functional instability without consideration for mechanical instability. Although not significant, it appears that the backward direction created the greatest discrepancy in TTS between the groups. We question the sensitivity of our TTS calculations as others have reported different techniques. Additional research is needed employing these refined methods.