tbuckley/cabot-search huggingface dataset:
Role of Adjuvant Chemotherapy in Patients With Resected Non–Small-Cell Lung Cancer: Reappraisal With a Meta-Analysis of Randomized Controlled Trials
Authors: Katsuyuki Hotta, Keitaro Matsuo, Hiroshi Ueoka, Katsuyuki Kiura, Masahiro Tabata, Mitsune Tanimoto
Journal: Journal of Clinical Oncology (2004)

The role of adjuvant chemotherapy in patients with resected non-small-cell lung cancer (NSCLC) remains to be defined. This study was aimed at re-evaluating the effectiveness of adjuvant chemotherapy in patients with resected NSCLC, by performing a meta-analysis of relevant trials.We performed a literature search to identify trials reported after the publication of a meta-analysis in 1995, comparing patients with NSCLC receiving chemotherapy after surgery with those undergoing surgery alone. The hazard ratio (HR) was estimated to assess the survival advantage of adjuvant chemotherapy.Eleven trials conducted on a total of 5,716 patients were identified by the literature search. In these trials, hazard ratio estimates suggested that adjuvant chemotherapy yielded a survival advantage over surgery alone (HR, 0.872; 95% CI, 0.805 to 0.944; P =.001). In a subset analysis, both cisplatin-based chemotherapy (HR, 0.891; 95% CI, 0.815 to 0.975; P =.012) and single-agent therapy with tegafur and uracil (UFT; HR, 0.799; 95% CI, 0.668 to 0.957; P =.015) were found to yield a significant survival benefit. The toxicities of adjuvant chemotherapy were found to be generally mild.This is the first updated meta-analysis demonstrating the importance of cisplatin-based chemotherapy and single-agent UFT therapy as adjuvant chemotherapy in the treatment of resected NSCLC. Although the results must be carefully interpreted because of one limitation (the meta-analysis was performed with abstracted data), they raise critical issues that must be resolved in future studies.
Murine Microenvironment Metaprofiles Associate with Human Cancer Etiology and Intrinsic Subtypes
Authors: David H. Nguyen, Erik Fredlund, Wei Zhao, Charles M. Perou, Allan Balmain, Jian-Hua Mao, Mary Helen Barcellos-Hoff
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Ionizing radiation is a well-established carcinogen in rodent models and a risk factor associated with human cancer. We developed a mouse model that captures radiation effects on host biology by transplanting unirradiated Trp53-null mammary tissue to sham or irradiated hosts. Gene expression profiles of tumors that arose in irradiated mice are distinct from those that arose in naïve hosts. We asked whether expression metaprofiles could discern radiation-preceded human cancer or be informative in sporadic breast cancers. Experimental Design: Affymetrix microarray gene expression data from 56 Trp53-null mammary tumors were used to define gene profiles and a centroid that discriminates tumors arising in irradiated hosts. These were applied to publicly available human cancer datasets. Results: Host irradiation induces a metaprofile consisting of gene modules representing stem cells, cell motility, macrophages, and autophagy. Human orthologs of the host irradiation metaprofile discriminated between radiation-preceded and sporadic human thyroid cancers. An irradiated host centroid was strongly associated with estrogen receptor–negative breast cancer. When applied to sporadic human breast cancers, the irradiated host metaprofile strongly associated with basal-like and claudin-low breast cancer intrinsic subtypes. Comparing host irradiation in the context of TGF-β levels showed that inflammation was robustly associated with claudin-low tumors. Conclusions: Detection of radiation-preceded human cancer by the irradiated host metaprofile raises possibilities of assessing human cancer etiology. Moreover, the association of the irradiated host metaprofiles with estrogen receptor–negative status and claudin-low subtype suggests that host processes similar to those induced by radiation underlie sporadic cancers. Clin Cancer Res; 19(6); 1353–62. ©2013 AACR.
Activated Human T Cells, B Cells, and Monocytes Produce Brain-derived Neurotrophic Factor In Vitro and in Inflammatory Brain Lesions: A Neuroprotective Role of Inflammation?
Authors: Martin Kerschensteiner, Eike Gallmeier, Lüder Behrens, Vivian Vargas Leal, Thomas Misgeld, Wolfgang E.F. Klinkert, Roland Kolbeck, Edmund Hoppe, Rosa-Laura Oropeza-Wekerle, Ilse Bartke, Christine Stadelmann, Hans Lassmann, Hartmut Wekerle, Reinhard Hohlfeld
Journal: The Journal of Experimental Medicine (1999)

Brain-derived neurotrophic factor (BDNF) has potent effects on neuronal survival and plasticity during development and after injury. In the nervous system, neurons are considered the major cellular source of BDNF. We demonstrate here that in addition, activated human T cells, B cells, and monocytes secrete bioactive BDNF in vitro. Notably, in T helper (Th)1- and Th2-type CD4+ T cell lines specific for myelin autoantigens such as myelin basic protein or myelin oligodendrocyte glycoprotein, BDNF production is increased upon antigen stimulation. The BDNF secreted by immune cells is bioactive, as it supports neuronal survival in vitro. Using anti-BDNF monoclonal antibody and polyclonal antiserum, BDNF immunoreactivity is demonstrable in inflammatory infiltrates in the brain of patients with acute disseminated encephalitis and multiple sclerosis. The results raise the possibility that in the nervous system, inflammatory infiltrates have a neuroprotective effect, which may limit the success of nonselective immunotherapies.
Treating brain tumor-initiating cells using a combination of myxoma virus and rapamycin
Authors: F. J. Zemp, X. Lun, B. A. McKenzie, H. Zhou, L. Maxwell, B. Sun, J. J. P. Kelly, O. Stechishin, A. Luchman, S. Weiss, J. G. Cairncross, M. G. Hamilton, B. A. Rabinovich, M. M. Rahman, M. R. Mohamed, S. Smallwood, D. L. Senger, J. Bell, G. McFadden, P. A. Forsyth
Journal: Neuro-Oncology (2013)

Intratumoral heterogeneity in glioblastoma multiforme (GBM) poses a significant barrier to therapy in certain subpopulation such as the tumor-initiating cell population, being shown to be refractory to conventional therapies. Oncolytic virotherapy has the potential to target multiple compartments within the tumor and thus circumvent some of the barriers facing conventional therapies. In this study, we investigate the oncolytic potential of myxoma virus (MYXV) alone and in combination with rapamycin in vitro and in vivo using human brain tumor–initiating cells (BTICs). We cultured fresh GBM specimens as neurospheres and assayed their growth characteristics in vivo. We then tested the susceptibility of BTICs to MYXV infection with or without rapamycin in vitro and assessed viral biodistribution/survival in vivo in orthotopic xenografts. The cultured neurospheres were found to retain stem cell markers in vivo, and they closely resembled human infiltrative GBM. In this study we determined that (i) all patient-derived BTICs tested, including those resistant to temozolomide, were susceptible to MYXV replication and killing in vitro; (ii) MYXV replicated within BTICs in vivo, and intratumoral administration of MYXV significantly prolonged survival of BTIC-bearing mice; (iii) combination therapy with MYXV and rapamycin improved antitumor activity, even in mice bearing "advanced" BTIC tumors; (iv) MYXV treatment decreased expression of stem cell markers in vitro and in vivo. Our study suggests that MYXV in combination with rapamycin infects and kills both the BTICs and the differentiated compartments of GBM and may be an effective treatment even in TMZ-resistant patients.
Tuberculosis contact investigation in low prevalence countries: a European consensus
Authors: C.G.M. Erkens, M. Kamphorst, I. Abubakar, G.H. Bothamley, D. Chemtob, W. Haas, G.B. Migliori, H.L. Rieder, J-P. Zellweger, C. Lange
Journal: European Respiratory Journal (2010)

Contact investigation to identify individuals with tuberculosis and latent infection with Mycobacterium tuberculosis is an important component of tuberculosis control in low tuberculosis incidence countries. This document provides evidence-based and best-practice policy recommendations for contact tracing among high- and medium-priority contacts in a variety of settings. It provides a basis for national guidelines on contact investigation and tuberculosis outbreak management, and should support countries and tuberculosis control managers in evaluating and revising national policies. A review of existing guidelines, a literature search, several meetings and consultation with experts were used to formulate and grade recommendations for action during contact investigation. Available tests to identify individuals with latent infection with M. tuberculosis are designed to identify immune response against mycobacterial antigens and have variable predictive value for the likelihood to develop active tuberculosis in different populations. Contact investigation should therefore be limited to situations with a clear likelihood of transmission or to those with a higher probability of developing active tuberculosis, for instance, young children and immunocompromised persons. A risk assessment-based approach is recommended, where the need to screen contacts is prioritised on the basis of the infectiousness of the index case, intensity of exposure and susceptibility of contacts.
The Small GTPase Arf1 Modulates Arp2/3-Mediated Actin Polymerization via PICK1 to Regulate Synaptic Plasticity
Authors: Daniel L. Rocca, Mascia Amici, Anna Antoniou, Elena Blanco Suarez, Nagaraj Halemani, Kai Murk, Jennifer McGarvey, Nadia Jaafari, Jack R. Mellor, Graham L. Collingridge, Jonathan G. Hanley
Journal: Neuron (2013)

Inhibition of Arp2/3-mediated actin polymerization by PICK1 is a central mechanism to AMPA receptor (AMPAR) internalization and long-term depression (LTD), although the signaling pathways that modulate this process in response to NMDA receptor (NMDAR) activation are unknown. Here, we define a function for the GTPase Arf1 in this process. We show that Arf1-GTP binds PICK1 to limit PICK1-mediated inhibition of Arp2/3 activity. Expression of mutant Arf1 that does not bind PICK1 leads to reduced surface levels of GluA2-containing AMPARs and smaller spines in hippocampal neurons, which occludes subsequent NMDA-induced AMPAR internalization and spine shrinkage. In organotypic slices, NMDAR-dependent LTD of AMPAR excitatory postsynaptic currents is abolished in neurons expressing mutant Arf1. Furthermore, NMDAR stimulation downregulates Arf1 activation and binding to PICK1 via the Arf-GAP GIT1. This study defines Arf1 as a critical regulator of actin dynamics and synaptic function via modulation of PICK1.
Psychological Impact of Changing the Scale of Reported HbA1c Results Affects Metabolic Control
Authors: Ragnar Hanas
Journal: Diabetes Care (2002)

HbA1c has been an invaluable tool for the monitoring of long-term complications in type 1 and type 2 diabetes. However, in spite of the wide international use of HbA1c, there has been a substantial lack of harmonization among methods (1). Both the Diabetes Control and Complications Trial (DCCT) (2) and the U.K. Prospective Diabetes Study (UKPDS) (3) used the same method for analysis of HbA1c and, with the help of the National Glycohemoglobin Standardization Program (NGSP), many HbA1c methods have been standardized to the results reported in these landmark trials (4). Pure reference material and reference methods for HbA1c have been under development for many years by the International Federation of Clinical Chemistry (IFCC) (5) and are now in the final stages (6).

From a clinical point of view, it is essential that HbA1c test results can be traced to the DCCT/UKPDS results where the relationships to risk for vascular complications have been established. Several experts have recommended that HbA1c should be reported in “DCCT-equivalent” percentage units (7,8) in order to avoid the confusion of adding another scale of numbers.

We evaluated the effect on a diabetic patient population of raising the reference scale up to the DCCT level in 1992 and then down to the Swedish national standard in 1997.

All patients at our center who had …
Health-related quality of life in patients with idiopathic pulmonary fibrosis
Authors: Franziska Ihle, Werner von Wulffen, Carlos Baezner, Nikolaus Kneidinger, Gregor Zimmermann, Carolin Schild, Vivian Arias Herrera, Jürgen Behr, Claus Neurohr
Journal: European Respiratory Journal (2013)

Background:  The aims of the present study were (1) to investigate overall health-related quality of life (HRQOL) in individuals with idiopathic pulmonary fibrosis (IPF), (2) to compare patients9 ratings with the age-matched general German population and (3) to investigate the correlation between HRQOL and vital capacity (VC).   Methods:  38 consecutive IPF patients (age 62±10.9 years; 23 male [59%]; 22 [58%] pirfenidon therapy; 3 [8%] nintedanib; 13 [34%] prednisolone and/or N-acetylcysteine; 20 [54%] long-term oxygen therapy; BMI 26.4±3.8kg/m 2 ) were evaluated by the standardized global Short Form-36 health questionnaire.   Results:  IPF patients were found to have a reduced HRQOL in physical SF-36 domains. In contrast, the socio- as well as the mental health of our IPF patients was good with SF-36 subscales reaching the upper tertile. Compared to the age-matched norm population, HRQOL self-ratings were significant reduced in three of eight SF-36 subscales: “physical functioning” (p≤0.01); “role limitations physical” (p=0.093) and “general medical health” (p=0.3). Only SF-36 subscale “physical functioning” significantly correlated with VC (r=0.564; p=0.01).   Conclusion:  The study results suggest especially a physical HRQOL limitation for IPF patients. HRQOL adds important patient sensitive information beyond objective clinical data and should be considered for clinical study design.
Surgery for Chronic Suppurative Otitis Media
Authors: Herbert Silverstein
Journal: New England Journal of Medicine (1972)

WITH the advent of the operating microscope, microsurgery and antibiotics, otology has rapidly developed into a sophisticated subspecialty involved in the eradication of chronic infection from the mastoid and middle-ear spaces, at the same time attempting to restore or improve hearing by reconstructive procedures on the tympanic membrane and ossicular chain.Cases of chronic suppurative otitis media are usually divided into two main pathologic groups: the benign or nondangerous and the dangerous bone-invading chronic suppurations. The benign type is characterized by a central perforation involving the pars tensa of the tympanic membrane. Such perforations are usually caused by acute necrotic . . .
The LIM Protein Leupaxin Is Enriched in Smooth Muscle and Functions As an Serum Response Factor Cofactor to Induce Smooth Muscle Cell Gene Transcription
Authors: Liisa J. Sundberg-Smith, Laura A. DiMichele, Rebecca L. Sayers, Christopher P. Mack, Joan M. Taylor
Journal: Circulation Research (2008)

Leupaxin is a LIM domain-containing adapter protein belonging to the paxillin family that has been previously reported to be preferentially expressed in hematopoietic cells. Herein, we identified leupaxin in a screen for focal adhesion kinase binding partners in aortic smooth muscle, and we show that leupaxin is enriched in human and mouse vascular smooth muscle and that leupaxin expression is dynamically regulated during development. In addition, our studies reveal that leupaxin can undergo cytoplasmic/nuclear shuttling and functions as an serum response factor cofactor in the nucleus. We found that leupaxin forms a complex with serum response factor and associates with CArG-containing regions of smooth muscle promoters and that ectopic expression of leupaxin induces smooth muscle marker gene expression in both 10T1/2 cells and rat aortic smooth muscle cells. Subsequent studies indicated that enhanced focal adhesion kinase activity (induced by fibronectin or expression of constitutively active focal adhesion kinase) attenuates the nuclear accumulation of leupaxin and limits the ability of leupaxin to enhance serum response factor-dependent gene transcription. Thus, these studies indicate that modulation of the subcellular localization of serum response factor cofactors is 1 mechanism by which extracellular matrix-dependent signals may regulate phenotypic switching of smooth muscle cells.
V kappa gene family in (Glu60 Ala30 Tyr10)n (GAT)-specific antibodies that express CGAT (or pGAT) public idiotypic specificities. Protein and mRNA sequencing of eight monoclonal V kappa chains.
Authors: C Tonnelle, J Rocca-Serra, A Moulin, D Moinier, M Fougereau
Journal: The Journal of Experimental Medicine (1983)

A large proportion of (Glu60 Ala30 Tyr10)n (GAT)-specific antibodies expresses public idiotypic specificities, termed CGAT (or pGAT), that require the presence of both the heavy and the light chains in order to be expressed. We report in this paper the complete sequence of eight V kappa regions pertaining to eight anti-GAT monoclonal antibodies derived from three strains of mice: BALB/c, DBA/2, and C57BL/6. The methodology used a combination of NH2-terminal amino acid and mRNA nucleotide sequencing. All eight sequences analyzed, although highly homologous and all pertaining to the same V kappa 1 subgroup, allowed definition of three germline genes that are likely to be present in all three strains of mice and also in NZB. It seems likely, however, that any given strain may not necessarily use all three genes for making anti-GAT antibodies. The search for structural correlates of idiotypes could not be framed in a simple picture, but our data suggest that similar idiotopes may result from different interacting primary structures, leading to structural homologies that should be visualized at three-dimensional level.
Restricted replication of lentiviruses. Visna viruses induce a unique interferon during interaction between lymphocytes and infected macrophages.
Authors: O Narayan, D Sheffer, J E Clements, G Tennekoon
Journal: The Journal of Experimental Medicine (1985)

Lentivirus infections are characterized by a persistent, restricted type of virus replication in tissues. Using sheep and goat lentiviruses, whose target cells in vivo are macrophages, we explored virus-host cell interactions to determine whether an interferon (IFN) is produced during virus replication in vivo which causes restricted replication. We show that the lentiviruses were incapable of inducing IFN directly in any infected cell, including macrophages and lymphocytes. However, after infection with these viruses, sheep and goat macrophages acquired a factor that triggered IFN production by T lymphocytes. Only sheep/goat lentiviruses were capable of inducing the factor and, although these viruses replicated productively in various cell cultures of the natural host animal, only infected macrophages developed the IFN-inducing factor. The factor was produced continuously and was strictly cell associated, requiring direct contact with lymphocytes. The lymphocytes responded with a single, sudden release of IFN beginning 7 h after cocultivation and reaching peak values at 48 h, after which they ceased production and became refractory. IFN production was not immunologically specific and did not require histocompatibility between donors of the two cell types. The IFN is a nonglycosylated protein of molecular weight 54,000-64,000, and is stable to heat and acid treatments. These findings identify a unique IFN and a new method for virus induction of IFN. The novel two-stage process of induction provides a mechanism for local amplification and continuity of production of IFN in vivo. This is compatible with infection in the animal whose lentivirus-induced pathologic lesions consist of accumulations of lymphocytes and infected macrophages in target tissues.
Direct and indirect immunofluorescence staining patterns in the diagnosis of paraneoplastic pemphigus
Authors: A.M. Poot, J. Siland, M.F. Jonkman, H.H. Pas, G.F.H. Diercks
Journal: British Journal of Dermatology (2015)

Paraneoplastic pemphigus (PNP) is a rare but severe multiorgan autoimmune disease that occurs in the presence of an underlying neoplasm. It is clinically characterized by a painful oral stomatitis, and a range of skin eruptions. In PNP, autoantibodies are directed against the intracellular desmosomal and hemidesmosomal plaque proteins of the plakin family: envoplakin, periplakin, desmoplakin, BP230 and plectin. In addition, the desmosomal proteins desmoglein (Dsg) 3 and less frequently Dsg 1 are targeted, as well as the protease inhibitor alpha-2-macroglobulin-like antigen-1 (A2ML1).(1-4) Diagnosing PNP largely depends on the demonstration of these autoantibodies. Immunoblotting and immunoprecipitation are sensitive and specific methods to detect these circulating antibodies. This article is protected by copyright. All rights reserved.
Procoagulant Soluble Tissue Factor Is Released From Endothelial Cells in Response to Inflammatory Cytokines
Authors: Björn Szotowski, Silvio Antoniak, Wolfgang Poller, Heinz-Peter Schultheiss, Ursula Rauch
Journal: Circulation Research (2005)

Inflammatory cytokines alter the hemostatic balance of endothelial cells (ECs). Alternatively spliced human tissue factor (asHTF), a soluble isoform of tissue factor (TF), has recently been detected in ECs, possibly contributing to procoagulability. Agonists regulating asHTF expression and release are yet unknown. This study examines the effect of TNF-α and IL-6 on the endothelial expression of both TF variants and delineates the impact of asHTF on the procoagulability of extracellular fluids. asHTF and TF mRNA were assessed by real-time PCR, and asHTF, TF, and tissue factor pathway inhibitor (TFPI) proteins by Western blot and fluorescence microscopy before and after stimulation with TNF-α (10 ng/mL) or IL-6 (10 ng/L). The procoagulability of cell supernatant was analyzed by a chromogenic assay with or without phospholipid vesicles. We found asHTF mRNA to be maximally increased 10 minutes after TNF-α and 40 minutes after IL-6 treatment (asHTF/GAPDH ratio 0.0223±0.0069 versus 0.0012±0.0006 for control, P &lt;0.001 and 0.0022±0.0004 versus 0.0012±0.0007, P &lt;0.05, respectively). Not only was asHTF increased, but also TFPI decreased after cytokine treatment. asHTF was found in the supernatant as early as 5 hours after TNF-α stimulation, supporting factor Xa generation after relipidation (6.55±1.13 U versus 2.99±0.59 U in control supernatant, P &lt;0.00001). Removal of asHTF from supernatants by immunoprecipitation diminished its procoagulability to baseline. The soluble TF isoform expressed and released from ECs in response to inflammatory cytokines becomes procoagulant in the presence of phospholipids. Thus, asHTF released from ECs is a marker for and a contributor to imbalanced hemostasis.
Impaired recovery of Epstein-Barr virus (EBV)—specific CD8+ T lymphocytes after partially T-depleted allogeneic stem cell transplantation may identify patients at very high risk for progressive EBV reactivation and lymphoproliferative disease
Authors: Pauline Meij, Joost W. J. van Esser, Hubert G. M. Niesters, Debbie van Baarle, Frank Miedema, Neil Blake, Alan B. Rickinson, Ingrid Leiner, Eric Pamer, Bob Löwenberg, Jan J. Cornelissen, Jan W. Gratama
Journal: Blood (2003)