tbuckley/cabot-search huggingface dataset:
Unraveling the Role of KIAA1199, a Novel Endoplasmic Reticulum Protein, in Cancer Cell Migration
Authors: Nikki A. Evensen, Cem Kuscu, Hoang-Lan Nguyen, Kevin Zarrabi, Antoine Dufour, Pournima Kadam, You-jun Hu, Ashleigh Pulkoski-Gross, Wadie F. Bahou, Stanley Zucker, Jian Cao
Journal: JNCI Journal of the National Cancer Institute (2013)

Cell migration is a critical determinant of cancer metastasis, and a better understanding of the genes involved will lead to the identification of novel targets aimed at preventing cancer dissemination. KIAA1199 has been shown to be upregulated in human cancers, yet its role in cancer progression was hitherto unknown.Clinical relevance was assessed by examining KIAA1199 expression in human cancer specimens. In vitro and in vivo studies were employed to determine the function of KIAA1199 in cancer progression. Cellular localization of KIAA1199 was microscopically determined. SNAP-tag pull-down assays were used to identify binding partner(s) of KIAA1199. Calcium levels were evaluated using spectrofluorometric and fluorescence resonance energy transfer analyses. Signaling pathways were dissected by Western blotting. Student t test was used to assess differences. All statistical tests were two-sided.KIAA1199 was upregulated in invasive breast cancer specimens and inversely associated with patient survival rate. Silencing of KIAA1199 in MDA-MB-435 cancer cells resulted in a mesenchymal-to-epithelial transition that reduced cell migratory ability in vitro (75% reduction; P < .001) and decreased metastasis in vivo (80% reduction; P < .001). Gain-of-function assays further demonstrated the role of KIAA1199 in cell migration. KIAA1199-enhanced cell migration required endoplasmic reticulum (ER) localization, where it forms a stable complex with the chaperone binding immunoglobulin protein (BiP). A novel ER-retention motif within KIAA1199 that is required for its ER localization, BiP interaction, and enhanced cell migration was identified. Mechanistically, KIAA1199 was found to mediate ER calcium leakage, and the resultant increase in cytosolic calcium ultimately led to protein kinase C alpha activation and cell migration.KIAA1199 serves as a novel cell migration-promoting gene and plays a critical role in maintaining cancer mesenchymal status.
Systems Toxicology and the Chemical Effects in Biological Systems (CEBS) Knowledge Base
Authors: M Waters
Journal: Environmental Health Perspectives (2003)

The National Center for Toxicogenomics is developing the first public toxicogenomics knowledge base that combines molecular expression data sets from transcriptomics, proteomics, metabonomics, and conventional toxicology with metabolic, toxicologcal pathway, and gene regulatory network information relevant to environmental toxicology and human disease. It is called the Chemical Effects in Biological Systems (CEBS) knowledge base and is designed to meet the information needs of "systems toxicology," involving the study of perturbation by chemicals and stressors, monitoring changes in molecular expression and conventional toxicological parameters, and iteratively integrating biological response data to describe the functioning organism. Based upon functional genomics approaches used successfully in analyzing yeast gene expression data sets, relational and descriptive compendia will be assembled for toxicologically important genes, groups of genes, single nucleotide polymorphisms (SNPs), and mutant and knockout phenotypes. CEBS data sets will be fully documented in the experimental protocol and therefore searchable by compound, structure, toxicity end point, pathology and point, gene, gene group, SNP, pathway, and network as a function of dose, time, and the phenotype of the target tissue. A knowledge base is being developed by assimilating toxicological, biological, and chemical information from multiple public domain databases and by progressively refining that information about gene, protein, and metabolite expression for classes of chemicals and their biological effects in various species. By analogy to the GenBank database for genome sequences, researchers will globally query (or BLAST) CEBS using a transcriptome of a tissue of interest (or a list of outliers) to have the knowledge base return information on genes, groups of genes, metabolic and toxicological pathways, and contextually associated phenotypic information for compounds that display similar response profiles. With high-quality data content, CEBS will ultimately become a resource to support hypothesis-driven and discovery research that contributes effectively to drug safety and the improvement of risk assessments for chemicals in the environment. The CEBS development effort will span a decade or more.
Is eye contact the key to the social brain?
Authors: Atsushi Senju, Mark H. Johnson
Journal: Behavioral and Brain Sciences (2010)

Abstract Eye contact plays a critical role in many aspects of face processing, including the processing of smiles. We propose that this is achieved by a subcortical route, which is activated by eye contact and modulates the cortical areas involve in social cognition, including the processing of facial expression. This mechanism could be impaired in individuals with autism spectrum disorders.
Sleep Disturbance and Risk for Alcohol-Related Problems
Authors: Rosa M. Crum, Carla L. Storr, Ya-Fen Chan, Daniel E. Ford
Journal: American Journal of Psychiatry (2004)

OBJECTIVE: Using prospective data, the authors assessed the risk of alcohol-related problems among individuals with self-reported sleep disturbances because of worry. METHOD: As part of the Epidemiologic Catchment Area program, a probability sample of Baltimore residents selected by census tracts and households completed a baseline interview in 1981. Between 1993 and 1996, the original Baltimore cohort was traced. Of the 2,633 survivors, a total of 73% were reinterviewed. After excluding individuals with alcohol-related problems or a current or prior history of alcohol abuse and/or dependence at the time of the 1981 interview, the authors identified a cohort of 1,537 individuals who were at risk for problem drinking at the time of the follow-up interview, a median of 12.6 years after the baseline interview. Logistic regression was used to assess the association between sleep disturbance because of worry and the risk for incident reports of alcohol problems. RESULTS: Survey respondents with sleep disturbances because of worry at the time of the baseline interview had a twofold higher risk for developing an alcohol-related problem, relative to those without these sleep disturbances (odds ratio=2.32, 95% confidence interval [CI]=1.31–4.09), with adjustment for selected demographic and clinical variables. Sleep disturbance because of worry predicted the development of alcohol problems among respondents with lifetime anxiety disorders and lifetime dysphoria (odds ratio=3.82, 95% CI=1.56–9.38, and odds ratio=2.71, 95% CI=1.25–5.91, respectively), but not among those without a history of anxiety disorders or dysphoria. CONCLUSIONS: Sleep disturbances because of worry may increase risk for alcohol-related problems. Risk is highest for those with sleep disturbance and co-occurring anxiety disorders or dysphoria.
Metabolic Adaptation after Whole Genome Duplication
Authors: M. J. A. van Hoek, P. Hogeweg
Journal: Molecular Biology and Evolution (2009)

Whole genome duplications (WGDs) have been hypothesized to be responsible for major transitions in evolution. However, the effects of WGD and subsequent gene loss on cellular behavior and metabolism are still poorly understood. Here we develop a genome scale evolutionary model to study the dynamics of gene loss and metabolic adaptation after WGD. Using the metabolic network of Saccharomyces cerevisiae as an example, we primarily study the outcome of WGD on yeast as it currently is. However, similar results were obtained using a recontructed hypothetical metabolic network of the pre-WGD ancestor. We show that the retention of genes in duplicate in the model, corresponds nicely with those retained in duplicate after the ancestral WGD in S. cerevisiae. Also, we observe that transporter and glycolytic genes have a higher probability to be retained in duplicate after WGD and subsequent gene loss, both in the model as in S. cerevisiae, which leads to an increase in glycolytic flux after WGD. Furthermore, the model shows that WGD leads to better adaptation than small-scale duplications, in environments for which duplication of a whole pathway instead of single reactions is needed to increase fitness. This is indeed the case for adaptation to high glucose levels. Thus, our model confirms the hypothesis that WGD has been important in the adaptation of yeast to the new, glucose-rich environment that arose after the appearance of angiosperms. Moreover, the model shows that WGD is almost always detrimental on the short term in environments to which the lineage is preadapted, but can have immediate fitness benefits in "new" environments. This explains why WGD, while pivotal in the evolution of many lineages and an apparent "easy" genetic operator, occurs relatively rarely.
Oxygen Supply and Stability of Chromosomes in Mouse Embryo Cells &lt;italic&gt;In Vitro&lt;/italic&gt;&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: Ram Parshad, Katherine K. Sanford
Journal: JNCI Journal of the National Cancer Institute (1971)

Journal Article Oxygen Supply and Stability of Chromosomes in Mouse Embryo Cells In Vitro Get access Ram Parshad, Ram Parshad Laboratory of Biology, National Cancer Institut4, Bethesda, Maryland 20014 Search for other works by this author on: Oxford Academic PubMed Google Scholar Katherine K. Sanford Katherine K. Sanford Laboratory of Biology, National Cancer Institut4, Bethesda, Maryland 20014 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 47, Issue 5, November 1971, Pages 1033–1036, https://doi.org/10.1093/jnci/47.5.1033 Published: 01 November 1971 Article history Received: 05 May 1971 Accepted: 26 July 1971 Published: 01 November 1971
Sphingosine Kinase Modulates Microvascular Tone and Myogenic Responses Through Activation of RhoA/Rho Kinase
Authors: Steffen-Sebastian Bolz, Lukas Vogel, Daniel Sollinger, Roland Derwand, Christa Boer, Stuart M. Pitson, Sarah Spiegel, Ulrich Pohl
Journal: Circulation (2003)

RhoA and Rho kinase are important modulators of microvascular tone.We tested whether sphingosine kinase (Sphk1) that generates the endogenous sphingolipid mediator sphingosine-1-phosphate (S1P) is part of a signaling cascade to activate the RhoA/Rho kinase pathway. Using a new transfection model, we report that resting tone and myogenic responses of isolated resistance arteries increased with forced expression of Sphk1 in smooth muscle cells of these arteries. Overexpression of a dominant negative Sphk1 mutant or coexpression of dominant negative mutants of RhoA or Rho kinase together with Sphk1 completely inhibited development of tone and myogenic responses.The tone-increasing effects of a Sphk1 overexpression suggest that Sphk1 may play an important role in the control of peripheral resistance.
The role of free radical-mediated processes in oxygen-related damage in cultured murine myocardial cells.
Authors: J A Scott, B A Khaw, E Locke, E Haber, C Homcy
Journal: Circulation Research (1985)

A new approach to quantifying myocyte cell death utilizing fluorescence-activated sorting of antimyosin antibody-labeled cells was used to study the effects of oxygen-generated free radicals on cell survival. Uptake of antimyosin, reflecting sarcolemmal damage, increased under conditions which promoted elevated free radical formation and decreased in the presence of increased levels of free radical-scavenging agents. Superoxide dismutase decreased antimyosin uptake at pH 6.7 and 7.5. Mannitol decreased antimyosin uptake at pH 6.5 and 6.7 but not at pH 7.5, and dimethyl sulfoxide decreased antimyosin uptake at pH 6.4 but not at pH 7.5. These data suggest that a greater portion of hydroxyl radicals are produced at higher concentrations of hydrogen ion. Mannitol, a scavenger of hydroxyl radicals, was effective in reducing antimyosin uptake at pH 7.5 in the presence of ferrous sulfate, but had no effect on antimyosin uptake in the absence of ferrous sulfate, suggesting possible iron-mediated catalysis of hydroxyl radical formation. The data suggest that oxygen-derived free radicals can cause significant loss of membrane integrity in cultured myocytes, that the species of radical formed is dependent both on pH and the concentration of iron salts, and that this injury is, at least in part, preventable by the administration of exogenous radical scavenging agents.
Mutations in transcriptional regulator ATRX establish the functional significance of a PHD-like domain
Authors: Richard J. Gibbons, Satvinder Bachoo, David J. Picketts, Salim Aftimos, Bernhard Asenbauer, JoAnn Bergoffen, Susan A. Berry, Niklas Dahl, Alan Fryer, Kim Keppler, Kenji Kurosawa, Michael L. Levin, Mitsuo Masuno, Giovanni Neri, Mary Ella Pierpont, Sarah F. Slaney, Douglas R. Higgs
Journal: Nature Genetics (1997)
Prognostic factors in lung cancer: tables and comments
Authors: G Buccheri, D Ferrigno
Journal: European Respiratory Journal (1994)

Prognostic factors (PF) have a pivotal role in Clinical Oncology. They are helpful in the selection of treatment, provide insights into the disease process and the therapeutic response, and are fundamental in the design of clinical trials or in the interpretation of data from the literature. The number of possibly useful PFs in lung cancer is large (certainly more than one hundred). This paper attempts to provide a comprehensive listing of PFs and other variables potentially associated with outcome of lung cancer. This is achieved using tables, where studies relevant to each PF are referenced in relationship to their results, statistical power, type of analysis, number of variables incorporated in multivariate tests, and cell type. Tables include the outcome of an extensive retrieval of the literature and indicate visually where much of the evidence resides for the contribution of a variable to prognosis. Each table is briefly discussed and systematically comprises one group of PFs. Among the many pinpointed, the best predictive models still belong to studies based on clinical and routine laboratory data. Recent researches have clarified the role of new PFs (such as the biological factors); others (e.g. quality of life measures, the serum content of acute phase reaction proteins or the pathological evidence of tumour neoangiogenesis) might be recognized as important in the future. Like infinity, the fate of the individual patient will never become a completely measurable entity. However, as the discovery of new PFs proceeds, the assessment of the future prospects for patients is becoming more reliable.
Dlgh1 coordinates actin polymerization, synaptic T cell receptor and lipid raft aggregation, and effector function in T cells
Authors: June L. Round, Tamar Tomassian, Min Zhang, Viresh Patel, Stephen P. Schoenberger, M. Carrie Miceli
Journal: The Journal of Experimental Medicine (2005)

Lipid raft membrane compartmentalization and membrane-associated guanylate kinase (MAGUK) family molecular scaffolds function in establishing cell polarity and organizing signal transducers within epithelial cell junctions and neuronal synapses. Here, we elucidate a role for the MAGUK protein, Dlgh1, in polarized T cell synapse assembly and T cell function. We find that Dlgh1 translocates to the immune synapse and lipid rafts in response to T cell receptor (TCR)/CD28 engagement and that LckSH3-mediated interactions with Dlgh1 control its membrane targeting. TCR/CD28 engagement induces the formation of endogenous Lck–Dlgh1–Zap70–Wiskott-Aldrich syndrome protein (WASp) complexes in which Dlgh1 acts to facilitate interactions of Lck with Zap70 and WASp. Using small interfering RNA and overexpression approaches, we show that Dlgh1 promotes antigen-induced actin polymerization, synaptic raft and TCR clustering, nuclear factor of activated T cell activity, and cytokine production. We propose that Dlgh1 coordinates TCR/CD28-induced actin-driven T cell synapse assembly, signal transduction, and effector function. These findings highlight common molecular strategies used to regulate cell polarity, synapse assembly, and transducer organization in diverse cellular systems.
Adenosine A1 receptors mediate local anti-nociceptive effects of acupuncture
Authors: Nanna Goldman, Michael Chen, Takumi Fujita, Qiwu Xu, Weiguo Peng, Wei Liu, Tina K Jensen, Yong Pei, Fushun Wang, Xiaoning Han, Jiang-Fan Chen, Jurgen Schnermann, Takahiro Takano, Lane Bekar, Kim Tieu, Maiken Nedergaard
Journal: Nature Neuroscience (2010)
Acceleration of the gastrointestinal transit by polyethylene glycol effectively treats unconjugated hyperbilirubinaemia in Gunn rats
Authors: F. J. C. Cuperus, A. A. Iemhoff, M. van der Wulp, R. Havinga, H. J. Verkade
Journal: Gut (2009)

Several conditions that delay gastrointestinal transit are associated with unconjugated hyperbilirubinaemia. We hypothesised that the gastrointestinal transit time is directly related to plasma unconjugated bilirubin (UCB) concentrations, and that this relationship can be used to develop a new therapeutic strategy for severe unconjugated hyperbilirubinaemia in the Gunn rat model.Gunn rats received, for various time periods, oral polyethylene glycol (PEG) with or without conventional phototherapy treatment to accelerate, or oral loperamide to delay gastrointestinal transit. Gastrointestinal transit time and UCB concentrations in plasma, faeces, intestinal content and bile were determined. Results Within 36 h, PEG administration accelerated gastrointestinal transit by 45% and simultaneously decreased plasma UCB concentrations by 23% (each p<0.001). The decrease in plasma UCB coincided with an increased small intestinal UCB content (+340%, p<0.05) and an increased faecal UCB excretion (+153%, p<0.05). After 2 weeks, PEG decreased plasma UCB by 41% as single treatment, and by 62% if combined with phototherapy (each p<0.001). Loperamide delayed gastrointestinal transit by 57% and increased plasma UCB by 30% (each p<0.001). Dose-response experiments showed a strong, linear relation between the gastrointestinal transit time and plasma UCB concentrations (r=0.87, p<0.001).Gastrointestinal transit time and plasma UCB concentrations are linearly related in Gunn rats. This relationship can be exploited by pharmacologically accelerating the gastrointestinal transit, which increases transmucosal UCB diffusion and thereby effectively treats unconjugated hyperbilirubinaemia. Present results support the feasibility of PEG treatment, either solitary or combined with phototherapy, in patients with severe unconjugated hyperbilirubinaemia.
Abstract 362: [18F]-FLT Positron Emission Tomography can be used to image the response of sensitive tumours to PI3-Kinase inhibition with the novel agent GDC-0941.
Authors: Christopher Cawthorne, Ian A. Wilson, Antonios Danikas, Natalie Burrows, Mark Radigois, Jamil Gregory, Alison Smigova, Muhammed Babar, Kaye J. Williams
Journal: Cancer Research (2012)

Abstract Emerging targeted therapeutics are characterised by high efficacy rates in selected patient sub-populations as well as potentially high running costs. This calls for companion diagnostic tools that contribute to the better management of such therapies, in terms of patient selection and monitoring therapeutic response. The Phosphatidylinositide 3-kinase pathway is deregulated in a range of cancers, and several targeted inhibitors are entering the clinic. This study aimed to investigate whether the PET tracer [18F]-FLT is suitable to mark the effect of the novel PI-3K inhibitor GDC-0941 which has entered Phase II clinical trial. Methods Nude mice bearing U87 and HCT116 xenografts were imaged at baseline with [18F]-FLT (10-15MBq per mouse produced using a GE Tracerlab). GDC-0941 or vehicle was then administered at a concentration of 50mg/kg twice daily by gavage and animals were rescanned at acute (∼18h) and chronic (∼186h) timepoints post-therapy. Standard uptake value (SUV)s for tumour uptake were calculated, and tissue was analysed at sacrifice for phospho-AKT. To generate normalised uptake values (NUV)s the SUV [tumour] was divided by the SUV for heart. NUV figures are given for the 100-105min post-injection time interval. Results Growth of U87 xenografts was significantly inhibited by GDC-0941 treatment throughout the course of the study (average growth rate of treated = –1.0±9.3 mm3, control = 69.2±22.1mm3 per day). Growth of HCT116 xenografts was not significantly different between groups (average growth rate of treated = 34.6±15.9 mm3, control =54.8±11.1 mm3 per day). Tumour uptake of [18F]-FLT was significantly reduced in treated animals bearing U87 xenografts at the acute timepoint compared to baseline (NUVmax 2.17 ± 0.38 vs 1.59 ± 0.29, p&amp;lt;0.01), whereas uptake in HCT116 tumours was unchanged. Analysis of the downstream marker phospho-AKT showed that this was decreased in U87, but not HCT116, tumours. Conclusion [18F]-FLT is a strong candidate for the non-invasive measurement of GDC-0941 action. In addition to FLT, we are assessing the performance of a range of other imaging agents, including proprietary tracers, that can potentially bring value in monitoring of PI3-kinase targeting therapies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 362. doi:1538-7445.AM2012-362
Endothelin A receptor blockade alleviates hypertension and renal lesions associated with chronic nitric oxide synthase inhibition.
Authors: A M Verhagen, T J Rabelink, B Braam, T J Opgenorth, H J Gröne, H A Koomans, J A Joles
Journal: Journal of the American Society of Nephrology (1998)

Unopposed actions of vasoconstrictors, such as angiotensin, play an important role in the effects of chronic nitric oxide synthase (NOS) inhibition. In this study, it is hypothesized that endothelin (ET), another important vasoconstrictor, may also play a role in the development of hypertension and renal lesions during chronic NOS inhibition. The ET(A) receptor was blocked with A-127722 during chronic NOS inhibition with Nomega-nitro-L-arginine (L-NNA), a potent NOS inhibitor without antimuscarinic action. Male Sprague Dawley rats were treated for 3 wk with L-NNA (40 mg/kg per d), L-NNA (40 mg/kg per d) + A-127722 (30 mg/kg per d), or remained untreated (control). In preliminary experiments, L-NNA (40 mg/kg per d) had been found to cause the maximum increase of systolic BP and a 35% decrease in renal NOS activity. Three weeks of L-NNA treatment resulted in a marked rise in systolic BP (240+/-4 versus control 151+/-7 mmHg; P < 0.01), proteinuria (209+/-46 versus control 27+/-3 mg/d; P < 0.01), and a fall in GFR (1.41+/-0.16 versus control 2.23+/-0.19 ml/min; P < 0.05). Renal morphology showed severe vascular injury, characterized by focal adhesion and infiltration of mononuclear cells into the intima and media of preglomerular arteries and arterioles. This was sometimes associated with necrosis of the media and partial or total obstruction of the lumen with thrombotic material. Ischemic glomeruli were also present. Tubulointerstitial damage was moderate and accompanied by an influx of monocytes and macrophages. A-127722 administered simultaneously with L-NNA completely prevented the increase in proteinuria (39+/-8 mg/d) and glomerular ischemia. Vascular injury, tubulointerstitial damage, and the increase in systolic BP (191+/-6 mmHg) were partially prevented. The protective effects of ET(A) receptor blockade suggest that ET has hemodynamic as well as nonhemodynamic effects in the cascade of events following chronic NOS inhibition.