tbuckley/cabot-search huggingface dataset:
Modulation of P-Glycoprotein at the Blood-Brain Barrier: Opportunities to Improve Central Nervous System Pharmacotherapy
Authors: David S. Miller, Björn Bauer, Anika M. S. Hartz
Journal: Pharmacological Reviews (2008)

Pharmacotherapy of central nervous system (CNS) disorders (e.g., neurodegenerative diseases, epilepsy, brain cancer, and neuro-AIDS) is limited by the blood-brain barrier. P-glycoprotein, an ATP-driven, drug efflux transporter, is a critical element of that barrier. High level of expression, luminal membrane location, multispecificity, and high transport potency make P-glycoprotein a selective gatekeeper of the blood-brain barrier and thus a primary obstacle to drug delivery into the brain. As such, P-glycoprotein limits entry into the CNS for a large number of prescribed drugs, contributes to the poor success rate of CNS drug candidates, and probably contributes to patient-to-patient variability in response to CNS pharmacotherapy. Modulating P-glycoprotein could therefore improve drug delivery into the brain. Here we review the current understanding of signaling mechanisms responsible for the modulation of P-glycoprotein activity/expression at the blood-brain barrier with an emphasis on recent studies from our laboratories. Using intact brain capillaries from rats and mice, we have identified multiple extracellular and intracellular signals that regulate this transporter; several signaling pathways have been mapped. Three pathways are triggered by elements of the brain9s innate immune response, one by glutamate, one by xenobiotic-nuclear receptor (pregnane X receptor) interactions, and one by elevated β-amyloid levels. Signaling is complex, with several pathways sharing common signaling elements [tumor necrosis factor (TNF) receptor 1, endothelin (ET) B receptor, protein kinase C, and nitric-oxide synthase), suggesting a regulatory network. Several pathways include autocrine/paracrine elements, involving release of the proinflammatory cytokine, TNF-α, and the polypeptide hormone, ET-1. Finally, several steps in signaling are potential therapeutic targets that could be used to modulate P-glycoprotein activity in the clinic.
Pathophysiology of changes in absolute lung volumes
Authors: E Bancalari, J Clausen
Journal: European Respiratory Journal (1998)

Changes in absolute lung volumes are common in lung disease and result in significant impacts on gas exchange, respiratory muscle function, the sensation of dyspnoea, and limitations to maximal exercise. Though our knowledge regarding the magnitude and determinants of changes in lung volumes in health and disease has increased in the past 20 years, a number of important questions remain unanswered. Consideration of the limitations of specific methods for measuring lung volumes is essential when analysing published studies regarding absolute lung volumes in infants, children and adults. Though functional residual capacity is most commonly measured in children and adults with the subject awake and at rest, increasingly attention is being directed to making these measurements under clinically more relevant conditions (e.g. during exercise, sleep, anesthesia, or mechanical ventilation). The relationships between dynamic changes in functional residual capacity, flow limitation during tidal breaths, sensation of dyspnoea and exercise limitation are important to understand, and are the focus of current and future research. Improved understanding of these relationships may lead to improvements in therapy of patients with acute and chronic lung disease and are likely to be particularly important for evaluating the efficacy of and optimal patient selection for new modes of therapy, such as lung volume reduction surgery.
Diurnal Variation in Lung Function in Subgroups from Two Dutch Populations
Authors: GERARD J. J. M. BORSBOOM, WILFRID van PELT, HANS C. van HOUWELINGEN, BEN G. van VIANEN, JAN P. SCHOUTEN, PHILIP H. QUANJER
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

We studied circadian variation in FVC, FEV1, PEF, TLC, VC, and RV between 9:00 a.m. and 9:00 p.m. and analyzed how this variation affected estimated longitudinal change. Data from 876 adults were obtained in a longitudinal survey of samples from two Dutch areas. Subjects participated in four surveys held at 3-yr intervals between 1975 and 1985. FVC, FEV1, PEF, and VC increased from 9:00 a.m. until noon and decreased afterwards. TLC was constant over the day, whereas RV decreased from 9:00 a.m. to noon. Average variation in FVC, FEV1 and PEF, expressed as percentages of average level, was 4.8% (200 ml), 2.8% (86 ml), and 3.1% (250 ml / s), respectively. These results are compatible with circadian changes in airway size. No differences in variability were found between men and women. Significantly larger changes between 9:00 a.m. and noon were found in young adults, smokers, and those with respiratory symptoms than in other subgroups. Adjustment for diurnal variation reduced, albeit slightly, residual standard deviations of estimated longitudinal declines. Average diurnal change was large relative to underlying longitudinal change. Its effect on longitudinal change within an individual can therefore be large depending on age, smoking habits, symptomatology, number of visits, time of measurement, and difference in time between measurements. However, when people are measured at random times during the day for at least three visits, or when measurements are made after 11:00 a.m., effects of diurnal variation in pulmonary function on estimated average longitudinal decline are minimal.
Baseline airway hyperresponsiveness and its reversible component: role of airway inflammation and airway calibre
Authors: M Ichinose, T Takahashi, H Sugiura, N Endoh, M Miura, Y Mashito, K Shirato
Journal: European Respiratory Journal (2000)

Airway hyperresponsiveness (AHR), in which airway inflammation has been reported to be a key factor, is an important component of asthma. However the precise role of inflammation in AHR is still unclear. In this report, airway inflammatory changes were assessed using hypertonic saline-induced sputum examination and exhaled nitric oxide analysis, and the relation between AHR to methacholine, airway calibre forced expiratory volume in one second (FEV1) and airway inflammatory indices examined. Furthermore, the changes in these variables were also examined by means of 8 weeks' open uncontrolled inhaled steroid administration (800 microg x beclomethasone x day(-1)). Asthmatic subjects had higher eosinophil counts and bradykinin concentration in induced sputum and higher exhaled NO levels, and showed AHR to methacholine. Baseline AHR significantly correlated with FEV1 but not with indices of inflammation in sputum or exhaled air. Steroid inhalation therapy was associated with a reduction in eosinophil and bradykinin concentration in sputum and NO levels in exhaled air and an improvement in FEV1 and AHR. The changes in FEV1 and AHR were significantly related to changes in markers in sputum and exhaled air (p<0.01 for each). These results suggest that baseline airway hyperresponsiveness can be predicted from the airway calibre but not from inflammatory parameters in sputum or exhaled air. In contrast, the reversible component of airway hyperresponsiveness appeared to be associated with the reduction in airway inflammation.
Surgical management of pulmonary aspergilloma
Authors: P. H. Kay
Journal: Thorax (1997)

Non-motor symptoms are a key component of Parkinson9s disease, possibly representing a clinical biomarker of its premotor phase. The burden of non-motor symptoms can define a patient9s health-related quality of life. Non-motor symptoms substantially increase the cost of care—requiring increased hospitalisation and treatment—and pose a major challenge to healthcare professionals. However, clinicians often regard non-motor symptoms and their management as peripheral to that of the motor symptoms. Here, we address the clinical issues and unmet needs of non-motor symptoms in Parkinson9s disease.
Current concepts and novel targets in advanced pancreatic cancer
Authors: Patrick Michl, Thomas M Gress
Journal: Gut (2012)

Pancreatic cancer remains one of the most aggressive tumours with a 5-year survival rate of less than 5%. The dismal prognosis of this tumour entity that is associated with a high degree of drug resistance has not changed over the past decades. Since 1997, gemcitabine-based regimens have been the therapy of choice for advanced pancreatic cancer. Recently, however, new combination chemotherapy regimens achieved a significant survival benefit compared to gemcitabine-based therapies. In addition, novel approaches to improve drug delivery are currently being developed, and new drugs targeting signalling pathways both within the tumour cells and the tumour microenvironment are undergoing preclinical and clinical validation. Furthermore, efforts are being made to identify predictive markers for individualised treatment approaches based on molecular tumour characteristics. This review provides an overview on current and emerging concepts as well as novel targets for systemic treatment of advanced pancreatic cancer. Combination therapies incorporating drugs directed against these new targets may open new avenues for improving the efficacy of current treatment approaches and overcoming the devastating prognosis of pancreatic cancer patients.
Reversal of atopic dermatitis with narrow-band UVB phototherapy and biomarkers for therapeutic response
Authors: Suzanne Tintle, Avner Shemer, Mayte Suárez-Fariñas, Hideki Fujita, Patricia Gilleaudeau, Mary Sullivan-Whalen, Leanne Johnson-Huang, Andrea Chiricozzi, Irma Cardinale, Shenghui Duan, Anne Bowcock, James G. Krueger, Emma Guttman-Yassky
Journal: Journal of Allergy and Clinical Immunology (2011)
Criteria for Medical Repatriation and the Context of Inadequate Access to Care
Authors: Robert H. McLaughlin
Journal: The American Journal of Bioethics (2012)

Click to increase image sizeClick to decrease image size Acknowledgments The collection of cancer incidence data cited in this commentary was supported by the California Department of Health Services as part of the statewide cancer reporting program mandated by California Health and Safety Code Section 103885; the National Cancer Institute's Surveillance, Epidemiology, and End Results Program under contract HHSN261201000140C awarded to the Cancer Prevention Institute of California, contract HHSN261201000035C awarded to the University of Southern California, and contract HHSN261201000034C awarded to the Public Health Institute; and the Centers for Disease Control and Prevention National Program of Cancer Registries, under agreement 1U58 DP000807–01 awarded to the Public Health Institute. The ideas and opinions expressed herein are those of the author, and endorsement by the State of California, the California Department of Health Services, the National Cancer Institute, or the Centers for Disease Control and Prevention or their contractors and subcontractors is not intended nor should be inferred.
Failure of cholinergic stimulation to induce a secretory response from the rectal mucosa in cystic fibrosis.
Authors: J Hardcastle, P T Hardcastle, C J Taylor, J Goldhill
Journal: Gut (1991)

The secretory response to cholinergic stimulation was investigated in rectal biopsy specimens from children with cystic fibrosis and a control group using a modified Ussing chamber technique. Acetylcholine (10(-3) mol/l) increased the short circuit current in 12 control specimens by mean (SEM) 83.0 (16.4) microA/cm2, but samples from five children with cystic fibrosis failed to exhibit such a response (-1.4 (3.2) microA/cm2). Amiloride (10(-4) mol/l), which will inhibit electrogenic sodium absorption in viable tissues, caused similar reductions in the short circuit current of both control and cystic fibrosis tissues (control = -37.7 (7.7) microA/cm2; cystic fibrosis = -44.0 (9.3) microA/cm2). Thus, the failure of chloride secretion observed in the small intestine also exists in the rectal mucosa. This observation could be used both to aid diagnosis and to study the basic defect.
Smoking and asthma in adults
Authors: R. Piipari
Journal: European Respiratory Journal (2004)

Studies on the effect of smoking on adulthood asthma have provided contradictory results. The current authors conducted a population-based incident case-control study to assess the effects of current and past smoking on the development of asthma in adults. During a 2.5 yr study period, all new asthma cases clinically diagnosed (n=521) and randomly selected controls (n=932) from a geographically defined district in southern Finland were recruited. The risk of developing asthma was significantly higher among current smokers with an adjusted odds ratio (OR) of 1.33 (95% confidence interval 1.00–1.77) and among ex-smokers with an adjusted OR 1.49 (1.12–1.97) compared with never-smokers. Among current smokers, the risk increased up to 14 cigarettes·day<sup>−1</sup>, and a similar trend was observed in relation to cumulative smoking. In conclusion, the current results support the hypothesis that smoking causes asthma in adulthood.
Sixteen-Week Dose-Intense Chemotherapy in the Adjuvant Treatment of Breast Cancer
Authors: M. D. Abeloff, R. A. Beveridge, R. C. Donehower, J. H. Fetting, N. E. Davidson, G. G. Gordon, W. C. Waterfield, D. J. Damron
Journal: JNCI Journal of the National Cancer Institute (1990)

Journal Article Sixteen-Week Dose-Intense Chemotherapy in the Adjuvant Treatment of Breast Cancer Get access Martin D. Abeloff, Martin D. Abeloff * *Correspondence to : Martin D. Abeloff, M.D., The Johns Hopkins Oncology Center, 1st Floor, Rm. 124, 600 N. Wolfe St., Baltimore, MD 21205. Search for other works by this author on: Oxford Academic PubMed Google Scholar Roy A. Beveridge, Roy A. Beveridge Search for other works by this author on: Oxford Academic PubMed Google Scholar Ross C. Donehower, Ross C. Donehower Search for other works by this author on: Oxford Academic PubMed Google Scholar John H. Fetting, John H. Fetting supported in part by American Cancer Society Clinical Oncology Career Development Awards. N. E. Davidson was supported in part by the Susan Komen Foundation Search for other works by this author on: Oxford Academic PubMed Google Scholar Nancy E. Davidson, Nancy E. Davidson supported in part by American Cancer Society Clinical Oncology Career Development Awards. N. E. Davidson was supported in part by the Susan Komen Foundation Search for other works by this author on: Oxford Academic PubMed Google Scholar Gary G. Gordon, Gary G. Gordon Search for other works by this author on: Oxford Academic PubMed Google Scholar William C. Waterfield, William C. Waterfield Search for other works by this author on: Oxford Academic PubMed Google Scholar Dorothy J. Damron Dorothy J. Damron Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 82, Issue 7, 4 April 1990, Pages 570–574, https://doi.org/10.1093/jnci/82.7.570 Published: 04 April 1990 Article history Received: 18 October 1989 Accepted: 12 January 1990 Published: 04 April 1990
Chloroquine-induced autophagic vacuole accumulation and cell death in glioma cells is p53 independent
Authors: Geng, Ying, Kohli, Latika, Klocke, Barbara J., Roth, Kevin A.
Journal: Neuro-Oncology (2010)

Glioblastoma (GBM) is a high-grade central nervous system malignancy and despite aggressive treatment strategies, GBM patients have a median survival time of just 1 year. Chloroquine (CQ), an antimalarial lysosomotropic agent, has been identified as a potential adjuvant in the treatment regimen of GBMs. However, the mechanism of CQ-induced tumor cell death is poorly defined. We and others have shown that CQ-mediated cell death may be p53-dependent and at least in part due to the intrinsic apoptotic death pathway. Here, we investigated the effects of CQ on 5 established human GBM lines, differing in their p53 gene status. CQ was found to induce a concentration-dependent death in each of these cell lines. Although CQ treatment increased caspase-3–like enzymatic activity in all 5 cell lines, a broad-spectrum caspase inhibitor did not significantly attenuate death. Moreover, CQ caused an accumulation of autophagic vacuoles in all cell lines and was found to affect the levels and subcellular distribution of cathepsin D, suggesting that altered lysosomal function may also play a role in CQ-induced cell death. Thus, CQ can induce p53-independent death in gliomas that do not require caspase-mediated apoptosis. To potentially identify more potent chemotherapeutics, various CQ derivatives and lysosomotropic compounds were tested on the GBM cells. Quinacrine and mefloquine were found to be more potent than CQ in killing GBM cells in vitro and given their superior blood–brain barrier penetration compared with CQ may prove more efficacious as chemotherapeutic agents for GBM patients.
Obtaining Maximal Concatenated Phylogenetic Data Sets from Large Sequence Databases
Authors: M. J. Sanderson
Journal: Molecular Biology and Evolution (2003)

To improve the accuracy of tree reconstruction, phylogeneticists are extracting increasingly large multigene data sets from sequence databases. Determining whether a database contains at least k genes sampled from at least m species is an NP-complete problem. However, the skewed distribution of sequences in these databases permits all such data sets to be obtained in reasonable computing times even for large numbers of sequences. We developed an exact algorithm for obtaining the largest multigene data sets from a collection of sequences. The algorithm was then tested on a set of 100,000 protein sequences of green plants and used to identify the largest multigene ortholog data sets having at least 3 genes and 6 species. The distribution of sizes of these data sets forms a hollow curve, and the largest are surprisingly small, ranging from 62 genes by 6 species, to 3 genes by 65 species, with more symmetrical data sets of around 15 taxa by 15 genes. These upper bounds to sequence concatenation have important implications for building the tree of life from large sequence databases.
Insights From Mixture Cure Modeling of Molecular Markers for Prognosis in Breast Cancer
Authors: Yildiz E. Yilmaz, Jerald F. Lawless, Irene L. Andrulis, Shelley B. Bull
Journal: Journal of Clinical Oncology (2013)

With the ultimate aim of improving clinical management of breast cancer, investigators have sought to identify molecular genetic markers that stratify newly diagnosed patients into subtypes differing in short- or long-term prognosis. Conventional survival models can fail to describe adequately the relationship between subtype and disease recurrence, particularly when there is a substantial proportion of long-term disease-free survivors. The observed patterns of disease-free survival in an undifferentiated patient cohort may be explained by an underlying mixture of two subgroups: patients who will remain free of disease in the long term (ie, cured), and those who will experience disease recurrence within their lifetime (ie, susceptible.) In this article, we review the concepts and methods of the mixture cure models and apply them in the analysis of molecular genetic prognostic factors for disease-free survival and time to disease recurrence in a cohort of patients with axillary lymph node–negative breast cancer.
THE EFFECTS OF HETEROLOGOUS ANTI-THYMOCYTE SERA IN MICE
Authors: Mark A. Mandel, Richard Asofsky
Journal: The Journal of Experimental Medicine (1969)

A quantitative graft-vs.-host (GVH) assay was used to compare the reactivity of spleen cells from germfree (GF) and conventionally reared (CV) mice against allogeneic tissue before and after treatment with rabbit anti-mouse thymocyte serum (ATS) and its IgG fraction (AT-IgG). AT-IgG produced a far greater and longer lasting suppression of this reactivity in GF than in CV mice. Moreover, CV mice recovered from suppression twice as rapidly as did GF mice. In both groups, the rate of recovery was exponential. These results suggest that recovery from the suppressive effects of ATS or AT-IgG was the result of generation of new cells. Transfer of mice born and initially reared in a conventional animal room to germfree isolators, with subsequent maintenance on the same diet that the germfree mice received, did not change the reactivity of their spleen cells in the assay used nor their susceptibility to AT-IgG. Removal of GF mice to a conventional animal room resulted in a prompt reduction in susceptibility to AT-IgG. The possibility that this might be related to the elaboration of a plasma factor affecting lymphocyte stability was discussed. Spleen cells taken from GF mice at various times after such "conventionalization" showed a transient but marked hyperreactivity to tissues of the allogeneic recipients. The amount of reduction in reactivity of spleen cells from such mice treated with AT-IgG was always proportional to the activity of spleen cells from comparable untreated mice. It was suggested that the increased reactions evoked should be ascribed to an adjuvant effect rather than to specific immunologic sensitization. Blood lymphocyte counts correlated very poorly with the state of suppression, confirming previous observations. It was also shown that while AT-IgG had little or no effect on blood granulocyte counts in both GF and CV mice, marked reductions in circulating granulocytes followed administration of AT-IgG during the period of increased granulocytopoiesis that resulted from conventionalization. This demonstrated that AT-IgG can produce functional impairment of target cells other than lymphocytes.
1180 RITONAVIR SUBSTANTIALLY REDUCES REACTIVE METABOLITE FORMATION OF THE HCV PROTEASE INHIBITOR DANOPREVIR BOTH IN VITRO AND IN VIVO
Authors: P. Goelzer, P.N. Morcos, J.Q. Tran, B. Wen, N. Shulman, P. Smith, T. Singer, B.J. Brennan, J. Hammond
Journal: Journal of Hepatology (2012)