tbuckley/cabot-search huggingface dataset:
Synergistic tumour suppressor activity of E-cadherin and p53 in a conditional mouse model for metastatic diffuse-type gastric cancer
Authors: Shu Shimada, Ayako Mimata, Masaki Sekine, Kaoru Mogushi, Yoshimitsu Akiyama, Hiroshi Fukamachi, Jos Jonkers, Hiroshi Tanaka, Yoshinobu Eishi, Yasuhito Yuasa
Journal: Gut (2011)

<h3>Background</h3> Gastric cancer is the second most frequent cause of death from cancer in the world, diffuse-type gastric cancer (DGC) exhibiting a poor prognosis. Germline mutations of <i>CDH1</i>, encoding E-cadherin, have been reported in hereditary DGC, and genetic and/or epigenetic alterations of <i>CDH1</i> are frequently detected in sporadic DGC. Genetic alterations of <i>TP53</i> are also frequently found in DGC. To examine the synergistic effect of the loss of E-cadherin and p53 on gastric carcinogenesis, a mouse line was established in which E-cadherin and p53 are specifically inactivated in the stomach parietal cell lineage. <h3>Methods</h3> <i>Atp4b-Cre</i> mice were crossed with <i>Cdh1<sup>loxP/loxP</sup></i> and <i>Trp53<sup>loxP/loxP</sup></i> mice, and the gastric phenotype of <i>Atp4b-Cre<sup>+</sup></i>;<i>Cdh1<sup>loxP/loxP</sup></i>;<i>Trp53<sup>loxP/loxP</sup></i> double conditional knockout (DCKO) mice was examined. <h3>Results</h3> Non-polarised E-cadherin-negative parietal cells and proton pump-negative atypical foci were observed in DCKO mice. Intramucosal cancers and invasive cancers composed of poorly differentiated carcinoma cells and signet ring cells, histologically very similar to those in humans, were found from 6 to 9 months, respectively. Fatal DGC developed at 100% penetrance within a year, frequently metastasised to lymph nodes, and had tumourigenic activity in immunodeficient mice. Gene expression profiles of DGC in DCKO mice also resembled those of human DGC, and mesenchymal markers and epithelial-mesenchymal transition-related genes were highly expressed in mouse DGC as in human DGC. <h3>Conclusion</h3> This mouse line is the first genetically engineered mouse model of DGC and is very useful for clarifying the mechanism underlying gastric carcinogenesis, and provides a new approach to the treatment and prevention of DGC.
The mutational spectrum of PTPN11 in juvenile myelomonocytic leukemia and Noonan syndrome/myeloproliferative disease
Authors: Christian P. Kratz, Charlotte M. Niemeyer, Robert P. Castleberry, Mualla Cetin, Eva Bergsträsser, Peter D. Emanuel, Henrik Hasle, Gabriela Kardos, Cornelia Klein, Seiji Kojima, Jan Stary, Monika Trebo, Marco Zecca, Bruce D. Gelb, Marco Tartaglia, Mignon L. Loh
Journal: Blood (2005)
EphB2 as a Therapeutic Antibody Drug Target for the Treatment of Colorectal Cancer
Authors: Weiguang Mao, Elizabeth Luis, Sarajane Ross, Johnny Silva, Christine Tan, Craig Crowley, Clarissa Chui, Gretchen Franz, Peter Senter, Hartmut Koeppen, Paul Polakis
Journal: Cancer Research (2004)

Abstract Analysis of human colorectal cancer specimens revealed overexpression of the EphB2 receptor tyrosine kinase. Monoclonal antibodies (MAbs) to extracellular sequence of EphB2 were raised and tested for activity against colorectal cancer cells. One of the MAbs, 2H9, effectively blocked the interaction of ephB2 with ephrin ligands and inhibited the resulting autophosphorylation of the receptor. However, this antibody did not affect the proliferation of cancer cells expressing ephB2. Immunocytochemical analysis revealed rapid internalization of the MAb 2H9 on binding ephB2, suggesting that target-dependent cell killing could be achieved with an antibody-drug conjugate. When MAb 2H9 was conjugated to monomethylauristatin E through a cathepsin B-cleavable linker, it specifically killed ephB2-expressing cancer cells in vitro and in vivo. Our results suggest that ephB2 is an attractive target for immunoconjugate cancer therapy.
Hypersomnia and Manic-Depressive Disease
Authors: T. DETRE, J. HIMMELHOCH, M. SWARTZBURG, C. M. ANDERSON, R. BYCK, D. J. KUPFER
Journal: American Journal of Psychiatry (1972)

The authors studied 84 bipolar and unipolar depressed patients by means of a questionnaire to determine whether they showed symptoms of increased sleep time. Their finding that hypersomnia is not an unusual symptom of depression has implications both for the classification of affective disorders and for biologic research.
Suicidal Behavior and the Dexamethasone Suppression Test
Authors: MARIE ÅSBERG, RIITTA VARPILA-HANSSON, PAOLO TOMBA, ANNA-KARIN AMINOFF, BJÖRN MÅRTENSSON, PETER THORÉN, LIL TRÄSKMAN-BENDZ, PETER ENEROTH, GABY ÅSTRÖM
Journal: American Journal of Psychiatry (1981)
Rapalogs and mTOR inhibitors as anti-aging therapeutics
Authors: Dudley W. Lamming, Lan Ye, David M. Sabatini, Joseph A. Baur
Journal: Journal of Clinical Investigation (2013)

Rapamycin, an inhibitor of mechanistic target of rapamycin (mTOR), has the strongest experimental support to date as a potential anti-aging therapeutic in mammals. Unlike many other compounds that have been claimed to influence longevity, rapamycin has been repeatedly tested in long-lived, genetically heterogeneous mice, in which it extends both mean and maximum life spans. However, the mechanism that accounts for these effects is far from clear, and a growing list of side effects make it doubtful that rapamycin would ultimately be beneficial in humans. This Review discusses the prospects for developing newer, safer anti-aging therapies based on analogs of rapamycin (termed rapalogs) or other approaches targeting mTOR signaling.
HLA-DQA1 and PLCG2 Are Candidate Risk Loci for Childhood-Onset Steroid-Sensitive Nephrotic Syndrome
Authors: Rasheed A. Gbadegesin, Adebowale Adeyemo, Nicholas J.A. Webb, Larry A. Greenbaum, Asiri Abeyagunawardena, Shenal Thalgahagoda, Arundhati Kale, Debbie Gipson, Tarak Srivastava, Jen-Jar Lin, Deepa Chand, Tracy E. Hunley, Patrick D. Brophy, Arvind Bagga, Aditi Sinha, Michelle N. Rheault, Joanna Ghali, Kathy Nicholls, Elizabeth Abraham, Halima S. Janjua, Abiodun Omoloja, Gina-Marie Barletta, Yi Cai, David D. Milford, Catherine O'Brien, Atif Awan, Vladimir Belostotsky, William E. Smoyer, Alison Homstad, Gentzon Hall, Guanghong Wu, Shashi Nagaraj, Delbert Wigfall, John Foreman, Michelle P. Winn
Journal: Journal of the American Society of Nephrology (2014)

Steroid-sensitive nephrotic syndrome (SSNS) accounts for >80% of cases of nephrotic syndrome in childhood. However, the etiology and pathogenesis of SSNS remain obscure. Hypothesizing that coding variation may underlie SSNS risk, we conducted an exome array association study of SSNS. We enrolled a discovery set of 363 persons (214 South Asian children with SSNS and 149 controls) and genotyped them using the Illumina HumanExome Beadchip. Four common single nucleotide polymorphisms (SNPs) in HLA-DQA1 and HLA-DQB1 (rs1129740, rs9273349, rs1071630, and rs1140343) were significantly associated with SSNS at or near the Bonferroni-adjusted P value for the number of single variants that were tested (odds ratio, 2.11; 95% confidence interval, 1.56 to 2.86; P=1.68×10−6 (Fisher exact test). Two of these SNPs—the missense variants C34Y (rs1129740) and F41S (rs1071630) in HLA-DQA1—were replicated in an independent cohort of children of white European ancestry with SSNS (100 cases and ≤589 controls; P=1.42×10−17). In the rare variant gene set–based analysis, the best signal was found in PLCG2 (P=7.825×10−5). In conclusion, this exome array study identified HLA-DQA1 and PLCG2 missense coding variants as candidate loci for SSNS. The finding of a MHC class II locus underlying SSNS risk suggests a major role for immune response in the pathogenesis of SSNS.
WNK1, a Gene within a Novel Blood Pressure Control Pathway, Tissue-Specifically Generates Radically Different Isoforms with and without a Kinase Domain
Authors: Michelle O’Reilly, Elaine Marshall, Helen J.L. Speirs, Roger W. Brown
Journal: Journal of the American Society of Nephrology (2003)

WNK1 is a member of a novel serine/threonine kinase family, With-No-K, (lysine). Intronic deletions in the encoding gene cause Gordon syndrome, an autosomal dominant, hypertensive, hyperkalemic disorder particularly responsive to thiazide diuretics, a first-line treatment in essential hypertension. To elucidate the novel WNK1 BP control pathway active in distal nephron, WNK1 expression in mouse was studied. It was found that WNK1 is highly expressed in testis > heart, lung, kidney, placenta > skeletal muscle, brain, and widely at low levels. Several WNK1 transcript classes are demonstrated, showing tissue-, developmental-, and nephron-segment-specific expression. Importantly, in kidney, the most prominent transcripts are smaller than elsewhere, having the first four exons replaced by an alternative 5'-exon, deleting the kinase domain, and showing strong distal nephron expression, whereas larger transcripts show low-level widespread distribution. Alternative splicing of exons 11 and 12 is prominent-for example, transcripts containing exon 11 are abundant in neural tissues, testis, and secondary renal transcripts but are predominantly absent in placenta. The transcriptional diversity generated by these events would produce proteins greatly differing in both structure and function. These findings help further define and clarify the role of WNK1 and the thiazide-responsive pathway relevant to essential hypertension in which it participates.
Atrial Fibrillation in Patients with Cryptogenic Stroke
Authors: David J. Gladstone, Melanie Spring, Paul Dorian, Val Panzov, Kevin E. Thorpe, Judith Hall, Haris Vaid, Martin O'Donnell, Andreas Laupacis, Robert Côté, Mukul Sharma, John A. Blakely, Ashfaq Shuaib, Vladimir Hachinski, Shelagh B. Coutts, Demetrios J. Sahlas, Phil Teal, Samuel Yip, J. David Spence, Brian Buck, Steve Verreault, Leanne K. Casaubon, Andrew Penn, Daniel Selchen, Albert Jin, David Howse, Manu Mehdiratta, Karl Boyle, Richard Aviv, Moira K. Kapral, Muhammad Mamdani
Journal: New England Journal of Medicine (2014)

Atrial fibrillation is a leading preventable cause of recurrent stroke for which early detection and treatment are critical. However, paroxysmal atrial fibrillation is often asymptomatic and likely to go undetected and untreated in the routine care of patients with ischemic stroke or transient ischemic attack (TIA).
Relationship between mite, cat, and dog allergens in reservoir dust and ambient air
Authors: A Custovic, B Simpson, A Simpson, C Hallam, M Craven, A Woodcock
Journal: Allergy (1999)

Standardized methods to measure allergen exposure are essential to assess the relationship between exposure, sensitization, and asthma. Most studies have measured allergen levels in reservoir dust, although air samples may be more representative as a measure of inhaled allergen. The aim of this study was to define the relationship between mite, cat, and dog allergen content in the reservoir dust and the levels in the ambient air.Dust samples from the living-room floor (LF) and sofa (S) were collected in 127 homes: 62 without and 65 with pets (31 dogs, 34 cats). Air samples were taken in the same room, with a high-volume pump for 1 h (flow 60 l/min). Der p 1, Fel d 1, and Can f 1 were determined by mAb-based ELISA.Airborne Der p 1 was below the detection limit (0.8 ng/m3) in all homes, with reservoir levels (GM and range) being 1.14 microg/g (0.2-66) and 1.15 microg/g (0.2-127) in LF and S, respectively. Airborne Can f 1 was detected in 40/62 homes without pets (range 0.6-12.4 ng/m3) and in all homes with dogs (range 0.5-99 ng/m3). In the multiple linear regression analysis, Can f 1 level in the LF was an independent correlate of the airborne Can f 1 (P=0.01, homes with dogs; P=0.04, homes without dogs). Fel d 1 was detected in the air in 16/62 homes without pets (range 0.16-1.8 ng/m3) and in all homes with cats (range 0.4-22.3 ng/m3). Fel d 1 level in the LF was an independent correlate of the airborne Fel d 1 in homes without cats (P=0.008), but airborne levels in homes with cats did not correlate with reservoir levels.The aerodynamics of each allergen must be taken into account when assessing exposure: while levels in reservoir dust are the best available index for mite allergens, airborne levels might be more suitable for defining exposure to pets. If air samples are difficult to obtain, levels of Can f 1 and Fel d 1 in the LF samples should be used as a surrogate measure of personal exposure.
Cost to the NHS of accidents to children in the West Midlands
Authors: V Vipulendran, A R Mason, R Sunderland
Journal: BMJ (1988)

Cost to the NHS of accidents to children in the West Midlands Accidents consume about 1% of a developed country's gross national product (£2500m for the United Kingdom in 1984; Royal Society for Prevention of Accidents, personal communication).This estimate is vague and includes notional valuations for grief, suffering, and loss of earnings.Published data on the specific health costs of accidents in childhood are limited. Methods and resultsData on specific classes of accident and on outpatients were obtained from the Department of Trade's home accident surveillance system.Details of inpatients in the West Midlands were obtained from Hospital Activity Analysis.Details on treatment provided by general practitioners for children injured in accidents were taken from morbidity statistics for general practice.'An incidence of permanent disability (18 6/100000 accidents) and a breakdown of types of disability expected were provided by a report on long term disability after accidents in childhood.2Inpatient treatment (with hotel components), outpatient treatment, and Number ofchildren treated after accidents, and costs, in West Midlands, 1984 We are grateful to Dr Mike Drummond, Health Services Management Centre;
Protecting cognitive science from quantum theory
Authors: David Wallace
Journal: Behavioral and Brain Sciences (2004)

The relation between micro-objects and macro-objects advocated by Kim is even more problematic than Ross &amp; Spurrett (R&amp;S) argue, for reasons rooted in physics. R&amp;S's own ontological proposals are much more satisfactory from a physicist's viewpoint but may still be problematic. A satisfactory theory of macroscopic ontology must be as independent as possible of the details of microscopic physics.
Pleural plaques and asbestosis: dose- and time-response relationships based on HRCT data
Authors: C. Paris, S. Thierry, P. Brochard, M. Letourneux, E. Schorle, A. Stoufflet, J. Ameille, F. Conso, J. C. Pairon
Journal: European Respiratory Journal (2009)

Most studies on asbestos-related diseases are based on chest radiographs, and dose–response relationships are still controversial. The aim of this study was to describe the most relevant parameters of asbestos exposure linked to pleural plaques and asbestosis diagnosed by high-resolution computed tomography (HRCT). A large screening programme including systematic HRCT examinations was organised from 2003 to 2005 in France for formerly asbestos-exposed workers. The time since first exposure (TSFE), level, duration and cumulative exposure to asbestos were used in adjusted unconditional logistic regression to model the relationships of the two diseases. Analysis of a population of 5,545 subjects demonstrated that TSFE (p&lt;0.0001) and cumulative exposure (p = 0.02) (or level, depending on the models used), were independently associated with the frequency of pleural plaques. Only cumulative exposure (p&lt;0.0001) or level of exposure (p = 0.02) were significantly associated with asbestosis. All trend tests were significant for these parameters. To date and to our knowledge, this study is the largest programme based on HRCT for the screening of asbestos-exposed subjects. Both time–response and dose–response relationships were demonstrated for pleural plaques, while only dose–response relationships were demonstrated for asbestosis. These parameters must be included in the definition of high-risk populations for HRCT-based screening programmes.
Nitric oxide induces heat-shock protein 70 expression in vascular smooth muscle cells via activation of heat shock factor 1.
Authors: Q Xu, Y Hu, R Kleindienst, G Wick
Journal: Journal of Clinical Investigation (1997)

Current data suggest that nitric oxide (NO) is a double-edged sword that could result in relaxation and/or cytotoxicity of vascular smooth muscle cells (SMCs) via cGMP- dependent or -independent signal pathways. Stress or heat shock proteins (hsps) have been shown to be augmented in arterial SMCs during acute hypertension and atherosclerosis, both conditions that are believed to correlate with disturbed NO production. In the present study, we demonstrate that NO generated from sodium nitroprusside (SNP), S-nitroso-N-acetylpenicillamine, and spermine/nitric oxide complex leads to hsp70 induction in cultured SMCs. Western blot analysis demonstrated that hsp70 protein expression peaked between 6 and 12 h after treatment with SNP, and elevated protein levels were preceded by induction of hsp70 mRNA within 3 h. Induction of hsp70 mRNA was associated with the activation of heat shock transcription factor 1 (HSF1), suggesting that the response was regulated at the transcriptional level. HSF1 activation was completely blocked by hemoglobin, dithiothreitol, and cycloheximide, suggesting that the protein damage and nascent polypeptide formation induced by NO may initiate this activation. Furthermore, SMCs pretreated with heat shock (42 degrees C) for 30 min were significantly protected from death induced by NO. Thus, we provide evidence that NO induces hsp70 expression in SMCs via HSF1 activation. Induction of hsp70 could be important in protecting SMCs from injury resulting from NO stimulation.
Similarities and differences between asthma and chronic obstructive pulmonary disease: treatment and early outcomes
Authors: A.S. Buist
Journal: European Respiratory Journal (2003)

There are now many guidelines that provide direction for the diagnosis and management of asthma and chronic obstructive pulmonary disease (COPD). However, both diseases are still underdiagnosed (or misdiagnosed) and undertreated. There is considerable evidence that treatment with anti-inflammatory drugs reduces morbidity and mortality in asthma. The evidence is growing regarding their effect on slowing the remodelling that occurs in subsets of asthmatics. COPD is more challenging. There are no disease-modifying drugs available yet that will change the natural history of COPD. However, there is overwhelming evidence that smoking cessation will slow the progression of disease. Until better drugs are available for the treatment of COPD, emphasis must be placed on primary and secondary prevention by reducing exposure to noxious agents (cigarette smoke in particular). Inhaled corticosteroids appear to have a place in the management of severe chronic obstructive pulmonary disease, perhaps by decreasing the frequency of exacerbations.
Comprehensive genomic meta-analysis identifies intra-tumoural stroma as a predictor of survival in patients with gastric cancer
Authors: Yonghui Wu, Heike Grabsch, Tatiana Ivanova, Iain Beehuat Tan, Jacinta Murray, Chia Huey Ooi, Alexander Ian Wright, Nicholas P West, Gordon G A Hutchins, Jeanie Wu, Minghui Lee, Julian Lee, Jun Hao Koo, Khay Guan Yeoh, Nicole van Grieken, Bauke Ylstra, Sun Young Rha, Jaffer A Ajani, Jae Ho Cheong, Sung Hoon Noh, Kiat Hon Lim, Alex Boussioutas, Ju-Seog Lee, Patrick Tan
Journal: Gut (2012)

Gastric adenocarcinoma (gastric cancer, GC) is a major cause of global cancer mortality. Identifying molecular programmes contributing to GC patient survival may improve our understanding of GC pathogenesis, highlight new prognostic factors and reveal novel therapeutic targets. The authors aimed to produce a comprehensive inventory of gene expression programmes expressed in primary GCs, and to identify those expression programmes significantly associated with patient survival.Using a network-modelling approach, the authors performed a large-scale meta-analysis of GC transcriptome data integrating 940 gastric transcriptomes from multiple independent patient cohorts. The authors analysed a training set of 428 GCs and 163 non-malignant gastric samples, and a validation set of 288 GCs and 61 non-malignant gastric samples.The authors identified 178 gene expression programmes ('modules') expressed in primary GCs, which were associated with distinct biological processes, chromosomal location patterns, cis-regulatory motifs and clinicopathological parameters. Expression of a transforming growth factor β (TGF-β) signalling associated 'super-module' of stroma-related genes consistently predicted patient survival in multiple GC validation cohorts. The proportion of intra-tumoural stroma, quantified by morphometry in tissue sections from gastrectomy specimens, was also significantly associated with stromal super-module expression and GC patient survival.Stromal gene expression predicts GC patient survival in multiple independent cohorts, and may be closely related to the intra-tumoural stroma proportion, a specific morphological GC phenotype. These findings suggest that therapeutic approaches targeting the GC stroma may merit evaluation.
The accuracy of portable peak flow meters.
Authors: M R Miller, S A Dickinson, D J Hitchings
Journal: Thorax (1992)

BACKGROUND: The variability of peak expiratory flow (PEF) is now commonly used in the diagnosis and management of asthma. It is essential for PEF meters to have a linear response in order to obtain an unbiased measurement of PEF variability. As the accuracy and linearity of portable PEF meters have not been rigorously tested in recent years this aspect of their performance has been investigated. METHODS: The response of several portable PEF meters was tested with absolute standards of flow generated by a computer driven, servo controlled pump and their response was compared with that of a pneumotachograph. RESULTS: For each device tested the readings were highly repeatable to within the limits of accuracy with which the pointer position can be assessed by eye. The between instrument variation in reading for six identical devices expressed as a 95% confidence limit was, on average across the range of flows, +/- 8.5 l/min for the Mini-Wright, +/- 7.9 l/min for the Vitalograph, and +/- 6.4 l/min for the Ferraris. PEF meters based on the Wright meter all had similar error profiles with overreading of up to 80 l/min in the mid flow range from 300 to 500 l/min. This overreading was greatest for the Mini-Wright and Ferraris devices, and less so for the original Wright and Vitalograph meters. A Micro-Medical Turbine meter was accurate up to 400 l/min and then began to underread by up to 60 l/min at 720 l/min. For the low range devices the Vitalograph device was accurate to within 10 l/min up to 200 l/min, with the Mini-Wright overreading by up to 30 l/min above 150 l/min. CONCLUSION: Although the Mini-Wright, Ferraris, and Vitalograph meters gave remarkably repeatable results their error profiles for the full range meters will lead to important errors in recording PEF variability. This may lead to incorrect diagnosis and bias in implementing strategies of asthma treatment based on PEF measurement.
Aspects of platelet formation and release
Authors: G. Scurfield, J. M. Radley
Journal: American Journal of Hematology (1981)

Abstract The surface architecture and location of megakaryocytes in the extravascular compartment of mouse bone marrow are considered. The finger‐like cytoplasmic processes that extend into sinuses pass through apertures, approximately 3.0 mμ in diameter, occurring singly or in groups. The cytoplasmic processes enlarge on first entering a sinus and form villi that seem to anchor them to the endothelium. The villi consist largely of microfilaments. The cytoplasmic processes extend, attenuate, and undergo irregular constriction along their lengths. The constrictions demarcate modicums of cytoplasm of platelet size one from another that are released when they break. Extravascular platelet release may also occur, and evidence is presented that points to the likelihood of the platelet's being engulfed and phagocytosed by macrophages before reaching the microcirculation.