tbuckley/cabot-search huggingface dataset:
A Molecular Taxonomy for Urothelial Carcinoma
Authors: Gottfrid Sjödahl, Martin Lauss, Kristina Lövgren, Gunilla Chebil, Sigurdur Gudjonsson, Srinivas Veerla, Oliver Patschan, Mattias Aine, Mårten Fernö, Markus Ringnér, Wiking Månsson, Fredrik Liedberg, David Lindgren, Mattias Höglund
Journal: Clinical Cancer Research (2012)

Abstract Purpose: Even though urothelial cancer is the fourth most common tumor type among males, progress in treatment has been scarce. A problem in day-to-day clinical practice is that precise assessment of individual tumors is still fairly uncertain; consequently efforts have been undertaken to complement tumor evaluation with molecular biomarkers. An extension of this approach would be to base tumor classification primarily on molecular features. Here, we present a molecular taxonomy for urothelial carcinoma based on integrated genomics. Experimental Design: We use gene expression profiles from 308 tumor cases to define five major urothelial carcinoma subtypes: urobasal A, genomically unstable, urobasal B, squamous cell carcinoma like, and an infiltrated class of tumors. Tumor subtypes were validated in three independent publically available data sets. The expression of 11 key genes was validated at the protein level by immunohistochemistry. Results: The subtypes show distinct clinical outcomes and differ with respect to expression of cell-cycle genes, receptor tyrosine kinases particularly FGFR3, ERBB2, and EGFR, cytokeratins, and cell adhesion genes, as well as with respect to FGFR3, PIK3CA, and TP53 mutation frequency. The molecular subtypes cut across pathologic classification, and class-defining gene signatures show coordinated expression irrespective of pathologic stage and grade, suggesting the molecular phenotypes as intrinsic properties of the tumors. Available data indicate that susceptibility to specific drugs is more likely to be associated with the molecular stratification than with pathologic classification. Conclusions: We anticipate that the molecular taxonomy will be useful in future clinical investigations. Clin Cancer Res; 18(12); 3377–86. ©2012 AACR.
Isoform 1c of sterol regulatory element binding protein is less active than isoform 1a in livers of transgenic mice and in cultured cells.
Authors: H Shimano, J D Horton, I Shimomura, R E Hammer, M S Brown, J L Goldstein
Journal: Journal of Clinical Investigation (1997)

We have produced transgenic mice whose livers express a dominant positive NH2-terminal fragment of sterol regulatory element binding protein-1c (SREBP-1c). Unlike full-length SREBP-1c, the NH2-terminal fragment enters the nucleus without a requirement for proteolytic release from cell membranes, and hence it is immune to downregulation by sterols. We compared SREBP-1c transgenic mice with a line of transgenic mice that produces an equal amount of the NH2-terminal fragment of SREBP-1a. SREBP-1a and -1c are alternate transcripts from a single gene that differ in the first exon, which encodes part of an acidic activation domain. The 1a protein contains a long activation domain with 12 negatively charged amino acids, whereas the 1c protein contains a short activation domain with only 6 such amino acids. As previously reported, livers of the SREBP-1a transgenic mice were massively enlarged, owing to accumulation of triglycerides and cholesterol. SREBP-1c transgenic livers were only slightly enlarged with only a moderate increase in triglycerides, but not cholesterol. The mRNAs for the LDL receptor and several cholesterol biosynthetic enzymes were elevated in SREBP-la transgenic mice, but not in 1c transgenic mice. The mRNAs for fatty acid synthase and acetyl CoA carboxylase were elevated 9- and 16-fold in la animals, but only 2- and 4-fold in 1c animals. Experiments with transfected cells confirmed that SREBP-1c is a much weaker activator of transcription than SREBP-1a when both are expressed at levels approximating those found in nontransfected cells. SREBP-1c became a strong activator only when expressed at supraphysiologic levels. We conclude that SREBP-1a is the most active form of SREBP-1 and that SREBP-1c may be produced when cells require a lower rate of transcription of genes regulating cholesterol and fatty acid metabolism.
GENETIC CHARACTERS OF HUMAN γ-GLOBULINS IN MYELOMA PROTEINS
Authors: M. Harboe, C. K. Osterland, M. Mannik, H. G. Kunkel
Journal: The Journal of Experimental Medicine (1962)

The genetic factors Gm(a), Gm(b), Gm(x), and Inv(a), Inv(b) described for normal human gamma-globulin were all found in different myeloma proteins. A single myeloma protein never contained more than one product of alternate alleles even in heterozygous individuals. However, factors determined by the two different loci were often found in the same myeloma protein. The Gm(a) character of the myeloma protein parallelled that of the normal gamma-globulin of the same serum in most cases. In contrast, the Gm(b) character was usually absent in the myeloma protein when it was directly demonstrable in the normal gamma-globulin. The myeloma proteins from six Negroes were Gm(a+b-), whereas the normal gamma-globulin was Gm(a+b+). This indicates that the effect of gene Gm(b) is similar in Negroes and whites, even though its relation to gene Gm(a) is different in the two races. Gm factors were found only in the 7S gamma-globulin type myelomas and not in other products of plasma cell tumors. Inv characters were, however, present in all four types of proteins studied, namely 7S and 19S gamma-globulins, beta(2A)-globulins, and Bence Jones proteins. In two instances, genetic heterogeneity of the protein products was demonstrated suggesting the proliferation of more than one clone of plasma cells in some multiple myeloma patients. The accumulated evidence obtained in this study strongly suggested that the presence and absence of genetic characters was compatible with the concept that myeloma proteins were closely analogous to individual moieties in the spectrum of normal gamma-globulins rather than truly abnormal proteins. Their study offered evidence of a heterogeneity of genetic characters among the normal gamma-globulins in a given individual. It also appears probable that in normal individuals single plasma cells have a restricted capacity to express genetic information in their protein product.
Acid sphingomyelinase mediates IL-6 release in experimental LPS-induced lung injury
Authors: Rachele Pandolfi, Bianca Barreira, Andrea Martinez-Ramas, Enrique Moreno, Victor Lara-Acedo, Daniel Morales-Cano, Virginia Chamorro, Angel Cogolludo, Francisco Pérez-Vizcaíno F, Laura Moreno
Journal: European Respiratory Journal (2014)

Acute lung injury (ALI) is a major cause of mortality in intensive care units. Previous studies suggest that the acid sphingomyelinase (aSMase) might modulate pulmonary oedema in experimental models of ALI. The aim of this study was to analyze the possible role of aSMase on the effects induced by lipopolysaccharide (LPS) in pulmonary artery smooth muscle cells (PASMCs).

Rat PASMCs were treated with different inhibitors for 45-60 minutes and then incubated for 24 hours in the absence (Ctrl) or presence of LPS (1 μg/ml) or bacterial SMase (0.1 U/ml; Bacillus cereus). The effects of D609 (50 mg/Kg body weight: i.p.) were assessed in an experimental model of ALI (intratracheal administration of LPS; 300 μg/Kg). IL-6 levels were determined by ELISA.

Exposure to LPS for 24 hours significantly increased IL-6 release by rat PASMCs. This increase was inhibited by the TLR4 antagonist TAK242, the aSMase inhibitors desipramine and D609 and the TAK-1 inhibitor 5Z-7-oxozeaenol, but not by the iNOS inhibitor 1400W. Likewise, bacterial SMase stimulated PASMCs to release IL-6 and this effect was inhibited by 5Z-7-oxozeaenol, but not by TAK242 or 1400W. Finally, intratracheal administration of LPS increased lung aSMase activity by 30% and IL-6 levels in BAL. These effects were prevented by D609.

In summary, our data suggest that aSMase activation modulates the release of IL-6 induced by LPS in PASMCs through a mechanism which involves TAK-1 activation and seems to be independent of iNOS. These results suggest that aSMase may represent a potential therapeutic

target in ALI associated to bacterial sepsis.

Supported by Spanish MINECO (2011-28150) and ISCIII (CP12/03304).
Transcriptomic Analysis of Human Lung Development
Authors: Alvin T. Kho, Soumyaroop Bhattacharya, Kelan G. Tantisira, Vincent J. Carey, Roger Gaedigk, J. Steven Leeder, Isaac S. Kohane, Scott T. Weiss, Thomas J. Mariani
Journal: American Journal of Respiratory and Critical Care Medicine (2009)

Current understanding of the molecular regulation of lung development is limited and derives mostly from animal studies.To define global patterns of gene expression during human lung development.Genome-wide expression profiling was used to measure the developing lung transcriptome in RNA samples derived from 38 normal human lung tissues at 53 to 154 days post conception. Principal component analysis was used to characterize global expression variation and to identify genes and bioontologic attributes contributing to these variations. Individual gene expression patterns were verified by quantitative reverse transcriptase-polymerase chain reaction analysis.Gene expression analysis identified attributes not previously associated with lung development, such as chemokine-immunologic processes. Lung characteristics attributes (e.g., surfactant function) were observed at an earlier-than-anticipated age. We defined a 3,223 gene developing lung characteristic subtranscriptome capable of describing a majority of the process. In gene expression space, the samples formed a time-contiguous trajectory with transition points correlating with histological stages and suggesting the existence of novel molecular substages. Induction of surfactant gene expression characterized a pseudoglandular "molecular phase" transition. Individual gene expression patterns were independently validated. We predicted the age of independent human lung transcriptome profiles with a median absolute error of 5 days, supporting the validity of the data and modeling approach.This study extends our knowledge of key gene expression patterns and bioontologic attributes underlying early human lung developmental processes. The data also suggest the existence of molecular phases of lung development.
Comparison of the efficacy and safety of bilastine 20 mg <i>vs</i> levocetirizine 5 mg for the treatment of chronic idiopathic urticaria: a multi‐centre, double‐blind, randomized, placebo‐controlled study
Authors: T. Zuberbier, A. Oanta, E. Bogacka, I. Medina, F. Wesel, P. Uhl, I. Antépara, I. Jáuregui, R. Valiente
Journal: Allergy (2009)

To cite this article: Zuberbier T, Oanta A, Bogacka E, Medina I, Wesel F, Uhl P, Antépara I, Jáuregui I, Valiente R, the Bilastine International Working Group. Comparison of the efficacy and safety of bilastine 20 mg vs levocetirizine 5 mg for the treatment of chronic idiopathic urticaria: a multi‐centre, double‐blind, randomized, placebo‐controlled study. Allergy 2010; 65 : 516–528. Abstract Background: Bilastine is a novel nonsedative H 1 ‐receptor antagonist, which may be used for the symptomatic treatment of chronic idiopathic urticaria (CU). The aim of this study was to compare the clinical efficacy and safety of bilastine 20 mg vs levocetirizine 5 mg and placebo in CU patients with moderate‐to‐severe symptoms. Methods: Overall 525 male and female subjects aged 18–70 years were randomized to receive bilastine 20 mg, levocetirizine 5 mg or placebo, once daily for 28 days, in double‐blind manner, in 46 centres across Europe and Argentina. Patients rated symptoms of pruritus, number of wheals, and maximum size of wheals (on predefined scales) as reflective (over past 12 h) symptoms twice daily, for assessment of change from baseline in the total symptoms scores (TSS) over 28 days as the primary efficacy measure. Changes in reflective and instantaneous symptoms scores, Dermatology Life Quality Index (DLQI), and CU‐associated discomfort and sleep disturbance were assessed as secondary outcomes. Safety was assessed according to adverse events, laboratory tests and electrocardiograms. Results: Bilastine reduced patients’ mean reflective and instantaneous TSS from baseline to a significantly greater degree than placebo ( P &lt; 0.001); from day 2 onwards of treatment. The DLQI, general discomfort, and sleep disruption were also improved significantly in bilastine‐treated patients as compared with placebo‐treated patients ( P &lt; 0.001 for all parameters). Comparison with levocetirizine indicated both treatments to be equally efficacious as well as equally safe and well tolerated as compared with placebo. Conclusions: Bilastine 20 mg is a novel effective and safe treatment option for the management of CU.
David Versus Goliath: Decision Analysis Predicts Results of a Large Clinical Trial in Follicular Lymphoma
Authors: Rebecca L. Olin, Charalambos Andreadis
Journal: Journal of Clinical Oncology (2013)

TO THE EDITOR: The recently published FOLL05 trial, 1 conducted by the Fondazione Italiana Linformi, randomly assigned 543 patients with follicular lymphoma to three differentfirst-line chemotherapy regimens: rituximab plus cyclophosphamide, vincristine, andprednisone(R-CVP),rituximabpluscyclophosphamide,doxorubicin, vincristine, and prednisone (R-CHOP), and rituximab plus fludarabine and mitoxantrone (R-FM). The study concluded that R-CHOP and R-FM were similarly efficacious, and that both were better than R-CVP in terms of 3-year time-to-treatment failure and progression-free survival. Furthermore, R-CHOP was associated with less toxicity than R-FM and was therefore proclaimed the winning regimen. We would like to point out the results of our decision analysis, which was designed to examine the optimal first-line/second-line approach to follicular lymphoma using rigorous methodology that incorporated efficacy and quality-of-life measures. 2 Our study examined the same three regimens as the FOLL05 trial and arrived at precisely the same conclusions. The decision analysis, based on a meta-analysis of existing trials, was published in early 2010, 3 years before the current report. It required no patients to be randomly assigned, and only minimalfinancial resources. Although we acknowledge the value of randomized trials in answering important clinical questions, it is an unfortunate reality that thesestudiescannotbeperformedforeveryclinicalquestion,andeven
Development of insulitis without diabetes in transgenic mice lacking perforin-dependent cytotoxicity.
Authors: D Kägi, B Odermatt, P S Ohashi, R M Zinkernagel, H Hengartner
Journal: The Journal of Experimental Medicine (1996)

It is widely accepted that T cells play an important role in the destruction of beta cells leading to autoimmune type I diabetes, but the involved effector mechanisms have remained unclear. We addressed this issue by testing the role of perforin-dependent cytotoxicity in a disease model involving transgenic mice expressing glycoprotein of lymphocytic choriomeningitis virus (LCMV-GP) in the beta cells of the endocrine pancreas. In such mice, LCMV infection leads to a potent LCMV-GP-specific T cell response resulting in rapid development of diabetes. We report here that in perforin-deficient LCMV-GP transgenic mice, LCMV infection failed to induce diabetes despite the activation of LCMV-GP-specific T cells. Deletion of nu beta 6+ T cells in Mls-1a perforin-deficient mice and the activation of LCMV-GP-specific T cells in perforin-deficient LCMV-GP transgenic mice, however, indicated that thymic tolerance induction by negative selection was not affected by the disruption of the perforin gene and that there is no fundamental difference between the T cell repertoires of normal control and perforin-deficient mice. In addition, adoptive transfer of LCMV-GP-specific TCR transgenic perforin-deficient T cells activated by LCMV-GP recombinant vaccinia virus led to marked insulitis with infiltration of CD4+ and CD8+ T cells without the development of diabetes. These findings indicate that perforin-dependent cytotoxicity is not required for the initiation of insulitis but is crucial for the destruction of beta cells in the later phase of the disease process. Other mechanisms or soluble factors present in the inflammatory islet infiltrate apparently lack the ability to efficiently induce diabetogenic beta cell damage.
CCR6, a CC Chemokine Receptor that Interacts with Macrophage Inflammatory Protein 3α and Is Highly Expressed in Human Dendritic Cells
Authors: David R. Greaves, Wei Wang, Daniel J. Dairaghi, Marie Caroline Dieu, Blandine de Saint-Vis, Karin Franz-Bacon, Devora Rossi, Christophe Caux, Terrill McClanahan, Siamon Gordon, Albert Zlotnik, Thomas J. Schall
Journal: The Journal of Experimental Medicine (1997)

Dendritic cells initiate immune responses by ferrying antigen from the tissues to the lymphoid organs for presentation to lymphocytes. Little is known about the molecular mechanisms underlying this migratory behavior. We have identified a chemokine receptor which appears to be selectively expressed in human dendritic cells derived from CD34+ cord blood precursors, but not in dendritic cells derived from peripheral blood monocytes. When stably expressed as a recombinant protein in a variety of host cell backgrounds, the receptor shows a strong interaction with only one chemokine among 25 tested: the recently reported CC chemokine macrophage inflammatory protein 3α. Thus, we have designated this receptor as the CC chemokine receptor 6. The cloning and characterization of a dendritic cell CC chemokine receptor suggests a role for chemokines in the control of the migration of dendritic cells and the regulation of dendritic cell function in immunity and infection.
Postoperative Radiotherapy for Stage II or III Non–Small-Cell Lung Cancer Using the Surveillance, Epidemiology, and End Results Database
Authors: Brian E. Lally, Daniel Zelterman, Joseph M. Colasanto, Bruce G. Haffty, Frank C. Detterbeck, Lynn D. Wilson
Journal: Journal of Clinical Oncology (2006)

To investigate the association between survival and postoperative radiotherapy (PORT) in patients with resected non-small-cell lung cancer (NSCLC).Within the Surveillance, Epidemiology, and End Results database, we selected patients with stage II or III NSCLC who underwent a lobectomy or pneumonectomy. Only those patients coded as receiving PORT or observation were included. To account for perioperative mortality, we excluded patients who survived less than 4 months. As a result of our inclusion criteria, we selected a total of 7,465 patients, with a median follow-up time of 3.5 years for patients still alive.Predictors for the use of PORT included age less than 50 years, higher American Joint Committee on Cancer stage, T3-4 tumor stage, larger tumor size, advanced node stage, greater number of lymph nodes involved, and a ratio of lymph nodes involved to lymph nodes sampled approaching 1.00. On multivariate analysis, older age, T3-4 tumor stage, N2 node stage, male sex, fewer sampled lymph nodes, and greater number of involved lymph nodes had a negative impact on survival. The use of PORT did not have a significant impact on survival. However, in subset analysis for patients with N2 nodal disease (hazard ratio [HR] = 0.855; 95% CI, 0.762 to 0.959; P = .0077), PORT was associated with a significant increase in survival. For patients with N0 (HR = 1.176; 95% CI, 1.005 to 1.376; P = .0435) and N1 (HR = 1.097; 95% CI, 1.015 to 1.186; P = .0196) nodal disease, PORT was associated with a significant decrease in survival.In a population-based cohort, PORT use is associated with an increase in survival in patients with N2 nodal disease but not in patients with N1 and N0 nodal disease.
The protein tyrosine phosphatase receptor type R gene is an early and frequent target of silencing in human colorectal tumorigenesis
Authors: Mirco Menigatti, Elisa Cattaneo, Jacob Sabates-Bellver, Valery V Ilinsky, Philip Went, Federico Buffoli, Victor E Marquez, Josef Jiricny, Giancarlo Marra
Journal: Molecular Cancer (2009)

Abstract Background Tumor development in the human colon is commonly accompanied by epigenetic changes, such as DNA methylation and chromatin modifications. These alterations result in significant, inheritable changes in gene expression that contribute to the selection of tumor cells with enhanced survival potential. Results A recent high-throughput gene expression analysis conducted by our group identified numerous genes whose transcription was markedly diminished in colorectal tumors. One of these, the p rotein- t yrosine p hosphatase r eceptor type R ( PTPRR ) gene, was dramatically downregulated from the earliest stages of cellular transformation. Here, we show that levels of both major PTPRR transcript variants are markedly decreased (compared with normal mucosal levels) in precancerous and cancerous colorectal tumors, as well in colorectal cancer cell lines. The expression of the PTPRR-1 isoform was inactivated in colorectal cancer cells as a result of de novo CpG island methylation and enrichment of transcription-repressive histone-tail marks, mainly H3K27me3. De novo methylation of the PTPRR-1 transcription start site was demonstrated in 29/36 (80%) colorectal adenomas, 42/44 (95%) colorectal adenocarcinomas, and 8/8 (100%) liver metastases associated with the latter tumors. Conclusions Epigenetic downregulation of PTPRR seems to be an early alteration in colorectal cell transformation, which is maintained during the clonal selection associated with tumor progression. It may represent a preliminary step in the constitutive activation of the RAS/RAF/MAPK/ERK signalling, an effect that will later be consolidated by mutations in genes encoding key components of this pathway.
Forkhead box M1B is a determinant of rat susceptibility to hepatocarcinogenesis and sustains ERK activity in human HCC
Authors: D F Calvisi, F Pinna, S Ladu, R Pellegrino, M M Simile, M Frau, M R De Miglio, M L Tomasi, V Sanna, M R Muroni, F Feo, R M Pascale
Journal: Gut (2009)

<h3>Background and aim:</h3> Previous studies indicate unrestrained cell cycle progression in liver lesions from hepatocarcinogenesis-susceptible Fisher 344 (F344) rats and a block of G<sub>1</sub>–S transition in corresponding lesions from resistant Brown Norway (BN) rats. Here, the role of the Forkhead box M1B (<i>FOXM1</i>) gene during hepatocarcinogenesis in both rat models and human hepatocellular carcinoma (HCC) was assessed. <h3>Methods and results:</h3> Levels of FOXM1 and its targets were determined by immunoprecipitation and real-time PCR analyses in rat and human samples. FOXM1 function was investigated by either FOXM1 silencing or overexpression in human HCC cell lines. Activation of FOXM1 and its targets (Aurora Kinose A, Cdc2, cyclin B1, Nek2) occurred earlier and was most pronounced in liver lesions from F344 than BN rats, leading to the highest number of Cdc2–cyclin B1 complexes (implying the highest G<sub>2</sub>–M transition) in F344 rats. In human HCC, the level of FOXM1 progressively increased from surrounding non-tumorous livers to HCC, reaching the highest levels in tumours with poorer prognosis (as defined by patients' length of survival). Furthermore, expression levels of FOXM1 directly correlated with the proliferation index, genomic instability rate and microvessel density, and inversely with apoptosis. FOXM1 upregulation was due to extracellular signal-regulated kinase (ERK) and glioblastoma-associated oncogene 1 (GLI1) combined activity, and its overexpression resulted in increased proliferation and angiogenesis and reduced apoptosis in human HCC cell lines. Conversely, FOXM1 suppression led to decreased ERK activity, reduced proliferation and angiogenesis, and massive apoptosis of human HCC cell lines. <h3>Conclusions:</h3> FOXM1 upregulation is associated with the acquisition of a susceptible phenotype in rats and influences human HCC development and prognosis.