tbuckley/cabot-search huggingface dataset:
BIM Mediates EGFR Tyrosine Kinase Inhibitor-Induced Apoptosis in Lung Cancers with Oncogenic EGFR Mutations
Authors: Daniel B Costa, Balázs Halmos, Amit Kumar, Susan T Schumer, Mark S Huberman, Titus J Boggon, Daniel G Tenen, Susumu Kobayashi
Journal: PLoS Medicine (2007)

Background Epidermal growth factor receptor (EGFR) mutations are present in the majority of patients with non-small cell lung cancer (NSCLC) responsive to the EGFR tyrosine kinase inhibitors (TKIs) gefitinib or erlotinib. These EGFR-dependent tumors eventually become TKI resistant, and the common secondary T790M mutation accounts for half the tumors with acquired resistance to gefitinib. However, the key proapoptotic proteins involved in TKI-induced cell death and other secondary mutations involved in resistance remain unclear. The objective of this study was to identify the mechanism of EGFR TKI-induced apoptosis and secondary resistant mutations that affect this process. Methods and Findings To study TKI-induced cell death and mechanisms of resistance, we used lung cancer cell lines (with or without EGFR mutations), Ba/F3 cells stably transfected with EGFR mutation constructs, and tumor samples from a gefitinib-resistant patient. Here we show that up-regulation of the BH3-only polypeptide BIM (also known as BCL2-like 11) correlated with gefitinib-induced apoptosis in gefitinib-sensitive EGFR-mutant lung cancer cells. The T790M mutation blocked gefitinib-induced up-regulation of BIM and apoptosis. This blockade was overcome by the irreversible TKI CL-387,785. Knockdown of BIM by small interfering RNA was able to attenuate apoptosis induced by EGFR TKIs. Furthermore, from a gefitinib-resistant patient carrying the activating L858R mutation, we identified a novel secondary resistant mutation, L747S in cis to the activating mutation, which attenuated the up-regulation of BIM and reduced apoptosis. Conclusions Our results provide evidence that BIM is involved in TKI-induced apoptosis in sensitive EGFR-mutant cells and that both attenuation of the up-regulation of BIM and resistance to gefitinib-induced apoptosis are seen in models that contain the common EGFR T790M and the novel L747S secondary resistance mutations. These findings also suggest that induction of BIM may have a role in the treatment of TKI-resistant tumors.
Elevated healthcare utilisation in young adult males with obstructive sleep apnoea
Authors: H. Reuveni, S. Greenberg-Dotan, T. Simon-Tuval, A. Oksenberg, A. Tarasiuk
Journal: European Respiratory Journal (2007)

The aim of the present study was to explore morbidity and healthcare utilisation among young adult males with obstructive sleep apnoea (OSA) compared with middle-aged OSA patients over the 5-yr period preceding diagnosis. A prospective case–control study was performed; 117 young (22–39-yr-old) males with OSA were matched with 117 middle-aged (40–64-yr-old) OSA males for body mass index, apnoea/hypopnoea index, arterial oxygen saturation, arousal and awakening index, and Epworth Sleepiness Scale score. Each OSA patient was matched with controls by age, geographic area and physician. Young adult males with OSA showed no increase in specific comorbidity compared with controls. Middle-aged OSA patients exhibited increased risk of cardiovascular disease. Healthcare utilisation for the 5-yr period was ≥1.9 times higher among young and middle-aged male OSA patients than among controls. Multiple logistic regression analysis revealed that hyperlipidaemia in young adults and a body mass index of &gt;37 kg·m<sup>−2</sup> and cardiovascular disease in middle-aged adults are the only independent determinants of the upper third, most costly, OSA patients. Compared with middle-aged males with obstructive sleep apnoea, in whom increased expenditure was related to cardiovascular disease and body mass index, utilisation was not related to any specific disease in younger cases.
BMS-936564/MDX-1338: A Fully Human Anti-CXCR4 Antibody Induces Apoptosis <i>In Vitro</i> and Shows Antitumor Activity <i>In Vivo</i> in Hematologic Malignancies
Authors: Michelle R. Kuhne, Tanya Mulvey, Blake Belanger, Sharline Chen, Chin Pan, Colin Chong, Fei Cao, Wafa Niekro, Tom Kempe, Karla A. Henning, Lewis J. Cohen, Alan J. Korman, Pina M. Cardarelli
Journal: Clinical Cancer Research (2012)

CXCR4 has been identified as a prognostic marker for acute myeloid leukemia (AML) and other malignancies. We describe the development and characterization of a fully human antibody to CXCR4 and its application for therapy of AML, non-Hodgkin lymphoma (NHL), chronic lymphoid leukemia (CLL), and multiple myeloma.Human transgenic mice were immunized with CXCR4-expressing cells, and antibodies reactive with CXCR4 were analyzed for apoptosis induction and ability to interfere with CXCL12-induced migration and calcium flux. In vivo efficacy was determined in multiple AML, NHL, and multiple myeloma xenograft tumors in severe combined immunodeficient mice.BMS-936564/MDX-1338 is a fully human IgG(4) monoclonal antibody that specifically recognizes human CXCR4. In vitro studies show that MDX-1338 binds to CXCR4-expressing cells with low nanomolar affinity, blocks CXCL12 binding to CXCR4-expressing cells, and inhibits CXCL12-induced migration and calcium flux with low nanomolar EC(50) values. When given as monotherapy, MDX-1338 exhibits antitumor activity in established tumors including AML, NHL, and multiple myeloma xenograft models. In addition, we show that MDX-1338 induced apoptosis on a panel of cell lines and propose that antibody-induced apoptosis is one of the mechanisms of tumor growth inhibition.BMS-936564/MDX-1338 is a potent CXCR4 antagonist which is efficacious as monotherapy in tumor-bearing mice and is currently in phase I for the treatment of relapsed/refractory AML, NHL, CLL, and multiple myeloma.
Cost-Effectiveness of Cervical Cancer Screening: Comparison of Screening Policies
Authors: M. E. van den Akker-van Marle
Journal: JNCI Journal of the National Cancer Institute (2002)

Background: Recommended screening policies for cervical cancer differ widely among countries with respect to targeted age range, screening interval, and total number of scheduled screening examinations (i.e., Pap smears). We compared the efficiency of cervical cancer-screening programs by performing a cost-effectiveness analysis of cervical cancer-screening policies from high-income countries. Methods: We used the microsimulation screening analysis (MISCAN) program to model and determine the costs and effects of almost 500 screening policies, some fictitious and some actual (i.e., recommended by national guidelines). The costs (in U.S. dollars) and effects (in years of life gained) were compared for each policy to identify the most efficient policies. Results: There were 15 efficient screening policies (i.e., no alternative policy exists that results in more life-years gained for lower costs). For these policies, which considered two to 40 total scheduled examinations, the age range expanded gradually from 40–52 years to 20–80 years as the screening interval decreased from 12 to 1.5 years. For the efficient policies, the predicted gain in life expectancy ranged from 11.6 to 32.4 days, compared with a gain of 46 days if cervical cancer mortality were eliminated entirely. The average cost-effectiveness ratios increased from $6700 (for the longest screening interval) to $23 900 per life-year gained. For some countries, the recommended screening policies were close to efficient, but the cost-effectiveness could be improved by reducing the number of scheduled examinations, starting them at later ages, or lengthening the screening interval. Conclusions: The basis for the diversity in the screening policies among high-income countries does not appear to relate to the screening policies' cost-effectiveness ratios, which are highly sensitive to the number of Pap smears offered during a lifetime.
The C3H/St/Ha Mammary Tumor. I. Thromboplastin Content&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: E D Holyoke, H Ichihashi
Journal: JNCI Journal of the National Cancer Institute (1966)

The thromboplastin activities of homogenates and extracts prepared from a mammary tumor in C3H/St/Ha mice, breast tissue from force-bred C3H siblings, and from T241 Lewis sarcoma were compared. There was more thromboplastin activity in the tumor homogenate of the C3H spontaneous mammary tumor than in the homogenate of “control” breast tissue. This greater activity of tumor tissue was more than could be accounted for by the greater amount of protein in the tumor tissue as compared to that in the breast tissue. Most of the tumor-homogenate thromboplastin activity was heat-stable. The activity of the homogenate of “control” breast tissue was almost completely heat-labile. Extracts of both the T241 sarcoma and the C3H mammary tumor contained heat-stable as well as a significant amount of heat-labile thromboplastin activity. The breast tissue from precancerous force-bred females showed very little extractable thromboplastin activity and just a trace of heat-labile activity.
Hyperosmolarity-induced Interleukin-8 Expression in Human Bronchial Epithelial Cells through p38 Mitogen-activated Protein Kinase
Authors: SHU HASHIMOTO, KEN MATSUMOTO, YASUHIRO GON, TOMOKO NAKAYAMA, IKUKO TAKESHITA, TAKASHI HORIE
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

The changes in airway osmolarity have been described to contribute to the production of exercise- induced bronchoconstriction (EIB) and the development of the late-phase response (LPR). The mechanism has been investigated; however, the responsiveness of bronchial epithelial cells (BEC) to hyperosmolarity and the intracellular signals leading to cell activation have not been determined. In this study, we examined the effect of hyperosmolar medium on interleukin-8 (IL-8) expression and the role of p38 mitogen-activated protein (MAP) kinase and c-Jun NH2 terminal kinase ( JNK) in human BEC in this response in order to clarify the intracellular signals regulating IL-8 expression in hyperosmolarity-stimulated BEC. The results showed that hyperosmolarity induced IL-8 expression in a concentration dependent manner, p38 MAP kinase phosphorylation and activation, and JNK activation whether NaCl or mannitol was used as the solute. SB 203580 as the specific p38 MAP kinase inhibitor inhibited hyperosmolarity-induced p38 MAP kinase activation and partially inhibited hyperosmolarity-induced IL-8 expression. These results indicate that p38 MAP kinase, at least in part, regulates hyperosmolarity-induced IL-8 expression in BEC. However, other signals such as JNK are possibly also involved. These results provide new evidence on the mechanism responsible for the development of the LPR induced by EIB, and a strategy for treatment with the specific p38 MAP kinase inhibitor.
Secretable Storage Pools in Platelets
Authors: H Holmsen, H J Weiss
Journal: Annual Review of Medicine (1979)

Knowledge gained during the past two decades has greatly increased our understanding of the roles of platelets in hemostasis, thrombosis, and other biological processes (1-3). However, much remains to be learned. The present review summarizes our current knowledge about granule-bound platelet substances that are released extracellularly after platelet stimula­ tion. We briefly review the in vitro responses of platelets to various agonists, emphasizing the granule-bound substances and the mechanism(s) involved in their storage and release. These substances (some of which are also present in plasma, adsorbed on platelets, or present in nonsecretable platelet pools) comprise the secretable storage pool substances of the platelet. Where information is available, we discuss the physiological significance of the secreted substances and their stability following release into the blood. Finally we review congenital and acquired disorders of hemostasis in which the deficiencies of storage pool substances have been described.
Human liver chimeric mice provide a model for hepatitis B and C virus infection and treatment
Authors: Karl-Dimiter Bissig, Stefan F. Wieland, Phu Tran, Masanori Isogawa, Tam T. Le, Francis V. Chisari, Inder M. Verma
Journal: Journal of Clinical Investigation (2010)

A paucity of versatile small animal models of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection has been an impediment to both furthering understanding of virus biology and testing antiviral therapies. We recently described a regulatable system for repopulating the liver of immunodeficient mice (specifically mice lacking fumaryl acetoacetate hydrolase [Fah], recombination activating gene 2 [Rag2], and the gamma-chain of the receptor for IL-2 [Il-2rgamma]) with human hepatocytes. Here we have shown that a high transplantation dose (3 x 106 to 5 x 106 human hepatocytes/mouse) generates a higher rate of liver chimerism than was previously obtained in these mice, up to 95% human hepatocyte chimerism. Mice with a high level of human liver chimerism propagated both HBV and HCV, and the HCV-infected mice were responsive to antiviral treatment. This human liver chimeric mouse model will expand the experimental possibilities for studying HBV and HCV infection, and possibly other human hepatotropic pathogens, and prove useful for antiviral drug testing.
Reduced Expression of<i>CAMTA1</i>Correlates with Adverse Outcome in Neuroblastoma Patients
Authors: Kai-Oliver Henrich, Matthias Fischer, Daniel Mertens, Axel Benner, Ruprecht Wiedemeyer, Benedikt Brors, André Oberthuer, Frank Berthold, Jun Stephen Wei, Javed Khan, Manfred Schwab, Frank Westermann
Journal: Clinical Cancer Research (2006)

Abstract Purpose: A distal portion of 1p is frequently deleted in human neuroblastomas, and it is generally assumed that this region harbors at least one gene relevant for neuroblastoma development. A 1p36.3 commonly deleted region, bordered by D1S2731 and D1S214 has been defined. The present study surveys whether expression of genes mapping to this region is associated with tumor behavior. Experimental Design: Candidate genes localized within the deleted region were identified by sequence data analysis. Their expression was assessed in a cohort of 49 primary neuroblastomas using cDNA microarray analysis. Gene expression patterns associated with known prognostic markers and patient outcome were further evaluated by quantitative real-time reverse transcription-PCR in a cohort of 102 neuroblastomas. Results: The commonly deleted region spans 261 kb and encompasses two genes, FLJ10737 and CAMTA1. We found no evidence for an association of FLJ10737 expression with established prognostic variables or outcome. In contrast, low CAMTA1 expression characterized tumors with 1p deletion, MYCN amplification, and advanced tumor stages 3 and 4. Moreover, low CAMTA1 expression was significantly associated with poor outcome (P &amp;lt; 0.001). In multivariate analysis of event-free survival, the prognostic information of low CAMTA1 expression was independent of 1p status, MYCN status, tumor stage, and age of the patient at diagnosis (hazard ratio, 3.52; 95% confidence interval, 1.21-10.28; P = 0.02). Conclusions: Our data suggest that assessment of CAMTA1 expression may improve the prognostic models for neuroblastoma and that it will be important to define the biological function of CAMTA1 in this disease.
Application of Microbial Genomic Science to Advanced Therapeutics
Authors: Claire M. Fraser, Rino Rappuoli
Journal: Annual Review of Medicine (2004)

Since the publication of the first complete microbial genome sequence of Haemophilus influenzae in 1995, more than 200 additional microbial genome sequences have become available in the public domain. Approximately 40% of these represent important human pathogens. Comparative in silico methods, along with large-scale approaches such as transcriptomics and proteomics, are beginning to reveal insights into new virulence genes, pathogen-host interactions, and the molecular basis of host specificity. Sequence data are also starting to accumulate from multiple isolates or strains of a single pathogen, and this type of data has proven to be quite valuable in providing new insights into the genetic variability that is present in a particular species as well as in facilitating correlations between genotype and phenotype. Ultimately, a major goal of genome-enabled infectious disease research is the development of novel diagnostics, therapeutics, and vaccines.
Postnatal NMDA receptor ablation in corticolimbic interneurons confers schizophrenia-like phenotypes
Authors: Juan E Belforte, Veronika Zsiros, Elyse R Sklar, Zhihong Jiang, Gu Yu, Yuqing Li, Elizabeth M Quinlan, Kazu Nakazawa
Journal: Nature Neuroscience (2009)
Extended drotrecogin alfa (activated) treatment in patients with prolonged septic shock
Authors: Jean-Francois Dhainaut, Massimo Antonelli, Patrick Wright, Arnaud Desachy, Jean Reignier, Sylvain Lavoue, Julien Charpentier, Mark Belger, Michael Cobas-Meyer, Cornelia Maier, Mariano A. Mignini, Jonathan Janes
Journal: Intensive Care Medicine (2009)
BT-PABA test with plasma PABA measurements: evaluation of sensitivity and specificity
Authors: J-C Delchier, J-C Soule
Journal: Gut (1983)

Plasma concentrations of prostaglandins E and F have been measured by radioimmunoassay in patients undergoing diagnostic upper intestinal endoscopy. The results fail to support a previously reported deficiency of plasma PGE in duodenal ulcer patients. Plasma prostaglandin concentrations failed to correlate with the parameters of gastric secretion studied; and were unaffected by histamine H2-receptor blockade or the activity of duodenal ulceration. During combined pentagastrin and insulin secretory studies there was a significant correlation between the outputs of PGE and acid into gastric juice.
Erectile Impotence Treated With an Implantable, Inflatable Prosthesis
Authors: F. Brantley Scott
Journal: JAMA (1979)

Erectile impotence can now be treated with a device that mimics a natural erection. Between 1973 and 1977, we implanted an inflatable prosthesis in 245 men (235 with organic impotence and ten with psychogenic impotence). Of these, 234 are able to use the device to their satisfaction; no failures have occurred in the 152 cases treated in 1976 and 1977. The success of this treatment rests in part on the careful selection of patients by a team—a urologist, a sleep researcher, a psychologist, and a psychiatrist— each evaluating the patient independently. Our experience suggest that erectile impotence may be more common than generally believed and that impotence from organic causes may account for a greater percentage of cases than formerly thought. (<i>JAMA</i>241:2609-2612, 1979)
Review of health -related quality of life and patient-reported outcome in patients receiving EPs 7630 treatment for acute bronchitis
Authors: Heinrich Matthys, Wolfgang Kamin
Journal: European Respiratory Journal (2012)

BACKGROUND: Health-related quality of life (HRQL) and patient-reported outcome (PRO) are important outcome parameters for the evaluation of both medical treatment within clinical trials and efficiency in clinical practice. For EPs ®  7630 (Umckaloabo ® ) treatment, clinically relevant improvements in HRQL/PRO have been reported recently (Matthys, H.  et al.  Wien Med Wochenschr 2010;160:564-70; Matthys, H.  et al.  Eur Respir J 2011;38(Suppl 55):18s-19s).  AIMS: We systematically reviewed randomised controlled trials (RCTs) in order to assess the impact of EPs 7630 treatment on HRQL and PRO of patients with acute bronchitis (AB).  METHODS: Trials published 2010 or earlier were included for the review if they were RCTs investigating EPs 7630 vs placebo (PL) in adults or children suffering from AB and assessing HRQL and PRO by means of the EQ-5D questionnaire and the Integrative Medicine Patient Satisfaction Scale (IMPSS).  RESULTS: 6 trials with a total of 1164 patients (EPs 7630: 586, PL: 578; 53% 1-18 yrs) were identified. After 7 days of treatment, clear and mostly statistically significant advantages were seen for EPs 7630 compared to PL in the 5 EQ-5D dimensions (mobility, usual activities, pain/discomfort and anxiety/depression: p  CONCLUSIONS: There is encouraging evidence from currently available data derived from placebo-controlled trials that EPs 7630 treatment improves HRQL and PRO in both children (>1 year) and adults with acute bronchitis.
Risk of pneumonia and pneumococcal disease in people with severe mental illness: English record linkage studies
Authors: Olena O Seminog, Michael J Goldacre
Journal: Thorax (2012)

<h3>Background</h3> People with severe mental illness have a higher risk than others of some physical diseases. The risk of pneumococcal disease in people with mental disorders is unknown. This is potentially important because vaccines against the pneumococcus are available. <h3>Methods</h3> We used two datasets of linked hospital admission and death records, the Oxford Record Linkage Study and all-England linked Hospital Episode Statistics, to estimate the risk of lobar pneumonia and other pneumococcal disease (here, all collectively termed pneumococcal disease) in people hospitalised with schizophrenia, bipolar disorder, depression or anxiety. We compared rates of pneumococcal disease in each cohort with rates in a comparison cohort of people without a record of hospitalisation for these psychiatric disorders. <h3>Findings</h3> The risk of pneumococcal disease in each psychiatric group was significantly high in both datasets. In the English national dataset (spanning 1999–2011), the risk of pneumococcal disease in people hospitalised with schizophrenia, bipolar disorder, depression or anxiety was, respectively, 2.3 (95% CI 2.2 to 2.4), 2.3 (2.2 to 2.3), 2.1 (2.0 to 2.1) and 2.2 (2.1 to 2.2). The risk remained high for years after discharge, suggesting an association with the psychiatric disorder rather than with the event of hospitalisation. <h3>Conclusions</h3> Severe mental illness is a risk factor for lobar pneumonia, pneumococcal pneumonia, pneumococcal septicaemia and meningitis. Possible explanations for the elevated risk include factors relating to lifestyle and health-risk activities. If our findings are replicated elsewhere, there would be a case for considering routine pneumococcal immunisation for people with severe mental illness.
Effect of the antitussive glaucine on bronchomotor tone in man.
Authors: O Constant, B Slavin, J R Lehane, C Jordan, J G Jones
Journal: Thorax (1983)

In view of the observation that the antitussive agent glaucine prevents histamine-induced bronchoconstriction in guinea pigs we investigated this agent for a possible peripheral action in man, using a new method for measuring changes in bronchomotor tone. The forced airflow oscillation method was used to determine respiratory resistance (Rrs) over a range of lung volumes (VL) in seven healthy supine subjects. Computer analysis of the hyperbolic relationship between Rrs and VL was used to determine the asymptotic resistance and yield estimates of lower airways conductance (Glaw). Specific lower airways conductance (sGlaw) was expressed as the slope of the linear plot of Glaw against VL and is a sensitive index of bronchomotor tone. After baseline measurements of sGlaw subjects received placebo or 60 mg glaucine orally according to a double-blind crossover protocol. Histamine, 500 micrograms, was inhaled 45 minutes later. Measurements of sGlaw were repeated every 10 minutes for two hours. Although there was a trend towards bronchodilatation after glaucine administration (sGlaw = 130% of baseline) there was no significant difference from the effect of placebo (sGlaw = 89% of baseline). After inhalation of histamine sGlaw fell to 26% of baseline after both glaucine and placebo (p less than 0.01). In a further study three subjects received glaucine and placebo according to an identical protocol except that the histamine was omitted. Again the increase in sGlaw failed to achieve significance. Glaucine does not affect the bronchoconstrictor response to histamine in man and there is no convincing evidence of an effect on resting bronchomotor tone.