tbuckley/cabot-search huggingface dataset:
The β-Catenin Axis Integrates Multiple Signals Downstream from RET/Papillary Thyroid Carcinoma Leading to Cell Proliferation
Authors: Maria Domenica Castellone, Valentina De Falco, Deva Magendra Rao, Roberto Bellelli, Magesh Muthu, Fulvio Basolo, Alfredo Fusco, J. Silvio Gutkind, Massimo Santoro
Journal: Cancer Research (2009)

RET/papillary thyroid carcinoma (RET/PTC) oncoproteins result from the in-frame fusion of the RET receptor tyrosine kinase domain with protein dimerization motifs encoded by heterologous genes. Here, we show that RET/PTC stimulates the beta-catenin pathway. By stimulating PI3K/AKT and Ras/extracellular signal-regulated kinase (ERK), RET/PTC promotes glycogen synthase kinase 3beta (GSK3beta) phosphorylation, thereby reducing GSK3beta-mediated NH(2)-terminal beta-catenin (Ser33/Ser37/Thr41) phosphorylation. In addition, RET/PTC physically interacts with beta-catenin and increases its phosphotyrosine content. The increased free pool of S/T(nonphospho)/Y(phospho)beta-catenin is stabilized as a result of the reduced binding affinity for the Axin/GSK3beta complex and activates the transcription factor T-cell factor/lymphoid enhancer factor. Moreover, through the ERK pathway, RET/PTC stimulates cyclic AMP-responsive element binding protein (CREB) phosphorylation and promotes the formation of a beta-catenin-CREB-CREB-binding protein/p300 transcriptional complex. Transcriptional complexes containing beta-catenin are recruited to the cyclin D1 promoter and a cyclin D1 gene promoter reporter is active in RET/PTC-expressing cells. Silencing of beta-catenin by small interfering RNA inhibits proliferation of RET/PTC-transformed PC Cl3 thyrocytes, whereas a constitutively active form of beta-catenin stimulates autonomous proliferation of thyroid cells. Thus, multiple signaling events downstream from RET/PTC converge on beta-catenin to stimulate cell proliferation.
Nonconventional (TL-encoded) major histocompatibility complex molecules present processed viral antigen to cytotoxic T lymphocytes.
Authors: G N Milligan, L Flaherty, V L Braciale, T J Braciale
Journal: The Journal of Experimental Medicine (1991)

A large number of class I-like genes are located distal to the K and D regions of the murine major histocompatibility complex (MHC) within the Q and TL region. The function of the molecules encoded within this region is obscure since unlike conventional MHC gene products, these molecules have not been reported to present processed environmental antigens to T cells. In the present report, we demonstrate that a peptide corresponding to processed influenza virus hemagglutinin can be recognized by CD8+ T cell receptor alpha/beta-positive cytotoxic T lymphocytes (CTL) in association with a MHC class I-like product encoded within the TL region. Thus, nonconventional class I MHC molecules can bind and present processed environmental antigens, and TCR-alpha/beta CTL directed to such peptide MHC complexes are represented in the mature T cell pool. Our data imply that Q/TL region products may be charged by peptides generated through an antigen processing and presentation pathway distinct from the pathway used by conventional MHC molecules and not normally available to environmental antigens.
Use of the Forced Oscillation Technique to Assess Airway Obstruction and Reversibility in Children
Authors: CHRISTOPHE DELACOURT, HUBERT LORINO, MARTINE HERVE-GUILLOT, PHILIPPE REINERT, ALAIN HARF, BRUNO HOUSSET
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

The forced oscillation technique (FOT) is particularly attractive in a pediatric setting as it requires only passive cooperation from the child. We assessed the sensitivity and specificity of this method for detecting airway obstruction and its reversibility in 313 children (3 to 16 yr of age) with asthma or chronic nocturnal cough. Baseline and post-bronchodilator (n = 251) resistance were measured (R(0)) with the FOT. Baseline R(0) was normalized for height and weight [R(0)(SD)]. In children able to perform forced expiratory maneuvers (n = 181), R(0)(SD) was independently correlated with FEV(1) (p < 0.02) and maximal expiratory flow at 50% (MEF(50)) (p < 0.004). The optimal R(0)(SD) cutoff value given by receiver operating characteristic (ROC) curves to discriminate between children with baseline FEV(1) < 80% or >/= 80% of predicted values yielded 84% sensitivity and 73% specificity. Post-bronchodilator changes in R(0)(SD) [DeltaR(0)(SD)] were mostly correlated to changes in MEF(50). The optimal DeltaR(0)(SD) cutoff value to discriminate between children with the presence or absence of significant reversibility in FEV(1) yielded 69% sensitivity and 78% specificity. In children unable to perform forced expiratory maneuvers (n = 132), this DeltaR(0)(SD) cutoff clearly identified a subgroup of young children with high R(0) values at baseline, that returned to normal after bronchodilation. We conclude that FOT measurements allow reliable evaluation of bronchial obstruction and its reversibility in asthmatic children over 3 yr old.
Comparison of the safety of drug delivery via HFA- and CFC-metered dose inhalers in CAO
Authors: G. Huchon, P. Hofbauer, G. Cannizzaro, P Iacono, F Wald
Journal: European Respiratory Journal (2000)

The objective of this study was to compare the long-term safety of a fixed combination of fenoterol hydrobromide (50 microg) and ipratropium bromide (20 microg) delivered using a metered dose inhaler (MDI) formulated with a non-chlorinated propellant, hydrofluoroalkanel34a (HFA-MDI), with delivery using the conventional chlorofluorocarbon propellant (CFC-MDI, Berodual/Bronchodual). The study was designed according to Safety Assessment of Marketed Medicines (SAMM) guidelines, to reflect as far as possible the use of MDls under normal prescribing conditions. Two thousand and twenty-seven patients with chronic airways obstruction (CAO) were enrolled from 99 centres in France, 95 centres in Germany and 24 centres in Italy. Following a 2-week run-in period, patients were randomized on a 2:1 basis (1,348 patients to HFA-MDI, 679 patients to CFC-MDI) to receive a flexible dose regimen of the combination (2 puffs, 2-4 times a day, as prescribed by the investigator) during a 12-week open label phase. The overall incidence of adverse events was comparable between both groups. In addition, the incidence of respiratory side effects was also similar, with CAO exacerbations or bronchitis the most frequently recorded events. The safety profile of the HFA formulation was comparable to those of the marketed CFC-MDIs used in Germany and France/Italy. No clinically significant differences were detected between HFA134a or CFC driven inhalers on the switch from CFC- to HFA-MDI (2 weeks before randomisation versus 2 weeks after randomization). There was a trend for taste complaints to be reported more frequently by patients in the HFA-MDI group (0.7% before randomization versus 3.4% after randomization). This, however, was an expected finding as the HFA134a formulation does have a different taste to the CFC formulation. No difference between formulations was observed in the incidences of coughing or paradoxical bronchospasm. The incidence of falls in FEV1 >15% within 15 min following inhalation at each of the clinic visits was 1.2% for both CFC- and HFA-MDIs. In conclusion, administration of a fenoterol/ipratropium bromide combination via hydrofluoroalkane-metered dose inhaler is as safe as delivery by the currently available chlorofluorocarbon-metered dose inhaler, in an extended population of patients with CAO under normal prescribing conditions.
Class III P-glycoproteins mediate the formation of lipoprotein X in the mouse.
Authors: R P Elferink, R Ottenhoff, J van Marle, C M Frijters, A J Smith, A K Groen
Journal: Journal of Clinical Investigation (1998)

Cholestasis is associated with hypercholesterolemia and appearance of the abnormal lipoprotein X (LpX) in plasma. Using mice with a disrupted Mdr2 gene, we tested the hypothesis that LpX originates as a biliary lipid vesicle. Mdr2-deficient mice lack Mdr2 P-glycoprotein, the canalicular translocator for phosphatidylcholine, and secrete virtually no phospholipid and cholesterol in bile. Bile duct ligation of Mdr2(+)/+ mice induced a dramatic increase in the plasma cholesterol and phospholipid concentration. Agarose electrophoresis, density gradient ultracentrifugation, gel permeation, and electron microscopy revealed that the majority of phospholipid and cholesterol was present as LpX, a 40-100 nm vesicle with an aqueous lumen. In contrast, the plasma cholesterol and phospholipid concentration in Mdr2(-)/- mice decreased upon bile duct ligation, and plasma fractionation revealed a complete absence of LpX. In mice with various expression levels of Mdr2 or MDR3, the human homolog of Mdr2, we observed that the plasma level of cholesterol and phospholipid during cholestasis correlated very closely with the expression level of these canalicular P-glycoproteins. These data demonstrate that during cholestasis there is a quantitative shift of lipid secretion from bile to the plasma compartment in the form of LpX. The concentration of this lipoprotein is determined by the activity of the canalicular phospholipid translocator.
The mSCOFF for Screening Disordered Eating in Pediatric Type 1 Diabetes
Authors: Caroline Sarah Zuijdwijk, Susan A. Pardy, Jeff J. Dowden, Anna M. Dominic, Tracey Bridger, Leigh Anne Newhook
Journal: Diabetes Care (2014)

Screening for eating disorders (EDs) in adolescent females with type 1 diabetes (T1D) is recommended by national guidelines because of the increased risk of EDs in this population and the premature morbidity and mortality associated with this dual diagnosis (1). Currently, no ED screening tool has been validated and accepted for clinical use in T1D. We modified the SCOFF ED screening questionnaire for this population (mSCOFF) and compared it with the Eating Disorder Inventory-3 (EDI-3) in 43 adolescent females with T1D (mean ± SD age 15.8 ± 1.7 years, diabetes duration 7.6 ± 3.9 years, BMI 25.5 ± 3.5 kg/m2, A1C 8.4 ± 1.4% [68 mmol/mol]). Patients with known ED were excluded. This study had institutional ethics board approval.

The EDI-3 is a reliable, valid, 91-item self-report measure for screening ED risk (2). A modified form of the EDI (mEDI) eliminates questions related to diabetes-imposed dietary …
A Dual Inhibitor of Platelet-Derived Growth Factor β-Receptor and Src Kinase Activity Potently Interferes With Motogenic and Mitogenic Responses to PDGF in Vascular Smooth Muscle Cells
Authors: Johannes Waltenberger, Andrea Uecker, Jens Kroll, Hedwig Frank, Ulrike Mayr, Jeffrey D. Bjorge, Donald Fujita, Aviv Gazit, Vinzenz Hombach, Alexander Levitzki, Frank-D. Böhmer
Journal: Circulation Research (1999)

Abstract —PP1 has previously been described as an inhibitor of the Src -family kinases p56 Lck and FynT. We have therefore decided to use PP1 to determine the functional role of Src in platelet-derived growth factor (PDGF)–induced proliferation and migration of human coronary artery smooth muscle cells (HCASMCs). A synthetic protocol for PP1/AGL1872 has been developed, and the inhibitory activity of PP1/AGL1872 against Src was examined. PP1/AGL1872 potently inhibited recombinant p60 c-src in vitro and Src -dependent tyrosine phosphorylation in p60 c-srcF572 -transformed NIH3T3 cells. PP1/AGL1872 also potently inhibited PDGF-stimulated migration of HCASMCs, as determined in the modified Boyden chamber, as well as PDGF-stimulated proliferation of HCASMCs. Surprisingly, in addition to inhibition of Src kinase, PP1/AGL1872 was found to inhibit PDGF receptor kinase in cell-free assays and in various types of intact cells, including HCASMCs. PP1/AGL1872 did not inhibit phosphorylation of the vascular endothelial growth factor receptor KDR (VEGF receptor-2; kinase-insert domain containing receptor) in cell-free assays as well as in intact human coronary artery endothelial cells. In line with the insensitivity of KDR, PP1/AGL1872 had only a weak effect on vascular endothelial growth factor–stimulated migration of human coronary artery endothelial cells. On treatment of cells expressing different receptor tyrosine kinases, the activities of the epidermal growth factor receptor, fibroblast growth factor receptor-1, and insulin-like growth factor-1 receptor were resistant to PP1/AGL1872, whereas PDGF α-receptor was susceptible, albeit to a lesser extent than PDGF β-receptor. These data suggest that the previously described tyrosine kinase inhibitor PP1/AGL1872 is not selective for the Src family of tyrosine kinases. It is also a potent inhibitor of the PDGF β-receptor kinase but is not a ubiquitous tyrosine kinase inhibitor. PP1/AGL1872 inhibits migration and proliferation of HCASMCs probably by interference with 2 distinct tyrosine phosphorylation events, creating a novel and potent inhibitory principle with possible relevance for the treatment of pathological HCASMC activity, such as vascular remodeling and restenosis.
Association between family history and mismatch repair in colorectal cancer
Authors: R P Coggins
Journal: Gut (2005)

<b>Background and aims:</b> Germline mutations in mismatch repair (MMR) genes cause a greatly increased risk of cancer of the gastrointestinal and female reproductive tracts (hereditary non-polyposis colorectal cancer (HNPCC)). Loss of MMR expression is common in colorectal cancer (CRC) overall. Such loss is assumed to be acquired predominantly, although a population of CRC cases will include individuals with unrecognised MMR mutations. This study examines the association between MMR gene expression and family history of cancer among the CRC population. <b>Methods:</b> Individuals with CRC were identified from two well characterised populations: (1) consecutive hospital patients (n = 644) and (2) a population based cases series (n = 249). CRC was examined for expression of hMLH1 and hMSH2 using immunohistochemistry, and expression was related to family history using logistic regression. <b>Results:</b> hMLH1 and hMSH2 expression was assessed in 732 CRCs with 8% showing loss of expression. No association was seen overall for hMLH1 or hMSH2 expression and family history of CRC. Loss of hMSH2 was predicted by family history of extracolonic cancer (odds ratio (OR) 5.78 (95% confidence interval (CI) 0.95–35.18)) and family history suggestive of HNPCC (OR 27.84 (95% CI 4.37–177.56)). Loss of hMLH1 was not predicted by family history of extracolonic cancer or a family history suggestive of HNPCC but was for a family history of at least two affected relatives (OR 4.88 (95% CI 1.25–19.03)). <b>Conclusions:</b> Individuals with hMSH2 deficient CRC in the general population exhibit a family history and other characteristics suggestive of HNPCC, and may carry germline MMR mutations. Loss of hMLH1 is only associated with a strong family history of extracolonic cancer at older ages, suggesting a novel mechanism of susceptibility.
<i>N</i>-Acetylcysteine Protects Melanocytes against Oxidative Stress/Damage and Delays Onset of Ultraviolet-Induced Melanoma in Mice
Authors: Murray A. Cotter, Joshua Thomas, Pamela Cassidy, Kyle Robinette, Noah Jenkins, Scott R. Florell, Sancy Leachman, Wolfram E. Samlowski, Douglas Grossman
Journal: Clinical Cancer Research (2007)

Abstract Purpose: UV radiation is the major environmental risk factor for melanoma and a potent inducer of oxidative stress, which is implicated in the pathogenesis of several malignancies. We evaluated whether the thiol antioxidant N-acetylcysteine (NAC) could protect melanocytes from UV-induced oxidative stress/damage in vitro and from UV-induced melanoma in vivo. Experimental Design: In vitro experiments used the mouse melanocyte line melan-a. For in vivo experiments, mice transgenic for hepatocyte growth factor and survivin, shown previously to develop melanoma following a single neonatal dose of UV irradiation, were given NAC (7 mg/mL; mother's drinking water) transplacentally and through nursing until 2 weeks after birth. Results: NAC (1-10 mmol/L) protected melan-a cells from several UV-induced oxidative sequelae, including production of intracellular peroxide, formation of the signature oxidative DNA lesion 8-oxoguanine, and depletion of free reduced thiols (primarily glutathione). Delivery of NAC reduced thiol depletion and blocked formation of 8-oxoguanine in mouse skin following neonatal UV treatment. Mean onset of UV-induced melanocytic tumors was significantly delayed in NAC-treated compared with control mice (21 versus 14 weeks; P = 0.0003). Conclusions: Our data highlight the potential importance of oxidative stress in the pathogenesis of melanoma and suggest that NAC may be useful as a chemopreventive agent.
MM-ChIP enables integrative analysis of cross-platform and between-laboratory ChIP-chip or ChIP-seq data
Authors: Yiwen Chen, Clifford A Meyer, Tao Liu, Wei Li, Jun S Liu, Xiaole Shirley Liu
Journal: Genome biology (2011)

The ChIP-chip and ChIP-seq techniques enable genome-wide mapping of in vivo protein-DNA interactions and chromatin states. The cross-platform and between-laboratory variation poses a challenge to the comparison and integration of results from different ChIP experiments. We describe a novel method, MM-ChIP, which integrates information from cross-platform and between-laboratory ChIP-chip or ChIP-seq datasets. It improves both the sensitivity and the specificity of detecting ChIP-enriched regions, and is a useful meta-analysis tool for driving discoveries from multiple data sources.
CELL-MEDIATED IMMUNITY AND BLOCKING SERUM ACTIVITY TO TOLERATED ALLOGRAFTS IN RATS
Authors: S. C. Bansal, K. E. Hellström, I. Hellström, H. O. Sjögren
Journal: The Journal of Experimental Medicine (1973)

W/Fu rats were neonatally inoculated with bone marrow cells from B/N rats and vice versa. Of the inoculated rats, some were capable of accepting a foreign (B/N or W/Fu) skin graft over the period of observation (i.e. for more than 100 days), while other rats rejected their skin grafts as early as control animals (within 8-12 days) or after a prolonged period of acceptance (20-96 days). Using a microcytotoxicity test, it could be shown that both those rats that rapidly rejected skin grafts and those that kept their grafts during the observation period had lymphocytes capable of destroying cultivated allogeneic cells from the respective strains with whose cells the rats had been inoculated as newborns. The degree of lymphocyte reactivity decreased upon time, so that 4 of 13 rats that had carried "tolerated" skin grafts over more than 84 days had lymphocytes which were nonreactive in the highest dose tested, and the degree of reactivity in the other 9 rats was less than seen early after tolerance induction. Rats that were capable of accepting skin grafts over prolonged periods of time had sera that could specifically block lymphocyte-mediated cytotoxicity, while sera from rats that had rejected their grafts did not block. Sera from rats that rejected their skin grafts after 20-96 days lost the blocking activity 3-10 days before rejection.
Enhanced IL‐4 responses in children with a history of respiratory syncytial virus bronchiolitis in infancy
Authors: P. Pala, R. Bjarnason, F. Sigurbergsson, C. Metcalfe, N. Sigurs, P.J.M. Openshaw
Journal: European Respiratory Journal (2002)

Infants who recover from respiratory syncytial virus (RSV)-induced bronchiolitis are at high risk of developing asthma and recurrent wheezing. It is not known whether severe RSV infection itself causes persistent effects or is a marker of a "wheezy" predisposition. To determine the long-term immunological correlates of infantile bronchiolitis, interleukin (IL)-4 and interferon (IFN)-gamma responses to a panel of antigens were studied in a well-characterised cohort of 7-8-yr-old children with a history of severe RSV bronchiolitis in infancy. Peripheral blood lymphocytes from 37 children who were hospitalised with RSV bronchiolitis in infancy and from 69 age-, sex- and location-matched controls were stimulated in vitro with RSV, house-dust mite, birch and cat antigens. Cellular proliferation, and enzyme-linked immunoSPOT IFN-gamma and IL-4 production were measured. IL-4 producing T-cells responding to RSV and cat antigens were significantly more frequent in exbronchiolitics. Other responses (including the IFN-gamma response to RSV) were equally strong in exbronchiolitics and controls. Respiratory syncytial virus infection primes memory T-cells that make interferon-gamma, but virus and aeroallergen-specific and interleukin-4 producing T-cells are also frequently primed in bronchiolitics. Respiratory syncytial virus bronchiolitis in infancy may increase the risk of allergic sensitisation by providing a local interleukin-4-rich environment, in which airborne allergens are first encountered.
Derivation and Validation of Guidelines for Stool Cultures for Enteropathogenic Bacteria Other Than &lt;EMPH TYPE="ITAL"&gt;Clostridium difficile&lt;/EMPH&gt; in Hospitalized Adults
Authors: T M Bauer, A Lalvani, J Fehrenbach, I Steffen, J J Aponte, R Segovia, J Vila, G Philippczik, B Steinbrückner, R Frei, I Bowler, M Kist
Journal: JAMA (2001)

The yield of in-hospital stool cultures performed more than 72 hours after admission is low, and a commonly used policy dictates that laboratories reject these cultures to save costs. However, enteropathogenic bacteria other than Clostridium difficile (EPB) may cause nosocomial illness that would be missed by use of such a "3-day rule."To develop guidelines for hospital use of stool cultures that are sensitive to clinically relevant cases of sporadic and epidemic nosocomial diarrhea.Five-part study that incorporated a derivation sample based on retrospective chart review and a prospective cohort study (including cost savings analysis), and a validation sample based on retrospective chart review.Four European academic health care centers.Derivation sample: 1735 adult inpatients from whom 3416 stool cultures were obtained during a 19-month period (1995-1997) and 68 adult inpatients for whom EPB were grown from stool cultures during a 10-year period (1988-1998); validation sample: 65 patients with sporadic isolation of EPB (1993-1998), 56 patients involved in 2 nosocomial Salmonella outbreaks (1992 and 1997), and 330 patients who had stool cultures performed (1998).Performance of derived criteria in detecting pathogenic bacteria and outbreaks and reducing total number of stool cultures performed.Stool cultures grew EPB in 3.3% of samples obtained </=72 hours after admission and 0.5% of samples obtained thereafter (P<.001). Isolation of EPB >72 hours after admission was not associated with clinical symptoms or signs but was associated with community-acquired diarrhea (24%), age 65 years or older with preexisting comorbid disease (25%), neutropenia (13%), HIV infection (10%), and nondiarrheal manifestations of enteric infections (16%). Twelve percent were asymptomatic carriers. These characteristics were used to create criteria for selecting patients for whom stool cultures would be indicated. These criteria were applied post hoc to a series of 1025 stool cultures; the number of stool cultures would have been reduced by 52% and no clinically significant cases would have been missed. Annual savings to a 355-bed institution would be approximately $7800 for reagent costs and 75 hours of technician time. In the validation samples, only 2 patients of 65 who had EPB would not have been identified, and neither required treatment. If the 3-day rule had been applied, 52 cases would not have been identified, 28 of which required antibiotic treatment.Our modified 3-day rule for use in selecting cases for stool culture is sensitive to sporadic and epidemic cases of nosocomial diarrhea in hospitalized adults.