tbuckley/cabot-search huggingface dataset:
Tyrosine 284 phosphorylation is required for ClC-3 chloride channel activation in vascular smooth muscle cells
Authors: Xiao-Guang Wang, Jing Tao, Ming-Ming Ma, Yong-Bo Tang, Jia-Guo Zhou, Yong-Yuan Guan
Journal: Cardiovascular Research (2013)

AimsThe ClC-3 chloride channel (and current, ICl,ClC-3) plays an important role in cell volume regulation, proliferation, and apoptosis in vascular smooth muscle cells, and is a potential target for prevention of vascular remodelling and stroke. However, modulation of ICl,ClC-3 by intercellular signalling is not fully understood. Although it has been suggested that tyrosine phosphorylation is required for ICl,ClC-3 activation, the potential tyrosine residues in the ClC-3 protein are not clear. In the present study, the critical tyrosine residues in ClC-3 protein were investigated.
Global analysis of alternative splicing regulation by insulin and wingless signaling in Drosophila cells
Authors: Britta Hartmann, Robert Castelo, Marco Blanchette, Stephanie Boue, Donald C Rio, Juan Valcárcel
Journal: Genome biology (2009)

Despite the prevalence and biological relevance of both signaling pathways and alternative pre-mRNA splicing, our knowledge of how intracellular signaling impacts on alternative splicing regulation remains fragmentary. We report a genome-wide analysis using splicing-sensitive microarrays of changes in alternative splicing induced by activation of two distinct signaling pathways, insulin and wingless, in Drosophila cells in culture.Alternative splicing changes induced by insulin affect more than 150 genes and more than 50 genes are regulated by wingless activation. About 40% of the genes showing changes in alternative splicing also show regulation of mRNA levels, suggesting distinct but also significantly overlapping programs of transcriptional and post-transcriptional regulation. Distinct functional sets of genes are regulated by each pathway and, remarkably, a significant overlap is observed between functional categories of genes regulated transcriptionally and at the level of alternative splicing. Functions related to carbohydrate metabolism and cellular signaling are enriched among genes regulated by insulin and wingless, respectively. Computational searches identify pathway-specific sequence motifs enriched near regulated 5' splice sites.Taken together, our data indicate that signaling cascades trigger pathway-specific and biologically coherent regulatory programs of alternative splicing regulation. They also reveal that alternative splicing can provide a novel molecular mechanism for crosstalk between different signaling pathways.
Long-Acting Injectable Risperidone: Efficacy and Safety of the First Long-Acting Atypical Antipsychotic
Authors: John M. Kane, Mariëlle Eerdekens, Jean-Pierre Lindenmayer, Samuel J. Keith, Michael Lesem, Keith Karcher
Journal: American Journal of Psychiatry (2003)

The authors assessed the efficacy and safety of the first long-acting atypical antipsychotic (long-acting injectable risperidone) in patients with schizophrenia.In a 12-week, multicenter, double-blind, randomized study, patients received intramuscular injections every 2 weeks of placebo or long-acting risperidone (25 mg, 50 mg, or 75 mg). The primary measure of efficacy was the change in total score on the Positive and Negative Syndrome Scale.Of the 554 patients who were enrolled, 400 entered the double-blind study, and 370 received at least one postbaseline assessment. Mean changes in score of -6.2, -8.5, and -7.4 on the Positive and Negative Syndrome Scale were seen at endpoint for the 25-, 50-, and 75-mg risperidone groups, respectively; all three change scores were significantly different from that seen with placebo (+2.6). Improvements in positive and negative symptoms were also significantly greater in patients receiving risperidone. Long-acting risperidone was well tolerated. Adverse events related to extrapyramidal symptoms were spontaneously reported by 13% of patients receiving placebo and 10% of patients in the 25-mg risperidone group, with higher rates in the 50-mg and 75-mg groups. Severity of extrapyramidal symptoms was mild at baseline and throughout the trial in each treatment group. Mean weight changes were small in the 25-, 50-, and 75-mg risperidone groups (0.5 kg, 1.2 kg, and 1.9 kg, respectively). Injection site pain was rated as low by the patients, consistent with the investigators' pain ratings.Long-acting injectable risperidone was efficacious and well tolerated and provides both clinicians and patients with a new mode of treatment that can improve the outcome of long-term therapy.
Association between pre-diagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations:a nested case-control study
Authors: M. Jenab, H B. Bueno-de-Mesquita, P. Ferrari, F. J B van Duijnhoven, T. Norat, T. Pischon, E. H J M Jansen, N. Slimani, G. Byrnes, S. Rinaldi, A. Tjonneland, A. Olsen, K. Overvad, M.-C. Boutron-Ruault, F. Clavel-Chapelon, S. Morois, R. Kaaks, J. Linseisen, H. Boeing, M. M Bergmann, A. Trichopoulou, G. Misirli, D. Trichopoulos, F. Berrino, P. Vineis, S. Panico, D. Palli, R. Tumino, M. M Ros, C. H van Gils, P. H Peeters, M. Brustad, E. Lund, M.-J. Tormo, E. Ardanaz, L. Rodriguez, M.-J. Sanchez, M. Dorronsoro, C. A Gonzalez, G. Hallmans, R. Palmqvist, A. Roddam, T. J Key, K.-T. Khaw, P. Autier, P. Hainaut, E. Riboli
Journal: BMJ (2010)

Transplantation tolerance is induced reliably in experimental animals following intrathymic inoculation with the relevant donor strain Ags; however, the immunological mechanisms responsible for the induction and maintenance of the tolerant state remain unknown. We investigated these mechanisms using TCR transgenic mice (TS1) that carry T cells specific for an immunodominant, MHC class II-restricted peptide (S1) of the influenza PR8 hemagglutinin (HA) molecule. We demonstrated that TS1 mice reject skin grafts that have transgene-encoded HA molecules (HA104) as their sole antigenic disparity and that intrathymic but not i.v. inoculation of TS1 mice with S1 peptide induces tolerance to HA-expressing skin grafts. Intrathymic peptide inoculation was associated with a dose-dependent reduction in T cells bearing high levels of TCR specific for HA. However, this reduction was both incomplete and transient, with a full recovery of S1-specific thymocytes by 4 wk. Peptide inoculation into the thymus also resulted in the generation of immunoregulatory T cells (CD4<sup>+</sup>CD25<sup>+</sup>) that migrated to the peripheral lymphoid organs. Adoptive transfer experiments using FACS sorted CD4<sup>+</sup>CD25<sup>−</sup> and CD4<sup>+</sup>CD25<sup>+</sup> T cells from tolerant mice revealed that the former but not the latter maintain the capacity to induce rejection of HA bearing skin allografts in syngeneic hosts. Our results suggest that both clonal frequency reduction in the thymus and immunoregulatory T cells exported from the thymus are critical to transplantation tolerance induced by intrathymic Ag inoculation.
Characterization of novel genomic alterations and therapeutic approaches using acute megakaryoblastic leukemia xenograft models
Authors: Clarisse Thiollier, Cécile K. Lopez, Bastien Gerby, Cathy Ignacimouttou, Sandrine Poglio, Yannis Duffourd, Justine Guégan, Paola Rivera-Munoz, Olivier Bluteau, Vinciane Mabialah, M’Boyba Diop, Qiang Wen, Arnaud Petit, Anne-Laure Bauchet, Dirk Reinhardt, Beat Bornhauser, Daniel Gautheret, Yann Lecluse, Judith Landman-Parker, Isabelle Radford, William Vainchenker, Nicole Dastugue, Stéphane de Botton, Philippe Dessen, Jean-Pierre Bourquin, John D. Crispino, Paola Ballerini, Olivier A. Bernard, Françoise Pflumio, Thomas Mercher
Journal: The Journal of Experimental Medicine (2012)

Acute megakaryoblastic leukemia (AMKL) is a heterogeneous disease generally associated with poor prognosis. Gene expression profiles indicate the existence of distinct molecular subgroups, and several genetic alterations have been characterized in the past years, including the t(1;22)(p13;q13) and the trisomy 21 associated with GATA1 mutations. However, the majority of patients do not present with known mutations, and the limited access to primary patient leukemic cells impedes the efficient development of novel therapeutic strategies. In this study, using a xenotransplantation approach, we have modeled human pediatric AMKL in immunodeficient mice. Analysis of high-throughput RNA sequencing identified recurrent fusion genes defining new molecular subgroups. One subgroup of patients presented with MLL or NUP98 fusion genes leading to up-regulation of the HOX A cluster genes. A novel CBFA2T3-GLIS2 fusion gene resulting from a cryptic inversion of chromosome 16 was identified in another subgroup of 31% of non-Down syndrome AMKL and strongly associated with a gene expression signature of Hedgehog pathway activation. These molecular data provide useful markers for the diagnosis and follow up of patients. Finally, we show that AMKL xenograft models constitute a relevant in vivo preclinical screening platform to validate the efficacy of novel therapies such as Aurora A kinase inhibitors.
Fluconazole Prophylaxis of Fungal Infections in Patients with Acute Leukemia: Results of a Randomized Placebo-Controlled, Double-Blind, Multicenter Trial
Authors: Drew J. Winston, Pranatharthi H. Chandrasekar, Hillard M. Lazarus, Jesse L. Goodman, Jeffrey L. Silber, Harold Horowitz, Richard K. Shadduck, Craig S. Rosenfeld, Winston G. Ho, Muhammed Z. Islam, Donald N. Buell
Journal: Annals of Internal Medicine (1993)

Objective: To evaluate the efficacy and safety of fluconazole for prevention of fungal infections. Design: A randomized, placebo-controlled, double-blind, multicenter trial. Patients: Adults (257) undergoing chemotherapy for acute leukemia. Intervention: Patients were randomly assigned to receive either fluconazole (400 mg orally once daily or 200 mg intravenously every 12 hours) or placebo. The study drug was started at initiation of chemotherapy and continued until recovery of neutrophil count, development of proven or suspected invasive fungal infection, or the occurrence of a drug-related toxicity. Measurements: Fungal colonization, proven superficial or invasive fungal infection, empiric antifungal therapy with amphotericin B, drug-related side effects, and mortality. Main Results: Fluconazole decreased fungal colonization (83 of 122 [68%] placebo patients compared with 34 of 119 [29%] fluconazole patients colonized at end of prophylaxis, P < 0.001) and proven fungal infections (27 of 132 [21%] placebo patients compared with 11 of 123 [9%] fluconazole patients infected, P = 0.02). Superficial fungal infections occurred in 20 of 132 (15%) placebo patients but in only 7 of 123 (6%) fluconazole patients (P = 0.01), whereas invasive fungal infections developed in 10 of 132 (8%) placebo patients and in 5 of 123 (4%) fluconazole patients (P = 0.3). Fluconazole was especially effective in eliminating colonization and infection by Candida species other than Candida krusei (66 of 122 [64%] placebo patients colonized at end of prophylaxis compared with 11 of 119 (9%) fluconazole patients, P < 0.001; 22 of 132 (17%) placebo patients infected compared with 7 of 123 [6%] fluconazole patients, P = 0.005). Aspergillus infections were infrequent in both fluconazole (3 cases) and placebo groups (3 cases). The use of amphotericin B, the incidence of drug-related side effects, and overall mortality were similar in both study groups. Conclusion: Prophylactic fluconazole prevents colonization and superficial infections by Candida species other than Candida krusei in patients undergoing chemotherapy for acute leukemia and is well tolerated. Fluconazole could not be clearly shown to be effective for preventing invasive fungal infections, reducing the use of amphotericin B, or decreasing the number of deaths.
Multiparametric Monitoring of Tumor Response to Chemotherapy by Noninvasive Imaging
Authors: Zdravka Medarova, Leonid Rashkovetsky, Pamela Pantazopoulos, Anna Moore
Journal: Cancer Research (2009)

With the emerging concept of individualized cancer therapy, it becomes crucial to develop methods for the noninvasive assessment of treatment outcome. With this in mind, we designed a novel approach for the comprehensive evaluation of response to chemotherapy with the established agent doxorubicin in a preclinical breast cancer model. This approach delivers information not only about change in tumor size but also about target antigen expression. Our strategy relies on a tumor-specific contrast agent (MN-EPPT) targeting the underglycosylated MUC-1 (uMUC-1) tumor antigen, found on more than 90% of breast cancers and predictive of chemotherapeutic response. MN-EPPT consists of superparamagnetic iron oxide nanoparticles (MN) for magnetic resonance imaging, modified with Cy5.5 dye (for near-IR fluorescence optical imaging), and conjugated to peptides (EPPT), specifically recognizing uMUC-1. In vivo, treatment of mice bearing orthotopic human breast carcinomas with doxorubicin led to a reduction in tumor mass and resulted in down-regulation of uMUC-1. The tumor-specific accumulation of MN-EPPT allowed the assessment of change in tumor volume by noninvasive imaging. Furthermore, in mice injected with MN-EPPT, tumor delta-T2 was significantly reduced after treatment with doxorubicin, indicating a lower accumulation of MN-EPPT and reflecting the reduced expression of uMUC-1. With these studies, we have shown the utility of magnetic resonance imaging for the multiparametric characterization of breast tumor response to chemotherapy. This approach has the potential of significantly advancing our ability to better direct the development of molecularly targeted individualized therapy protocols because it permits the monitoring of therapy on a molecular scale.
Association between radiographic severity of rheumatoid arthritis and shared epitope alleles: differing mechanisms of susceptibility and protection
Authors: D Mewar, I Marinou, A L Coote, D J Moore, M Akil, D Smillie, M C Dickson, M H Binks, D S Montgomery, A G Wilson
Journal: Annals of the Rheumatic Diseases (2007)

<h3>Objective:</h3> To investigate the association of a recently described classification of Human leukocyte antigen (HLA)-DRB1 shared epitope alleles with rheumatoid factors (RF) and anti-cyclic citrullinated peptide (CCP) production and radiological severity in rheumatoid arthritis (RA). <h3>Methods:</h3> Patients with RA (n = 962) were studied. Genotyping of DRB1 alleles and assays for RF and anti-CCP were performed. Radiological severity was measured using the modified Larsen score. <h3>Results:</h3> In accordance with previous reports, we found carriage of S2 alleles (K-R-A-A at positions 71–74) to be associated with more severe disease with a gene–dose effect (p = 0.0059), and also associated with the presence of anti-CCP and RF (p&lt;0.001). Carriage of S1 alleles (D-E-R-A-A at positions 70–74) was associated with less severe disease (p = 0.01), however there was no association between S1 and either anti-CCP or RF, suggesting that the basis for this possible protective effect was not related to autoantibody-producing B cells. <h3>Conclusions:</h3> These data suggest that multiple biological mechanisms underlie the DRB1 association with rheumatoid arthritis severity.
Quantitative microfocal radiography accurately detects joint changes in rheumatoid arthritis.
Authors: J C Buckland-Wright, I Carmichael, S R Walker
Journal: Annals of the Rheumatic Diseases (1986)

Microfocal radiography, producing x5 magnified images of the wrist and hands with a high spacial resolution (25 microns) in the film, permitted direct measurement of erosion area and joint space width in patients with rheumatoid arthritis. The magnitude of errors relating to direct measurement, repositioning the wrist and hand on successive x ray visits, repeated identification of erosions and their area calculation were assessed. The coefficients of variation for length and area measurements were 3.7% and 13% respectively, while the change in joint space width and erosion area in five patients over 18 months had average coefficients of variation of 12.7% and 42.0% respectively. The combined errors correspond approximately to the fifth percentile level for the total changes in size of these x ray features. The remaining alterations were due to the disease, which was markedly greater that that attributable to errors of measurement.
Detection of PML‐retinoic acid receptor‐α fusion transcripts in acute promyelocytic leukemia with trisomy 8 but without t(15;17)
Authors: Kazuma Ikeda, Kazunori Sasaki, Taizo Tasaka, Masami Nagai, Koichi Kawanishi, Jiro Takahara, Shozo Irino
Journal: American Journal of Hematology (1994)

Abstract Chromosome translocation t(15;17), the breakpoints of which are in the PML gene on chromosome 15 and retinoic acid receptor‐α (RARα) gene on chromosome 17, is specifically found in acute promyelocytlc leukemia (APL). Clinically typical APL without t(15;17) and with the PML‐RARα fusion transcripts or rearrangements in PML and/or RARα gene has been reported, suggesting submicroscopic changes at the molecular level without apparent t(15;17) or observation of normal metaphases. Trisomy 8 is common in APL as a secondary chromosomal abnormality in addition to t(15;17), as well as in acute myelogenous leukemia in general, but it is rare as a sole chromosomal anomaly in APL. PML‐RARα fusion transcript was detected in an APL case with trisomy 8 but without t(15;17), indicating that the leukemic cells lacked t(15;17) and still expressed the PML‐RARα fusion transcripts. This indicates that the same submicroscopic molecular changes as in APL with t(15;17) do occur in APL without t(15;17) and supports the use of molecular analysis for PML‐RARα fusion in APL. © 1994 Wiley‐Liss, Inc.
Akt Mediates Mechanical Strain-Induced Collagen Production by Mesangial Cells
Authors: Joan C. Krepinsky, Yanxia Li, Yanfei Chang, Lieqi Liu, Fangfang Peng, Dongcheng Wu, Damu Tang, James Scholey, Alistair J. Ingram
Journal: Journal of the American Society of Nephrology (2005)

Increased glomerular hydrostatic pressure is an important determinant of glomerulosclerosis and can be modeled by in vitro exposure of mesangial cells to cyclic mechanical strain. Stretched mesangial cells increase extracellular matrix protein production, the hallmark of glomerulosclerosis. Recent data indicate that the serine/threonine kinase Akt may be involved in matrix modulation. Thus, Akt activation and matrix synthesis in stretched mesangial cells were studied. Exposure of mesangial cells to 1 Hz cyclic strain led to prompt Akt activation, which was biphasic to 24 h. Activation was dependent on signaling through phosphatidylinositol-3-kinase and required EGF receptor transactivation. Inhibition of signaling through the PDGF receptor, Src kinase, or cytoskeletal disruption failed to prevent strain-induced Akt activation. Collagen type 1A1 transcript expression, promoter activation, and protein secretion were increased by stretch at 24 h and were dependent on phosphatidylinositol-3 kinase. Overexpression of dominant-negative Akt inhibited strain-induced collagen 1A1 production. Conversely, overexpression of constitutively active Akt led to increased collagen 1A1 upregulation and secretion. Finally, Akt activation was observed in the glomeruli of remnant rat kidneys, a model marked by increased intraglomerular pressure. The authors conclude that mechanical strain induces Akt activation in mesangial cells through a mechanism requiring phosphatidylinositol-3-kinase and EGF receptor transactivation. Type 1 collagen production is dependent on Akt and can be induced by Akt overexpression. Akt activation is observed in remnant kidneys in vivo. Thus, the role of Akt in progression of chronic hemodynamic glomerular disease is worthy of further exploration.
Transporter-Mediated Protection against Thiopurine-Induced Hematopoietic Toxicity
Authors: Partha Krishnamurthy, Matthias Schwab, Kazumasa Takenaka, Deepa Nachagari, Jessica Morgan, Mark Leslie, Weinan Du, Kelli Boyd, Meyling Cheok, Hiromitsu Nakauchi, Catia Marzolini, Richard B. Kim, Balasubramanian Poonkuzhali, Erin Schuetz, William Evans, Mary Relling, John D. Schuetz
Journal: Cancer Research (2008)

Abstract Thiopurines are effective immunosuppressants and anticancer agents, but intracellular accumulation of their active metabolites (6-thioguanine nucleotides, 6-TGN) causes dose-limiting hematopoietic toxicity. Thiopurine S-methyltransferase deficiency is known to exacerbate thiopurine toxicity. However, many patients are highly sensitive to thiopurines for unknown reasons. We show that multidrug-resistance protein 4 (Mrp4) is abundant in myeloid progenitors and tested the role of the Mrp4, an ATP transporter of monophosphorylated nucleosides, in this unexplained thiopurine sensitivity. Mrp4-deficient mice experienced Mrp4 gene dosage-dependent toxicity caused by accumulation of 6-TGNs in their myelopoietic cells. Therefore, Mrp4 protects against thiopurine-induced hematopoietic toxicity by actively exporting thiopurine nucleotides. We then identified a single-nucleotide polymorphism (SNP) in human MRP4 (rs3765534) that dramatically reduces MRP4 function by impairing its cell membrane localization. This SNP is common (&amp;gt;18%) in the Japanese population and indicates that the increased sensitivity of some Japanese patients to thiopurines may reflect the greater frequency of this MRP4 SNP. [Cancer Res 2008;68(13):4983–9]
The pneumonectomy syndrome
Authors: L M Hannan, S A Joosten, D P Steinfort, P Antippa, L B Irving
Journal: Thorax (2011)

A 47-year-old woman presented with exertional dyspnoea, cough, nausea and weight loss 2 years after a right pneumonectomy for non-small cell lung cancer. CT demonstrated marked mediastinal shift and herniation of the left lung into the pneumonectomy cavity (figure 1A). The left lower lobe bronchus was compressed between the aorta and left pulmonary artery and the …
Endothelial tetraspanin microdomains regulate leukocyte firm adhesion during extravasation
Authors: Olga Barreiro, María Yáñez-Mó, Mónica Sala-Valdés, María Dolores Gutiérrez-López, Susana Ovalle, Adrian Higginbottom, Peter N. Monk, Carlos Cabañas, Francisco Sánchez-Madrid
Journal: Blood (2005)
Safety and Efficacy of Gemtuzumab Ozogamicin in Combination With Chemotherapy for Pediatric Acute Myeloid Leukemia: A Report From The Children's Oncology Group
Authors: Richard Aplenc, Todd A. Alonzo, Robert B. Gerbing, Beverly J. Lange, Craig A. Hurwitz, Robert J. Wells, Irwin Bernstein, Patrick Buckley, Kathleen Krimmel, Franklin O. Smith, Eric L. Sievers, Robert J. Arceci
Journal: Journal of Clinical Oncology (2008)

While gemtuzumab ozogamicin (GTMZ) is commonly used in the treatment of acute myeloid leukemia (AML) in combination with standard chemotherapy agents, the pediatric maximum-tolerated dose (MTD) of GMTZ in combination with chemotherapy has not been determined.The Children's Oncology Group AAML00P2 trial sought to define the MTD of GMTZ in combination with cytarabine and mitoxantrone and cytarabine and l-asparaginase chemotherapy regimens.The MTD for GMTZ in combination with cytarabine and mitoxantrone was 3 mg/m(2) while the MTD in combination with cytarabine and l-asparaginase was 2 mg/m(2). Toxicities observed in both treatment regimens were typical of those seen in the relapsed AML setting and consisted primarily of infectious complications. The overall remission response rate (mean +/- SE) was 45% +/- 15% and the 1 year event-free survival and overall survival estimates were 38% +/- 14% and 53% +/- 15%, respectively.This trial determined the pediatric MTD for GMTZ with two commonly used AML chemotherapy combinations. Based on these results, an ongoing phase III trial conducted within the Children's Oncology Group is evaluating the effect of GMTZ when added to standard AML therapy.