tbuckley/cabot-search huggingface dataset:
<i>FSTL5</i> Is a Marker of Poor Prognosis in Non-WNT/Non-SHH Medulloblastoma
Authors: Marc Remke, Thomas Hielscher, Andrey Korshunov, Paul A. Northcott, Sebastian Bender, Marcel Kool, Frank Westermann, Axel Benner, Huriye Cin, Marina Ryzhova, Dominik Sturm, Hendrik Witt, Daniel Haag, Grischa Toedt, Andrea Wittmann, Anna Schöttler, André O. von Bueren, Andreas von Deimling, Stefan Rutkowski, Wolfram Scheurlen, Andreas E. Kulozik, Michael D. Taylor, Peter Lichter, Stefan M. Pfister
Journal: Journal of Clinical Oncology (2011)

Integrated genomics approaches have revealed at least four distinct biologic variants of medulloblastoma: WNT (wingless), SHH (sonic hedgehog), group C, and group D. Because of the remarkable clinical heterogeneity of group D tumors and the dismal prognosis of group C patients, it is vital to identify molecular biomarkers that will allow early and effective treatment stratification in these non-WNT/non-SHH tumors.We combined transcriptome and DNA copy-number analyses for 64 primary medulloblastomas. Bioinformatic tools were used to discover marker genes of molecular variants. Differentially expressed transcripts were evaluated for prognostic value in the screening cohort. The prognostic power of follistatin-like 5 (FSTL5) immunopositivity was tested for 235 nonoverlapping medulloblastoma samples on two independent tissue microarrays.Comprehensive analyses of transcriptomic and genetic alterations delineate four distinct variants of medulloblastoma. Stable subgroup separation was achieved by using the 300 transcripts that varied the most. Distinct expression patterns of FSTL5 in each molecular subgroup were confirmed by quantitative real-time polymerase chain reaction. Immunopositivity of FSTL5 identified a large cohort of patients (84 of 235 patients; 36%) at high risk for relapse and death. Importantly, more than 50% of non-WNT/non-SHH tumors displayed FSTL5 negativity, delineating a large patient cohort with a good prognosis who would otherwise be considered intermediate or high-risk on the basis of current molecular subgrouping.FSTL5 expression denoted a dismal prognosis both within and across medulloblastoma subgroups. The addition of FSTL5 immunohistochemistry to existing molecular stratification schemes constitutes a reliable and cost-effective tool for prognostication in future clinical trials of medulloblastoma.
Phase I and Pharmacologic Trial of Cytosine Arabinoside with the Selective Checkpoint 1 Inhibitor Sch 900776 in Refractory Acute Leukemias
Authors: Judith E. Karp, Brian M. Thomas, Jacqueline M. Greer, Christopher Sorge, Steven D. Gore, Keith W. Pratz, B. Douglas Smith, Karen S. Flatten, Kevin Peterson, Paula Schneider, Karen Mackey, Tomoko Freshwater, Mark J. Levis, Michael A. McDevitt, Hetty E. Carraway, Douglas E. Gladstone, Margaret M. Showel, Sabine Loechner, David A. Parry, Jo Ann Horowitz, Randi Isaacs, Scott H. Kaufmann
Journal: Clinical Cancer Research (2012)

Incorporation of cytarabine into DNA activates checkpoint kinase 1 (Chk1), which stabilizes stalled replication forks, induces S-phase slowing, and diminishes cytarabine cytotoxicity. The selective Chk1 inhibitor SCH 900776 abrogates cytarabine-induced S-phase arrest and enhances cytarabine cytotoxicity in acute leukemia cell lines and leukemic blasts in vitro. To extend these findings to the clinical setting, we have conducted a phase I study of cytarabine and SCH 900776.Twenty-four adults with relapsed and refractory acute leukemias received timed sequential, continuous infusion cytarabine 2 g/m(2) over 72 hours (667 mg/m(2)/24 hours) beginning on day 1 and again on day 10. SCH 900776 was administered as a 15- to 30-minute infusion on days 2, 3, 11, and 12. The starting dose of SCH 900776 was 10 mg/m(2)/dose.Dose-limiting toxicities consisting of corrected QT interval prolongation and grade 3 palmar-plantar erythrodysesthesia occurred at 140 mg flat dosing (dose level 5, equivalent to 80 mg/m(2)). Complete remissions occurred in 8 of 24 (33%) patients, with 7 of 8 at 40 mg/m(2) or higher. SCH 900776 did not accumulate at any dose level. Marrow blasts obtained pretreatment and during therapy showed increased phosphorylation of H2Ax after SCH 900776 beginning at 40 mg/m(2), consistent with unrepaired DNA damage.These data support a randomized phase II trial of cytarabine +/- SCH 900776 at a recommended flat dose of 100 mg (equivalent to 56 mg/m(2)) for adults with poor-risk leukemias. The trial (SP P05247) was registered at www.clinicaltrials.gov as NCT00907517.
Inflammatory signaling pathway containing TRAF6 contributes to neointimal formation via diverse mechanisms
Authors: Takuya Miyahara, Hiroyuki Koyama, Tetsuro Miyata, Hiroshi Shigematsu, Jun-Ichiro Inoue, Tsuyoshi Takato, Hirokazu Nagawa
Journal: Cardiovascular Research (2004)

The purpose of this study was to investigate the contribution of inflammatory signaling containing tumor necrosis factor receptor-associated factor 6 (TRAF6) to neointimal formation in a balloon injury model of rabbit carotid artery.Male Japanese white rabbits fed a normal diet were used. We transferred the dominant negative (DN) form of TRAF6 to a rabbit carotid artery that was subjected to balloon injury by in vivo electroporation method, and then evaluated its effect on intimal lesion formation after balloon injury.An expression plasmid vector containing the TRAF6 DN sequence was successfully transferred to arterial wall cells, and its inhibitory effect on inflammatory signaling was confirmed by the marked suppression of nuclear factor-kappaB (NFkappaB) activity after injury. Morphometric analyses revealed significant inhibition of intimal lesion formation at 7 days after injury. Cell replication and accumulation of macrophages in the media were significantly decreased, and apoptosis was enhanced on day 2. Cell migration to the intima was suppressed on day 4. Extracellular signal-regulated kinase1/2 (ERK1/2) activity at 2 h after injury was also down-regulated. Interestingly, intimal cell replication was significantly blocked when TRAF6 DN was transfected at 7 days after injury.TRAF6 plays important roles in cell replication and migration, besides promotion of inflammatory cell infiltration and suppression of apoptosis.
Tissue factor-factor VIIa–specific up-regulation of IL-8 expression in MDA-MB-231 cells is mediated by PAR-2 and results in increased cell migration
Authors: Gertrud M. Hjortoe, Lars C. Petersen, Tatjana Albrektsen, Brit B. Sorensen, Peder L. Norby, Samir K. Mandal, Usha R. Pendurthi, L. Vijaya Mohan Rao
Journal: Blood (2004)
<i>KIT</i> and <i>PDGFRA</i> Mutations and the Risk of GI Stromal Tumor Recurrence
Authors: Heikki Joensuu, Piotr Rutkowski, Toshirou Nishida, Sonja E. Steigen, Peter Brabec, Lukas Plank, Bengt Nilsson, Chiara Braconi, Andrea Bordoni, Magnus K. Magnusson, Jozef Sufliarsky, Massimo Federico, Jon G. Jonasson, Isabelle Hostein, Pierre-Paul Bringuier, Jean-Francois Emile
Journal: Journal of Clinical Oncology (2015)

Purpose Mutated KIT and platelet-derived growth factor alpha gene (PDGFRA) drive GI stromal tumor (GIST) oncogenesis, but the clinical significance of their single mutations is known incompletely. Patients and Methods We identified 11 population-based series of patients with GIST through a literature search and pooled individual data from 3,067 patients treated with macroscopically complete tumor excision. Mutation analysis was done from 1,505 tumors. We analyzed associations between KIT and PDGFRA mutations and recurrence-free survival (RFS) in the subsets in which patients were treated with surgery alone. Results We identified 301 different single mutations in KIT and 33 in PDGFRA. Patients with PDGFRA mutations had more favorable RFS than those with KIT mutations (hazard ratio, 0.34; P = .004). Only one of the 35 GISTs with KIT exon 11 duplication mutations recurred. Patients with deletions of only one codon of KIT exon 11 had better RFS than those with another deletion type, and some KIT exon 11 substitution mutations (Trp557Arg, Val559Ala, and Leu576Pro) were also associated with favorable RFS. Patients with an identical mutation had greatly variable outcomes depending on the standard prognostic factors, notably, mitotic count. Commonly used risk stratification schemes tended to overestimate the risk for recurrence in subgroups with prognostically favorable mutations. Conclusion GISTs with an identical KIT or PDGFRA mutation may have widely varying risks for recurrence. Most of the patients with PDGFRA mutations and those with KIT exon 11 duplication mutation or deletion of one codon have favorable RFS with surgery alone and are usually not candidates for adjuvant therapy.
Systems pharmacology identifies drug targets for Stargardt disease–associated retinal degeneration
Authors: Yu Chen, Grazyna Palczewska, Debarshi Mustafi, Marcin Golczak, Zhiqian Dong, Osamu Sawada, Tadao Maeda, Akiko Maeda, Krzysztof Palczewski
Journal: Journal of Clinical Investigation (2013)

A systems pharmacological approach that capitalizes on the characterization of intracellular signaling networks can transform our understanding of human diseases and lead to therapy development. Here, we applied this strategy to identify pharmacological targets for the treatment of Stargardt disease, a severe juvenile form of macular degeneration. Diverse GPCRs have previously been implicated in neuronal cell survival, and crosstalk between GPCR signaling pathways represents an unexplored avenue for pharmacological intervention. We focused on this receptor family for potential therapeutic interventions in macular disease. Complete transcriptomes of mouse and human samples were analyzed to assess the expression of GPCRs in the retina. Focusing on adrenergic (AR) and serotonin (5-HT) receptors, we found that adrenoceptor α 2C (Adra2c) and serotonin receptor 2a (Htr2a) were the most highly expressed. Using a mouse model of Stargardt disease, we found that pharmacological interventions that targeted both GPCR signaling pathways and adenylate cyclases (ACs) improved photoreceptor cell survival, preserved photoreceptor function, and attenuated the accumulation of pathological fluorescent deposits in the retina. These findings demonstrate a strategy for the identification of new drug candidates and FDA-approved drugs for the treatment of monogenic and complex diseases.
Predictors of high-sensitivity cardiac troponin T during acute exacerbation of chronic obstructive pulmonary disease
Authors: Arne Didrik Høiseth, Anke Neukamm, Tor-Arne Hagve, Pål H. Brekke, Torbjørn Omland, Vidar Søyseth
Journal: European Respiratory Journal (2011)

Background:  A high-sensitivity cardiac troponin T (hs-cTnT) concentration above the 99th percentile (i.e. 14 ng/L) is common during Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD) and associated with increased mortality.   Objective:  To identify factors predictive of hs-cTnT levels during AECOPD.   Methods:  We included 99 patients with AECOPD on admission. As several patients had repeat admissions, there are 219 observations. We recorded clinical data, medication, spirometry, chest radiographs, ECG data and biochemical data including serum creatinine, hs-cTnT, and NT-proBNP. The data were analysed using a general linear mixed model with the natural logarithm of hs-cTnT as the dependent variable.   Results:  Mean age at inclusion was 71.5 years, mean FEV 1  was 37% of predicted, and median hs-cTnT was 39.7 ng/L. The variables associated with hs-cTnT (p 2 , creatinine, neutrophil count, NT-proBNP, and infiltrate and cephalisation on chest radiograph. In a multivariable model, patient age, history of hypertension, cephalisation, tachycardia, creatinine, neutrophil count >11.5×10 9 /L, and NT-proBNP remained significantly associated (p   Conclusion:  Multiple variables, including those reflecting heart failure, renal dysfunction, and inflammation are predictive of hs-cTnT during AECOPD, suggesting that the mechanisms underlying hs-cTnT elevation are multifactorial.
Immunoglobulin β Signaling Regulates Locus Accessibility for Ordered Immunoglobulin Gene Rearrangements
Authors: Kazushige Maki, Kisaburo Nagata, Fujiko Kitamura, Toshitada Takemori, Hajime Karasuyama
Journal: The Journal of Experimental Medicine (2000)

The antigen receptor gene rearrangement at a given locus is tightly regulated with respect to cell lineage and developmental stage by an ill-defined mechanism. To study the possible role of precursor B cell antigen receptor (pre-BCR) signaling in the regulation of the ordered immunoglobulin (Ig) gene rearrangement during B cell differentiation, a newly developed system using μ heavy (H) chain membrane exon (μm)-deficient mice was employed. In this system, the antibody-mediated cross-linking of Igβ on developmentally arrested progenitor B (pro-B) cells mimicked pre-BCR signaling to induce early B cell differentiation in vivo. Analyses with ligation-mediated polymerase chain reaction revealed that the Igβ cross-linking induced the redirection of Ig gene rearrangements, namely, the suppression of ongoing rearrangements at the H chain locus and the activation of rearrangements at the light (L) chain locus. Upon the cross-linking, the κL chain germline transcription was found to be upregulated whereas the VH germline transcription was promptly downregulated. Notably, this alteration of the accessibility at the H and L chain loci was detected even before the induction of cellular differentiation became detectable by the change of surface phenotype. Thus, the pre-BCR signaling through Igβ appears to regulate the ordered Ig gene rearrangement by altering the Ig locus accessibility.
Ran Is a Potential Therapeutic Target for Cancer Cells with Molecular Changes Associated with Activation of the PI3K/Akt/mTORC1 and Ras/MEK/ERK Pathways
Authors: Hiu-Fung Yuen, Ka-Kui Chan, Claire Grills, James T. Murray, Angela Platt-Higgins, Osama Sharaf Eldin, Ken O'Byrne, Pasi Janne, Dean A. Fennell, Patrick G. Johnston, Philip S. Rudland, Mohamed El-Tanani
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Cancer cells have been shown to be more susceptible to Ran knockdown than normal cells. We now investigate whether Ran is a potential therapeutic target of cancers with frequently found mutations that lead to higher Ras/MEK/ERK [mitogen-activated protein/extracellular signal-regulated kinase (ERK; MEK)] and phosphoinositide 3-kinase (PI3K)/Akt/mTORC1 activities. Experimental Design: Apoptosis was measured by flow cytometry [propidium iodide (PI) and Annexin V staining] and MTT assay in cancer cells grown under different conditions after knockdown of Ran. The correlations between Ran expression and patient survival were examined in breast and lung cancers. Results: Cancer cells with their PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways inhibited are less susceptible to Ran silencing–induced apoptosis. K-Ras–mutated, c-Met–amplified, and Pten-deleted cancer cells are also more susceptible to Ran silencing–induced apoptosis than their wild-type counterparts and this effect is reduced by inhibitors of the PI3K/Akt/mTORC1 and MEK/ERK pathways. Overexpression of Ran in clinical specimens is significantly associated with poor patient outcome in both breast and lung cancers. This association is dramatically enhanced in cancers with increased c-Met or osteopontin expression, or with oncogenic mutations of K-Ras or PIK3CA, all of which are mutations that potentially correlate with activation of the PI3K/Akt/mTORC1 and/or Ras/MEK/ERK pathways. Silencing Ran also results in dysregulation of nucleocytoplasmic transport of transcription factors and downregulation of Mcl-1 expression, at the transcriptional level, which are reversed by inhibitors of the PI3K/Akt/mTORC1 and MEK/ERK pathways. Conclusion: Ran is a potential therapeutic target for treatment of cancers with mutations/changes of expression in protooncogenes that lead to activation of the PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways. Clin Cancer Res; 18(2); 380–91. ©2011 AACR.
Magnesium and myocardial infarction
Authors: Matthias Egger, GeorgeDavey Smith, WilliamR Herzog, Dan Atar, Anders Galløe, Niels Graudal, Bruno Toussaint, Aldo Trylesinski, S.M Horner, HughE Montgomery, M.Elsya Speechly-Dick
Journal: The Lancet (1994)
Blockade of four-transmembrane L6 family member 5 (TM4SF5)-mediated tumorigenicity in hepatocytes by a synthetic chalcone derivative
Authors: Sin-Ae Lee, Hyung Won Ryu, Young Mee Kim, Suyong Choi, Mi Ji Lee, Tae Kyoung Kwak, Hyeon Jung Kim, Moonjae Cho, Ki Hun Park, Jung Weon Lee
Journal: Hepatology (2008)

We previously reported that the four-transmembrane L6 family member 5 (TM4SF5) was highly expressed in hepatocarcinoma, induced morphological elongation and epithelial-mesenchymal transition, and caused abnormal cell growth in multilayers in vitro and tumor formation in vivo. In this study, we identified a synthetic compound, 4'-(p-toluenesulfonylamido)-4-hydroxychalcone (TSAHC) that antagonized both the TM4SF5-mediated multilayer growth and TM4SF5-enhanced migration/invasion. TSAHC treatment induced multilayer-growing cells to grow in monolayers, recovering contact inhibition without accompanying apoptosis, and inhibited chemotactic migration and invasion. Tumor formation in nude mice injected with TM4SF5-expressing cells and the growth of cells expressing endogenous TM4SF5, but not of TM4SF5-null cells, was suppressed by treatment with TSAHC, but not by treatment with its analogs. The structure-activity relationship indicated the significance of 4'-p-toluenesulfonylamido and 4-hydroxy groups for the anti-TM4SF5 effects of TSAHC. Point mutations of the putative N-glycosylation sites abolished the TM4SF5-specific TSAHC responsiveness.These observations suggest that TM4SF5-enhanced tumorigenic proliferation and metastatic potential can be blocked by TSAHC, likely through targeting the extracellular region of TM4SF5, which is important for protein-protein interactions.
Effects of four different methods of sampling arterial blood and storage time on gas tensions and shunt calculation in the 100% oxygen test
Authors: FW Smeenk, JD Janssen, BJ Arends, GA Harff, JA van den Bosch, JP Schonberger, PE Postmus
Journal: European Respiratory Journal (1997)

At the present time, plastic syringes are most commonly used for collecting arterial blood. The oxygen tension of the arterial blood (Pa,O2) in these syringes may fall. We studied the effect of the type of syringe, metabolism, and storage time on the arterial oxygen pressures measured and on the pulmonary shunt calculated. In 10 patients, 2-3 h after aortacoronary bypass surgery, a 100% oxygen test was performed. Four arterial blood gas samples were withdrawn from each patient in random order, two in glass syringes and two in plastic syringes. One glass and one plastic syringe were stored at room temperature (RT), and the others were stored in ice-water (IW). Each sample was analysed as soon as possible, and repeated 15, 30, 60 and 120 min after sampling. The Pa,O2 measurement in blood in the glass syringe in IW measured as soon as possible after sampling was considered the "gold standard". Pulmonary shunt calculations were performed using the results of the various blood gas analyses. Compared with the "gold standard", all of the other methods showed significant deterioration in the Pa,O2 measurement. The effect due to diffusion was 0.05 kPa x min(-1), and that due to metabolism 0.11 kPa x min(-1). The Pa,O2 in the glass syringes stored in IW remained stable with time. The pulmonary shunt was significantly overestimated when the "gold standard" blood gas results were not used (range 0.8-9.9%). Glass (not plastic) syringes should be used in the 100% oxygen test. The syringe should be cooled immediately, even when the sample is analysed as soon as possible.
Case-Control Study of Hodgkin's Disease. I. Results of the Interview Questionnaire&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: Guy R. Newell, William Rawlings, B. Kay Kinnear, Pelayo Correa, Brian E. Henderson, Ruth Dworsky, Herman Menck, Ronald Thompson, William W. Sheehan
Journal: JNCI Journal of the National Cancer Institute (1973)

Journal Article Case-Control Study of Hodgkin's Disease. I. Results of the Interview Questionnaire Get access Guy R. Newell, Guy R. Newell 3Department of Epidemiology and Biostatistics, Tulane Medical Center, New Orleans, La. 70112 Search for other works by this author on: Oxford Academic PubMed Google Scholar William Rawlings, William Rawlings 3Department of Epidemiology and Biostatistics, Tulane Medical Center, New Orleans, La. 70112 Search for other works by this author on: Oxford Academic PubMed Google Scholar B. Kay Kinnear, B. Kay Kinnear 3Department of Epidemiology and Biostatistics, Tulane Medical Center, New Orleans, La. 70112 Search for other works by this author on: Oxford Academic PubMed Google Scholar Pelayo Correa, Pelayo Correa 4Biometry Branch, National Cancer Institute, National Institutes of Health, Public Health Service, U.S. Department of Health, Education, and Welfare, Bethesda, Md. 20014 Search for other works by this author on: Oxford Academic PubMed Google Scholar Brian E. Henderson, Brian E. Henderson 5University of Southern California School of Medicine, Los Angeles, Calif. 90033 Search for other works by this author on: Oxford Academic PubMed Google Scholar Ruth Dworsky, Ruth Dworsky 5University of Southern California School of Medicine, Los Angeles, Calif. 90033 Search for other works by this author on: Oxford Academic PubMed Google Scholar Herman Menck, Herman Menck 5University of Southern California School of Medicine, Los Angeles, Calif. 90033 Search for other works by this author on: Oxford Academic PubMed Google Scholar Ronald Thompson, Ronald Thompson 6University of California, Los Angeles, Calif. Search for other works by this author on: Oxford Academic PubMed Google Scholar William W. Sheehan William W. Sheehan 5University of Southern California School of Medicine, Los Angeles, Calif. 90033 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 51, Issue 5, November 1973, Pages 1437–1441, https://doi.org/10.1093/jnci/51.5.1437 Published: 01 November 1973 Article history Received: 16 April 1973 Accepted: 27 June 1973 Published: 01 November 1973
Spatial Neglect and Attention Networks
Authors: Maurizio Corbetta, Gordon L. Shulman
Journal: Annual Review of Neuroscience (2011)

Unilateral spatial neglect is a common neurological syndrome following predominantly right hemisphere injuries and is characterized by both spatial and non-spatial deficits. Core spatial deficits involve mechanisms for saliency coding, spatial attention, and short-term memory and occur in conjunction with nonspatial deficits that involve reorienting, target detection, and arousal/vigilance. We argue that neglect is better explained by the dysfunction of distributed cortical networks for the control of attention than by structural damage of specific brain regions. Ventral lesions in right parietal, temporal, and frontal cortex that cause neglect directly impair nonspatial functions partly mediated by a ventral frontoparietal attention network. Structural damage in ventral cortex also induces physiological abnormalities of task-evoked activity and functional connectivity in a dorsal frontoparietal network that controls spatial attention. The anatomy and right hemisphere dominance of neglect follow from the anatomy and laterality of the ventral regions that interact with the dorsal attention network.