tbuckley/cabot-search huggingface dataset:
Liver/kidney microsomal antibody type 1 targets CYP2D6 on hepatocyte plasma membrane
Authors: L Muratori
Journal: Gut (2000)

Liver/kidney microsomal antibody type 1 (LKM1) is the marker of type 2 autoimmune hepatitis (AIH) and is detected in up to 6% of patients with hepatitis C virus (HCV) infection. It recognises linear and conformational epitopes of cytochrome P450IID6 (CYP2D6) and may have liver damaging activity, provided that CYP2D6 is accessible to effector mechanisms of autoimmune attack.The presence of LKM1 in the plasma membrane was investigated by indirect immunofluorescence and confocal laser microscopy of isolated rat hepatocytes probed with 10 LKM1 positive sera (five from patients with AIH and five from patients with chronic HCV infection) and a rabbit polyclonal anti-CYP2D6 serum.Serum from both types of patient stained the plasma membrane of non-permeabilised cells, where the fluorescent signal could be visualised as discrete clumps. Conversely, permeabilised hepatocytes showed diffuse submembranous/cytoplasmic staining. Adsorption with recombinant CYP2D6 substantially reduced plasma membrane staining and LKM1 immunoblot reactivity. Plasma membrane staining of LKM1 colocalised with that of anti-CYP2D6. Immunoprecipitation experiments showed that a single 50 kDa protein recognised by anti-CYP2D6 can be isolated from the plasma membrane of intact hepatocytes.AIH and HCV related LKM1 recognise CYP2D6 exposed on the plasma membrane of isolated hepatocytes. This observation supports the notion that anti-CYP2D6 autoreactivity may be involved in the pathogenesis of liver damage.
Amyloid peptides ABri and ADan show differential neurotoxicity in transgenic Drosophila models of familial British and Danish dementia
Authors: María S Marcora, Agata C Fernández-Gamba, Luz A Avendaño, Cecilia Rotondaro, Osvaldo L Podhajcer, Rubén Vidal, Laura Morelli, María F Ceriani, Eduardo M Castaño
Journal: Molecular Neurodegeneration (2014)

Abstract Background Familial British and Familial Danish dementias (FBD and FDD, respectively) are associated with mutations in the BRI 2 gene. Processing of the mutated BRI 2 protein leads to the accumulation in the brain of the 34-mer amyloid Bri (ABri) and amyloid Dan (ADan) peptides, accompanied by neurofibrillary tangles. Recently, transgenic mice successfully reproduced different aspects of FDD, while modeling of FBD in vivo has been more difficult. In this work we have modeled FBD and FDD in Drosophila and tested the hypothesis that ABri and ADan are differentially neurotoxic. Results By using site-directed insertion, we generated transgenic lines carrying ABri, ADan, Bri 2 -23 (the normal product of wild-type BRI 2 processing) and amyloid-β (Aβ) 1–42 as a well-characterized neurotoxic peptide, alone or with a His-tag. Therefore, we avoided random insertion effects and were able to compare levels of accumulation accurately. Peptides were expressed with the GAL4 -Upstream Activating Sequence ( UAS ) system using specific drivers. Despite low levels of expression, toxicity in the eye was characterized by mild disorganization of ommatidia and amyloid peptides accumulation. The highest toxicity was seen for ADan, followed by Aβ42 and ABri. Pan-neuronal expression in the CNS revealed an age-dependent toxicity of amyloid peptides as determined by the ability of flies to climb in a geotaxis paradigm when compared to Bri 2 -23. This effect was stronger for ADan, detected at 7 days post-eclosion, and followed by ABri and Aβ42, whose toxicity became evident after 15 and 21 days, respectively. Histological analysis showed mild vacuolization and thioflavine-S-negative deposits of amyloid peptides. In contrast, the over-expression of amyloid peptides in the specific subset of lateral neurons that control circadian locomotor activity showed no toxicity. Conclusions Our results support the differential neurotoxicity of ADan and ABri in the Drosophila eye and CNS at low expression levels. Such differences may be partially attributed to rates of aggregation and accumulation. In the CNS, both peptides appear to be more neurotoxic than wild-type Aβ42. These Drosophila models will allow a systematic and unambiguous comparison of differences and similarities in the mechanisms of toxicity of diverse amyloid peptides associated with dementia.
Arginine-16 2 adrenoceptor genotype predisposes to exacerbations in young asthmatics taking regular salmeterol
Authors: C N A Palmer, B J Lipworth, S Lee, T Ismail, D F Macgregor, S Mukhopadhyay
Journal: Thorax (2006)

<b>Background:</b> The homozygous presence of the arginine-16 variant of the β<sub>2</sub> adrenoceptor gene <i>ADRB2</i> reverses the benefits from the regular use of short acting β<sub>2</sub> agonists in asthmatic adults compared with the homozygous glycine-16 genotype. We studied the effect of this polymorphic variation on asthma exacerbations in children and young adults and its relation to long acting β<sub>2</sub> agonists. <b>Methods:</b> A cross-sectional survey was undertaken using electronic records, direct interviews, and genotype determination of position 16 and 27 of the <i>ADRB2</i> gene in DNA from mouthwash samples of 546 children and young asthmatics attending paediatric and young adult asthma clinics in Tayside, Scotland during 2004–5. The primary outcome measure was asthma exacerbations over the previous 6 months. <b>Results:</b> There was an increased hazard of asthma exacerbations across all treatment steps of the British Thoracic Society (BTS) asthma guidelines when the homozygous genotypes Arg/Arg and Gly/Gly were compared (OR 2.05, 95% CI 1.19 to 3.53, p = 0.010), particularly in patients treated with salmeterol (OR 3.40, 95% CI 1.19 to 9.40, p = 0.022). The Glu27Gln polymorphism had no significant effect on asthma exacerbations in any treatment group. <b>Conclusions:</b> The arginine-16 genotype of <i>ADRB2</i> predisposes to exacerbations in asthmatic children and young adults, particularly in those exposed to regular salmeterol. This may be explained by genotype selective salmeterol induced downregulation and impaired receptor coupling, and associated subsensitivity of the response.
β-glucocerebrosidase gene locus as a link for Gaucher's disease and familial hypo-α-lipoproteinaemia
Authors: Miguel Pocovi, Ana Cenarro, Fernando Civeira, Miguel A Torralba, Juan I Perez-Calvo, Pilar Mozas, Pilar Giraldo, Manuel Giralt, Richard H Myers, L Adrienne Cupples, Jose M Ordovas
Journal: The Lancet (1998)
Preclinical Antitumor Activity of Cabazitaxel, a Semisynthetic Taxane Active in Taxane-Resistant Tumors
Authors: Patricia Vrignaud, Dorothée Sémiond, Pascale Lejeune, Hervé Bouchard, Loreley Calvet, Cecile Combeau, Jean-François Riou, Alain Commerçon, François Lavelle, Marie-Christine Bissery
Journal: Clinical Cancer Research (2013)

Taxanes are important chemotherapeutic agents with proven efficacy in human cancers, but their use is limited by resistance development. We report here the preclinical characteristics of cabazitaxel (XRP6258), a semisynthetic taxane developed to overcome taxane resistance.Cabazitaxel effects on purified tubulin and on taxane-sensitive or chemotherapy-resistant tumor cells were evaluated in vitro. Antitumor activity and pharmacokinetics of intravenously administered cabazitaxel were assessed in tumor-bearing mice.In vitro, cabazitaxel stabilized microtubules as effectively as docetaxel but was 10-fold more potent than docetaxel in chemotherapy-resistant tumor cells (IC50 ranges: cabazitaxel, 0.013-0.414 μmol/L; docetaxel, 0.17-4.01 μmol/L). The active concentrations of cabazitaxel in these cell lines were achieved easily and maintained for up to 96 hours in the tumors of mice bearing MA16/C tumors treated with cabazitaxel at 40 mg/kg. Cabazitaxel exhibited antitumor efficacy in a broad spectrum of murine and human tumors (melanoma B16, colon C51, C38, HCT 116, and HT-29, mammary MA17/A and MA16/C, pancreas P03 and MIA PaCa-2, prostate DU 145, lung A549 and NCI-H460, gastric N87, head and neck SR475, and kidney Caki-1). Of particular note, cabazitaxel was active in tumors poorly sensitive or innately resistant to docetaxel (Lewis lung, pancreas P02, colon HCT-8, gastric GXF-209, mammary UISO BCA-1) or with acquired docetaxel resistance (melanoma B16/TXT).Cabazitaxel is as active as docetaxel in docetaxel-sensitive tumor models but is more potent than docetaxel in tumor models with innate or acquired resistance to taxanes and other chemotherapies. These studies were the basis for subsequent clinical evaluation.
Dust Mite Allergen In Bed Dust Predicts Rhinitis Symptom Persistence In Urban Pre-Adolescent Children With Higher Elemental Carbon Particulate Matter Exposure
Authors: Young Yoo, Luis M. Acosta, Inge Goldstein, Andrew Rundle, Omar Olmedo, Adnan Divjan, Beihzhan Yan, Judith Jacobson, Rachel L. Miller, Steven Chillrud, Matthew S. Perzanowski
Journal: Journal of Allergy and Clinical Immunology (2014)
Comparison of descriptions of allocation concealment in trial protocols and the published reports: cohort study
Authors: Julie Pildal, An-Wen Chan, Asbjørn Hróbjartsson, Elisabeth Forfang, Douglas G Altman, Peter C Gøtzsche
Journal: BMJ (2005)

<h3>Abstract</h3> <b>Objectives</b> To compare how allocation concealment is described in publications of randomised clinical trials and corresponding protocols, and to estimate how often trial publications with unclear allocation concealment have adequate concealment according to the protocol. <b>Design</b> Cohort study of 102 sets of trial protocols and corresponding publications. <b>Setting</b> Protocols of randomised trials approved by the scientific and ethical committees for Copenhagen and Frederiksberg, 1994 and 1995. <b>Main outcome measures</b> Frequency of adequate, unclear, and inadequate allocation concealment and sequence generation in trial publications compared with protocols, and the proportion of protocols where methods were reported to be adequate but descriptions were unclear in the trial publications. <b>Results</b> 96 of the 102 trials had unclear allocation concealment according to the trial publication. According to the protocols, 15 of these 96 trials had adequate allocation concealment (16%, 95% confidence interval 9% to 24%), 80 had unclear concealment (83%, 74% to 90%), and one had inadequate concealment. When retrospectively defined loose criteria for concealment were applied, 83 of the 102 trial publications had unclear concealment. According to their protocol, 33 of these 83 trials had adequate allocation concealment (40%, 29% to 51%), 49 had unclear concealment (59%, 48% to 70%), and one had inadequate concealment. <b>Conclusions</b> Most randomised clinical trials have unclear allocation concealment on the basis of the trial publication alone. Most of these trials also have unclear allocation concealment according to their protocol.
Soleus accessorius, an anomalous muscle in a young athlete: case report and analysis of the literature
Authors: A Christodoulou, I Terzidis, K Natsis, I Gigis, J Pournaras
Journal: British Journal of Sports Medicine (2004)

The soleus accessory muscle is a rare anatomical variation. It usually appears as a soft tissue mass and may be mistaken for a tumour or an inflammatory lesion. The differential diagnoses include ganglion, lipoma, haemangioma, synovioma, and sarcoma. This is a report of such a muscle mass in the leg of a young athlete with 16 years follow up. A review of the English literature on this subject is also presented.
Précis of The Intentional Stance
Authors: Daniel C. Dennett
Journal: Behavioral and Brain Sciences (1988)

The intentional stance is the strategy of prediction and explanation that attributes beliefs, desires, and other "intentional" states to systems – living and nonliving – and predicts future behavior from what it would be rational for an agent to do, given those beliefs and desires. Any system whose performance can be thus predicted and explained is an intentional system, whatever its innards. The strategy of treating parts of the world as intentional systems is the foundation of "folk psychology," but is also exploited (and is virtually unavoidable) in artificial intelligence and cognitive science more generally, as well as in evolutionary theory. An analysis of the role of the intentional stance and its presuppositions supports a naturalistic theory of mental states and events, their content or intentionality, and the relation between "mentalistic" levels of explanation and neurophysiological or mechanistic levels of explanation. As such, the analysis of the intentional stance grounds a theory of the mind and its relation to the body.
Impact of dietary shift to higher-antioxidant foods in COPD: a randomised trial
Authors: E. Keranis, D. Makris, P. Rodopoulou, H. Martinou, G. Papamakarios, Z. Daniil, E. Zintzaras, K.I. Gourgoulianis
Journal: European Respiratory Journal (2010)

Chronic obstructive pulmonary disease (COPD) is characterised by increased oxidative stress. Dietary factors, such as ample consumption of foods rich in antioxidants, such as fruit and vegetables, might have beneficial effects in COPD patients. The association between dietary shift to foods rich in antioxidants and lung function in COPD was investigated in a 3-yr prospective study. A total of 120 COPD patients were randomised to follow either a diet based on increased consumption of fresh fruit and vegetables (intervention group (IG)) or a free diet (control group (CG)). The mean consumption of foods containing antioxidants was higher in the IG than in the CG throughout the study period (p&lt;0.05). The relationship between consumption of foods rich in antioxidants and percentage predicted forced expiratory volume in 1 s was assessed using a general linear model for repeated measures; the two groups overall were different in time (p = 0.03), with the IG showing a better outcome. In investigating the effect of several confounders (sex, age, smoking status, comorbid conditions and exacerbation) of group response over time, nonsignificant interactions were found between confounders, group and time. These findings suggest that a dietary shift to higher-antioxidant food intake may be associated with improvement in lung function, and, in this respect, dietary interventions might be considered in COPD management.
Molecular Features and Survival Outcomes of the Intrinsic Subtypes Within HER2-Positive Breast Cancer
Authors: Aleix Prat, Lisa A. Carey, Barbara Adamo, Maria Vidal, Josep Tabernero, Javier Cortés, Joel S. Parker, Charles M. Perou, José Baselga
Journal: JNCI Journal of the National Cancer Institute (2014)

BackgroundThe clinical impact of the biological heterogeneity within HER2-positive (HER2+) breast cancer is not fully understood. Here, we evaluated the molecular features and survival outcomes of the intrinsic subtypes within HER2+ breast cancer.
Long-term azithromycin for Indigenous children with non-cystic-fibrosis bronchiectasis or chronic suppurative lung disease (Bronchiectasis Intervention Study): a multicentre, double-blind, randomised controlled trial
Authors: Patricia C Valery, Peter S Morris, Catherine A Byrnes, Keith Grimwood, Paul J Torzillo, Paul A Bauert, I Brent Masters, Abbey Diaz, Gabrielle B McCallum, Charmaine Mobberley, Irene Tjhung, Kim M Hare, Robert S Ware, Anne B Chang
Journal: The Lancet Respiratory Medicine (2013)
New Strategies in Myelodysplastic Syndromes: Application of Molecular Diagnostics to Clinical Practice
Authors: Zuzana Tothova, David P. Steensma, Benjamin L. Ebert
Journal: Clinical Cancer Research (2013)

An increasingly complete compendium of recurrently mutated genes in myelodysplastic syndromes (MDS) has been defined, and the application of massively parallel sequencing to identify mutations in clinical practice now promises to improve the care of patients with this disease. More than 25 recurrent MDS-associated somatic mutations have been identified, involving biologic pathways as diverse as chromatin remodeling and pre-mRNA splicing. Several of these mutations have been shown to have prognostic implications that are independent of existing risk stratification systems based on clinical and pathologic parameters. Application of these recent discoveries to diagnosis, prognosis, risk stratification, and treatment selection for patients with MDS has the potential to improve patient outcomes. Here, we review recent advances in MDS and discuss potential applications of these discoveries to clinical practice.
Selective inhibition of HER2 inhibits AKT signal transduction and prolongs disease-free survival in a micrometastasis model of ovarian carcinoma
Authors: J.P. Delord, C. Allal, M. Canal, E. Mery, P. Rochaix, I. Hennebelle, A. Pradines, E. Chatelut, R. Bugat, S. Guichard, P. Canal
Journal: Annals of Oncology (2005)
The Relationship between Prostate-Specific Antigen and Prostate Cancer Risk: The Prostate Biopsy Collaborative Group
Authors: Andrew J. Vickers, Angel M. Cronin, Monique J. Roobol, Jonas Hugosson, J. Stephen Jones, Michael W. Kattan, Eric Klein, Freddie Hamdy, David Neal, Jenny Donovan, Dipen J. Parekh, Donna Ankerst, George Bartsch, Helmut Klocker, Wolfgang Horninger, Amine Benchikh, Gilles Salama, Arnauld Villers, Steve J. Freedland, Daniel M. Moreira, Fritz H. Schröder, Hans Lilja
Journal: Clinical Cancer Research (2010)

The relationship between prostate-specific antigen (PSA) level and prostate cancer risk remains subject to fundamental disagreements. We hypothesized that the risk of prostate cancer on biopsy for a given PSA level is affected by identifiable characteristics of the cohort under study.We used data from five European and three U.S. cohorts of men undergoing biopsy for prostate cancer; six were population-based studies and two were clinical cohorts. The association between PSA and prostate cancer was calculated separately for each cohort using locally weighted scatterplot smoothing.The final data set included 25,772 biopsies and 8,503 cancers. There were gross disparities between cohorts with respect to both the prostate cancer risk at a given PSA level and the shape of the risk curve. These disparities were associated with identifiable differences between cohorts: for a given PSA level, a greater number of biopsy cores increased the risk of cancer (odds ratio for >6- versus 6-core biopsy, 1.35; 95% confidence interval, 1.18-1.54; P < 0.0005); recent screening led to a smaller increase in risk per unit change in PSA (P = 0.001 for interaction term) and U.S. cohorts had higher risk than the European cohorts (2.14; 95% confidence interval, 1.99-2.30; P < 0.0005).Our results suggest that the relationship between PSA and risk of a positive prostate biopsy varies, both in terms of the probability of prostate cancer at a given PSA value and the shape of the risk curve. This poses challenges to the use of PSA-driven algorithms to determine whether biopsy is indicated.
CAV1 Inhibits Metastatic Potential in Melanomas through Suppression of the Integrin/Src/FAK Signaling Pathway
Authors: Casey Trimmer, Diana Whitaker-Menezes, Gloria Bonuccelli, Janet N. Milliman, Kristin M. Daumer, Andrew E. Aplin, Richard G. Pestell, Federica Sotgia, Michael P. Lisanti, Franco Capozza
Journal: Cancer Research (2010)

Abstract Caveolin-1 (CAV1) is the main structural component of caveolae, which are plasma membrane invaginations that participate in vesicular trafficking and signal transduction events. Although evidence describing the function of CAV1 in several cancer types has recently accumulated, its role in melanoma tumor formation and progression remains poorly explored. Here, by using B16F10 melanoma cells as an experimental system, we directly explore the function of CAV1 in melanoma tumor growth and metastasis. We first show that CAV1 expression promotes proliferation, whereas it suppresses migration and invasion of B16F10 cells in vitro. When orthotopically implanted in the skin of mice, B16F10 cells expressing CAV1 form tumors that are similar in size to their control counterparts. An experimental metastasis assay shows that CAV1 expression suppresses the ability of B16F10 cells to form lung metastases in C57Bl/6 syngeneic mice. Additionally, CAV1 protein and mRNA levels are found to be significantly reduced in human metastatic melanoma cell lines and human tissue from metastatic lesions. Finally, we show that following integrin activation, B16F10 cells expressing CAV1 display reduced expression levels and activity of FAK and Src proteins. Furthermore, CAV1 expression markedly reduces the expression of integrin β3 in B16F10 melanoma cells. In summary, our findings provide experimental evidence that CAV1 may function as an antimetastatic gene in malignant melanoma. Cancer Res; 70(19); 7489–99. ©2010 AACR.
Persistent disruption of ciliated epithelium following paediatric lung transplantation
Authors: Biju Thomas, Paul Aurora, Helen Spencer, Martin Elliott, Andrew Rutman, Robert A. Hirst, Christopher O'Callaghan
Journal: European Respiratory Journal (2012)

It is unclear whether ciliary function following lung transplantation is normal or not. Our aim was to study the ciliary function and ultrastructure of epithelium above and below the airway anastomosis and the peripheral airway of children following lung transplantation. We studied the ciliary beat frequency (CBF) and beat pattern, using high speed digital video imaging and ultrastructure by transmission electron microscopy, of bronchial epithelium from above and below the airway anastomosis and the peripheral airway of 10 cystic fibrosis (CF) and 10 non-suppurative lung disease (NSLD) paediatric lung transplant recipients. Compared to epithelium below the anastomosis, the epithelium above the anastomosis in the CF group showed reduced CBF (median (interquartile range): 10.5 (9.0–11.4) Hz versus 7.4 (6.4–9.2) Hz; p&lt;0.01) and increased dyskinesia (median (IQR): 16.5 (12.9–28.2)% versus 42.2 (32.6–56.4)%; p&lt;0.01). In both CF and NSLD groups, compared with epithelium above the anastomosis, the epithelium below the anastomosis showed marked ultrastructural abnormalities (median duration post-transplant 7–12 months). Ciliary dysfunction is a feature of native airway epithelium in paediatric CF lung transplant recipients. The epithelium below the airway anastomosis shows profound ultrastructural abnormalities in both CF and NSLD lung transplant recipients, many months after transplantation.