tbuckley/cabot-search huggingface dataset:
Predictive Biomarkers of Sensitivity to the Phosphatidylinositol 3′ Kinase Inhibitor GDC-0941 in Breast Cancer Preclinical Models
Authors: Carol O'Brien, Jeffrey J. Wallin, Deepak Sampath, Debraj GuhaThakurta, Heidi Savage, Elizabeth A. Punnoose, Jane Guan, Leanne Berry, Wei Wei Prior, Lukas C. Amler, Marcia Belvin, Lori S. Friedman, Mark R. Lackner
Journal: Clinical Cancer Research (2010)

Abstract Purpose: The class I phosphatidylinositol 3′ kinase (PI3K) plays a major role in proliferation and survival in a wide variety of human cancers. A key factor in successful development of drugs targeting this pathway is likely to be the identification of responsive patient populations with predictive diagnostic biomarkers. This study sought to identify candidate biomarkers of response to the selective PI3K inhibitor GDC-0941. Experimental Design: We used a large panel of breast cancer cell lines and in vivo xenograft models to identify candidate predictive biomarkers for a selective inhibitor of class I PI3K that is currently in clinical development. The approach involved pharmacogenomic profiling as well as analysis of gene expression data sets from cells profiled at baseline or after GDC-0941 treatment. Results: We found that models harboring mutations in PIK3CA, amplification of human epidermal growth factor receptor 2, or dual alterations in two pathway components were exquisitely sensitive to the antitumor effects of GDC-0941. We found that several models that do not harbor these alterations also showed sensitivity, suggesting a need for additional diagnostic markers. Gene expression studies identified a collection of genes whose expression was associated with in vitro sensitivity to GDC-0941, and expression of a subset of these genes was found to be intimately linked to signaling through the pathway. Conclusion: Pathway focused biomarkers and the gene expression signature described in this study may have utility in the identification of patients likely to benefit from therapy with a selective PI3K inhibitor. Clin Cancer Res; 16(14); 3670–83. ©2010 AACR.
Genetic susceptibility according to three metabolic pathways in cancers of the lung and bladder and in myeloid leukemias in nonsmokers
Authors: P. Vineis, F. Veglia, S. Garte, C. Malaveille, G. Matullo, A. Dunning, M. Peluso, L. Airoldi, K. Overvad, O. Raaschou-Nielsen, F. Clavel-Chapelon, J.P. Linseisen, R. Kaaks, H. Boeing, A. Trichopoulou, D. Palli, P. Crosignani, R. Tumino, S. Panico, H.B. Bueno-De-Mesquita, P.H. Peeters, E. Lund, C.A. Gonzalez, C. Martinez, M. Dorronsoro, A. Barricarte, C. Navarro, J.R. Quiros, G. Berglund, B. Jarvholm, N.E. Day, T.J. Key, R. Saracci, E. Riboli, H. Autrup
Journal: Annals of Oncology (2007)
PWE-145 Characterisation Of Circulating And Liver Infiltrating Mait Cells In Human Inflammatory Liver Diseases
Authors: K Parekh, H Jeffery, J Shaw, T Iqbal, DH Adams, YH Oo
Journal: Gut (2014)

<h3>Introduction</h3> Mucosal-Associated Invariant T (MAIT) cells are characterised by expression of the semi-invariant TCR α-chain Vα7.2-Jα33 and high expression of CD161 and shown to play a role at mucosal barriers. They display a limited T cell receptor repertoire being restricted by the MHC class 1-related molecule, MR1 but secrete high levels of pro-inflammatory cytokines suggesting they may play an important role in liver inflammation. We have shown before that the majority of MAIT cells in circulation are CD8<sup>+</sup> MAIT cells. Recently, presence of MIAT cells have been described within human liver perfusate. However, very little is known about the phenotype and functions of liver infiltrating MAIT cells. In this study we investigated the frequencies and phenotypes of human liver infiltrating MAIT cells in healthy donors and diseased livers. <h3>Methods</h3> Peripheral blood and explanted liver infiltrating lymphocytes were freshly isolated and phenotyped by multicolour flow cytometry. The MAIT population was defined as CD3<sup>+</sup>CD16<sup>Hi </sup>Va7.2<sup>+</sup>. <h3>Results</h3> There was no difference in frequencies of circulating CD3<sup>Pos</sup>CD161<sup>Hi</sup>Va7.2<sup>Pos</sup> MAIT cells between patients with inflammatory liver disease and healthy controls (1.4 ± 0.7% vs. 2.3 ± 1.0%) and the majority were CD8<sup>Pos</sup> (82.3 ± 3.1%) with a smaller population of CD4<sup>Pos</sup> (2.7 ± 0.6%) and double negative CD8<sup>Neg</sup>CD4<sup>Neg</sup> cells (14.8 ± 2.9%). Total CD3<sup>Pos</sup>CD161<sup>Hi</sup>Va7.2<sup>Pos</sup> MAIT frequencies were not significantly altered in inflamed liver tissue compared to blood (4.4 ± 1.0% vs. 1.4 ± 0.7%). However, in the inflamed liver, the CD8<sup>+</sup> subset was reduced (61.2 ± 6.2 vs. 82.3 ± 3.1, P = 0.006) while the CD4<sup>+</sup> MAIT subset was increased (15.9 ± 5.6 vs. 2.7 ± 0.6, P = 0.02). CXCR3, liver homing chemokine receptor was highly enriched on circulating and liver infiltrating CD3<sup>Pos</sup>CD161<sup>Hi</sup>Va7.2<sup>Pos</sup> MAIT cells (&gt;75%). Liver infiltrating MAIT cells expressed chemokine receptors CCR5 (78.4 ± 7.2), CX3CR1 (51.3 ± 10), CCR6 (46.3 ± 14.8) and CXCR6 (36 ± 6.2%). Interestingly they expressed high levels of the integrin β7 (39.1 ± 3.6) and CD103 (19.6 ± 5.5%), which are associated with mucosal immune responses. They also expressed the cytokine receptors IL23R (27.1 ± 8.5%) and IL18Rα (76.7 ± 5%). <h3>Conclusion</h3> We have described for the first time that CD3<sup>Pos</sup>CD161<sup>Hi</sup>Va7.2<sup>Pos</sup> MAIT cells are present in inflamed human liver and express high levels of CXCR3 receptor implicated in lymphocyte recruitment to the liver and three other chemokine receptors CX3CR1 and CCR6 and CXCR6 that are associated with homing to portal tracts and bile ducts. Thus MAIT cells may play a role in biliary pathology. <h3>Disclosure of Interest</h3> None Declared.
Chemerin reveals its chimeric nature
Authors: Teizo Yoshimura, Joost J. Oppenheim
Journal: The Journal of Experimental Medicine (2008)

Chemerin is a proinflammatory plasma protein that binds to the GPCR ChemR23/CMKLR1 on macrophages and plasmacytoid dendritic cells, and promotes chemotaxis. An orphan GPCR, CCRL2, has now been identified as an additional receptor for chemerin, providing a unique mechanism by which chemerin enhances inflammation. Furthermore, because recent data shows that chemerin-derived peptides possess antiinflammatory properties, chemerin may be involved in both the initiation and resolution of inflammation.
Phase I and Pharmacokinetic Study of Daily Oral AZD2171, an Inhibitor of Vascular Endothelial Growth Factor Tyrosine Kinases, in Combination With Carboplatin and Paclitaxel in Patients With Advanced Non–Small-Cell Lung Cancer: The National Cancer Institute of Canada Clinical Trials Group
Authors: Scott A. Laurie, Isabelle Gauthier, Andrew Arnold, Frances A. Shepherd, Peter M. Ellis, Eric Chen, Glenwood Goss, Jean Powers, Wendy Walsh, Dongsheng Tu, Jane Robertson, Thomas A. Puchalski, Lesley Seymour
Journal: Journal of Clinical Oncology (2008)

AZD2171 is a potent inhibitor of vascular endothelial growth factor receptors that showed broad antitumor activity in preclinical models. Doses of up to 45 mg/d of AZD2171 are tolerable when administered alone. This study evaluated escalating doses of AZD2171 in combination with standard chemotherapy in patients with advanced non-small-cell lung cancer.Eligible patients received carboplatin targeted to an area under the concentration time curve of 6 mg . min/mL and paclitaxel 200 mg/m(2), both on day 1 of a 3-week cycle; daily oral AZD2171 at either 30 mg or 45 mg commenced day 2 of cycle 1. Pharmacokinetics of all drugs were performed, and tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST).Twenty patients were enrolled. No dose-limiting toxicities were observed during cycle 1 at either dose. Fatigue, diarrhea, anorexia, and granulocytopenia were common; hypertension was manageable with a treatment algorithm designed for this protocol. No clinically significant drug-related bleeding was observed. At 45 mg/d, fatigue and diarrhea were increased, and headache and hoarseness were observed. Paclitaxel clearance decreased during cycle 2, but no other significant pharmacokinetic interactions were observed. After radiology review, confirmed responses were observed in nine patients (response rate, 45%; 95% CI, 23% to 68%); all but one enrolled patient showed evidence of tumor shrinkage, some with cavitation.AZD2171 can be combined with standard doses of carboplatin/paclitaxel with encouraging antitumor activity. Toxicity is increased, but predictable and manageable.
No (social) construction without (meta-)representation: Modular mechanisms as a basis for the capacity to acquire an understanding of mind
Authors: Tim P. German, Alan M. Leslie
Journal: Behavioral and Brain Sciences (2004)

Theories that propose a modular basis for developing a “theory of mind” have no problem accommodating social interaction or social environment factors into either the learning process, or into the genotypes underlying the growth of the neurocognitive modules. Instead, they can offer models which constrain and hence explain the mechanisms through which variations in social interaction affect development. Cognitive models of both competence and performance are critical to evaluating the basis of correlations between variations in social interaction and performance on mental state reasoning tasks.
Deoxycytidine Kinase Expression Underpins Response to Gemcitabine in Bladder Cancer
Authors: Martin Kerr, Helen E. Scott, Blaz Groselj, Michael R.L. Stratford, Katalin Karaszi, Naomi L. Sharma, Anne E. Kiltie
Journal: Clinical Cancer Research (2014)

In a recent phase II clinical trial, low-dose (100 mg/m(2)) gemcitabine showed promise as a radiosensitizer in bladder cancer, but underlying mechanisms lack elucidation. Here, we investigated the mechanism of radiosensitization by low-dose gemcitabine in bladder cancer cell lines.
A simple assessment of dyspnoea as a prognostic indicator in idiopathic pulmonary fibrosis
Authors: O. Nishiyama, H. Taniguchi, Y. Kondoh, T. Kimura, K. Kato, K. Kataoka, T. Ogawa, F. Watanabe, S. Arizono
Journal: European Respiratory Journal (2010)

The prognosis in idiopathic pulmonary fibrosis (IPF) is poor. No therapy has been shown to prolong survival. The objective of this study was to examine the prognostic significance of dyspnoea in daily living at baseline in IPF using a simple assessment tool. 93 consecutive patients with IPF, who had undergone evaluation at diagnosis, were included. The level of dyspnoea was assessed using the modified Medical Research Council (MRC) scale. The relationship between data at baseline and survival was examined. A univariate Cox proportional-hazard model showed that forced vital capacity % predicted (hazard ratio (HR) 0.965, 95% CI 0.948–0.982; p&lt;0.0001), diffusing capacity of the lung for carbon monoxide % predicted (HR 0.978, 95% CI 0.963–0.993; p = 0.0041), baseline arterial oxygen tension (HR 0.963, 95% CI 0.938–0.989; p = 0.0060) and modified MRC score (HR 2.402, 95% CI 1.495–3.858; p = 0.0003) were significantly predictive of survival. All variables of the 6-min walk test, including walk distance (HR 0.995, 95% CI 0.992–0.998; p = 0.0020), the lowest arterial oxygen saturation measured by pulse oximetry ( S p,O 2 ) (HR 0.944, 95% CI 0.918–0.972; p&lt;0.0001) and the Borg scale (HR 1.285, 95% CI 1.091–1.514; p = 0.0027), were also significant. With stepwise, multivariate Cox proportional analysis, the modified MRC score (HR 2.181, 95% CI 1.333–3.568; p = 0.0019) and the lowest S p,O 2 during the 6-min walk test (HR 0.952, 95% CI 0.924–0.981; p = 0.0014) were the most significant. Dyspnoea in daily living, assessed with the modified MRC scale at baseline, provides additional prognostic information for patients with IPF.
Expression of the c-raf Protooncogene, γ-Glutamyltranspeptidase, and Gap Junction Protein in Rat Liver Neoplasms
Authors: David G. Beer, Mark J. Neveu, David L. Paul, Ulf R. Rapp, Henry C. Pitot
Journal: Cancer Research (1988)

Abstract  Female Harlan Sprague-Dawley and F-344 rats were subjected to a 70% hepatectomy and 18 h later given one dose of 30 mg diethylnitrosamine/kg body weight. Beginning 1 week later, the animals were fed a diet containing 0.05% phenobarbital. Groups of rats were sacrificed 6 and 15 months later, and the livers were either frozen for cryostat sectioning or used to isolate RNA. Primary liver tumors present in these animals were used for RNA isolation, and a portion was taken for histopathological analysis. Eleven of 13 primary lesions, consisting of either neoplastic nodules or hepatocellular carcinomas, showed elevated levels of mRNA for the c- raf  protooncogene. Increased c- raf  mRNA in these tumors appeared to be unrelated to their cellular proliferative status inasmuch as the levels of c- raf  mRNA did not correlate with levels of H4 histone mRNA. Decreased expression of the major rat liver gap junction protein mRNA was observed in all of the primary tumors. Immunocytochemical analysis using an anti-gap junction antibody revealed a decrease in gap junction immunoreactivity in some but not all preneoplastic focal lesions. All preneoplastic foci having positive γ-glutamyltranspeptidase enzyme staining also exhibited a marked increase in γ-glutamyltranspeptidase mRNA as determined by  in situ  hybridization. The possible relation of alternations of the mRNA levels of c- raf  and the gap junction protein to the further development of preneoplastic foci is discussed.
Human respiratory mucins
Authors: G Lamblin, JP Aubert, JM Perini, A Klein, N Porchet, P Degand, P Roussel
Journal: European Respiratory Journal (1992)

Human respiratory mucins are secreted by goblet cells and mucous glands of the respiratory mucosa. They consist of a broad family of complex glycoproteins with different peptides, or apomucins, corresponding to several genes located on at least three different chromosomes. Glycosylation, the major posttranslational phenomenon, is responsible for about 70-80% of the weight of mucins: it produces an extraordinary diversity of O-glycosidically linked carbohydrate chains which are expressed as several hundreds of different chains in the mucins of a single individual. The variety of mucin peptides and the diversity of carbohydrate chains probably allows many interactions, especially with microorganisms: this may be an essential factor in the defence of the underlying respiratory mucosa.
Diurnal variation in airflow obstruction in chronic bronchitis.
Authors: K D Dawkins, M F Muers
Journal: Thorax (1981)

Twelve patients fulfilling strict criteria for chronic obstructive bronchitis recorded serial peak expiratory flow rates (PEFR) five times daily for a two-week period. Despite a 9.2% improvement in forced expiratory volume in one second (FEV1) with ipratropium bromide, and an 11.3% improvement with ipratropium bromide plus salbutamol, the inherent diurnal variation in PEFR while on no medication was greater than the improvement caused by either bronchodilator. In the group as a whole, the difference between the highest and the lowest daily PEFR over the two weeks was 24% of the mean daily value. Using cosinor analysis, 10 of the 12 patients showed a significant rhythm in PEFR with a computed mean amplitude between highest and lowest readings of 8.6% of the mean daily value. This is no greater than that found in normal subjects, but is considerably less than the variation in PEFR in patients with bronchial asthma.
BRCA1 Testing in Families With Hereditary Breast-Ovarian Cancer
Authors: Caryn Lerman
Journal: JAMA (1996)

To identify predictors of utilization of breast-ovarian cancer susceptibility (BRCA1 gene) testing and to evaluate outcomes of participation in a testing program.Prospective cohort study with baseline interview assessment of predictor variables (eg, sociodemographic factors, knowledge about hereditary cancer and genetic testing, perceptions of testing benefits, limitations, and risks). BRCA1 test results were offered after an education and counseling session in a research setting. Outcome variables (including depression, functional health status, and prophylactic surgery plans [follow-up only]) were assessed at baseline and 1-month follow-up interviews.Adult male and female members (n=279) of families with BRCA1-linked hereditary breast-ovarian cancer (HBOC).Of subjects who completed a baseline interview (n=192), 60% requested BRCA1 test results (43% of all study subjects requested results). Requests for results were more frequent for persons with health insurance (odds ration [OR], 3.74; 95% confidence interval [CI], 2.06-6.80); more first-degree relatives affected with breast cancer (OR, 1.59; 95% CI, 1.16-2.16); more knowledge about BRCA1 testing (OR, 1.85; 95% CI, 1.36-2.50); and indicating that test benefits are important (OR, 1.45; 95% CI, 1.13-1.86). At follow-up, noncarriers of BRCA1 mutations showed statistically significant reductions in depressive symptoms and functional impairment compared with carriers and nontested individuals. Individuals identified as mutation carriers did not exhibit increases in depression and functional impairment. Among unaffected women with no prior prophylactic surgery, 17% of carriers (2/12) intended to have mastectomies and 33% (4/12) to have oophorectomies.Only a subset of HBOC family members are likely to request BRCA1 testing when available. Rates of test use may be higher in persons of a higher socioeconomic status and those with more relatives affected with breast cancer. For some high-risk individuals who receive test results in a research setting that includes counseling, there may be psychological benefits. More research is needed to assess the generalizability of these results and evaluate the long-term consequences of BRCA1 testing.
Mitochondrial DNA transmission, replication and inheritance: a journey from the gamete through the embryo and into offspring and embryonic stem cells
Authors: J. C. St. John, J. Facucho-Oliveira, Y. Jiang, R. Kelly, R. Salah
Journal: Human Reproduction Update (2010)

Mitochondrial DNA (mtDNA) encodes key proteins associated with the process of oxidative phosphorylation. Defects to mtDNA cause severe disease phenotypes that can affect offspring survival. The aim of this review is to identify how mtDNA is replicated as it transits from the fertilized oocyte into the preimplantation embryo, the fetus and offspring. Approaches for deriving offspring and embryonic stem cells (ESCs) are analysed to determine their potential application for the prevention and treatment of mtDNA disease. The scientific literature was investigated to determine how mtDNA is transmitted, replicated and segregated during pluripotency, differentiation and development. It was also probed to understand how the mtDNA nucleoid is regulated in somatic cells. mtDNA replication is strictly down-regulated from the fertilized oocyte through the preimplantation embryo. At the blastocyst stage, the onset of mtDNA replication is specific to the trophectodermal cells. The inner cell mass cells restrict mtDNA replication until they receive the key signals to commit to specific cell types. However, it is necessary to determine whether somatic cells reprogrammed through somatic cell nuclear transfer, induced pluripotency or fusion to an ESC are able to regulate mtDNA replication so that they can be used for patient-specific cell therapies and to model disease. Prevention of the transmission of mtDNA disease from one generation to the next is still restricted by our lack of understanding as to how to ensure that a donor karyoplast transferred to an enucleated oocyte is free of accompanying mutant mtDNA. Techniques still need to be developed if stem cells are to be used to treat mtDNA disease in those patients already suffering from the phenotype.
Galectin-1(L11A) Predicted from a Computed Galectin-1 Farnesyl-Binding Pocket Selectively Inhibits Ras-GTP
Authors: Barak Rotblat, Hagit Niv, Sabine André, Herbert Kaltner, Hans-Joachim Gabius, Yoel Kloog
Journal: Cancer Research (2004)

Abstract Ras biological activity necessitates membrane anchorage that depends on the Ras farnesyl moiety and is strengthened by Ras/galectin-1 interactions. We identified a hydrophobic pocket in galectin-1, analogous to the Cdc42 geranylgeranyl-binding cavity in RhoGDI, possessing homologous isoprenoid-binding residues, including the critical L11, whose RhoGDI L77 homologue changes dramatically on Cdc42 binding. By substituting L11A, we obtained a dominant interfering galectin-1 that possessed normal carbohydrate-binding capacity but inhibited H-Ras GTP-loading and extracellular signal-regulated kinase activation, dislodged H-Ras(G12V) from the cell membrane, and attenuated H-Ras(G12V) fibroblast transformation and PC12-cell neurite outgrowth. Thus, independently of carbohydrate binding, galectin-1 cooperates with Ras, whereas galectin-1(L11A) inhibits it.
Secretory protein traffic. Chromogranin A contains a dominant targeting signal for the regulated pathway.
Authors: R J Parmer, X P Xi, H J Wu, L J Helman, L N Petz
Journal: Journal of Clinical Investigation (1993)

Secretory proteins are targeted into either constitutive (secreted upon synthesis) or regulated (stored in vesicles and released in response to a secretagogue) pathways. To investigate mechanisms of protein targeting into catecholamine storage vesicles (CSV), we stably expressed human chromogranin A (CgA), the major soluble protein in human CSV, in the rat pheochromocytoma PC-12 cell line. Chromaffin cell secretagogues (0.1 mM nicotinic cholinergic agonist, 55 mM K+, or 2 mM Ba++) caused cosecretion of human CgA and catecholamines from human CgA-expressing cells. Sucrose gradients colocalized human CgA and catecholamines to subcellular particles of the same buoyant density. Chimeric proteins, in which human CgA (either full-length [457 amino acids] or truncated [amino-terminal 226 amino acids]) was fused in-frame to the ordinarily nonsecreted protein chloramphenicol acetyltransferase (CAT), were expressed transiently in PC-12 cells. Both constructs directed CAT activity into regulated secretory vesicles, as judged by secretagogue-stimulated release. These data demonstrate that human CgA expressed in PC-12 cells is targeted to regulated secretory vesicles. In addition, human CgA can divert an ordinarily non-secreted protein into the regulated secretory pathway, consistent with the operation of a dominant targeting signal for the regulated pathway within the peptide sequence of CgA.