tbuckley/cabot-search huggingface dataset:
High-density lipoproteins as modulators of endothelial cell functions: alterations in patients with coronary artery disease
Authors: A. Kratzer, H. Giral, U. Landmesser
Journal: Cardiovascular Research (2014)

Alteration of endothelial cell functions, including reduced endothelial nitric oxide (NO) availability, increased endothelial cell apoptosis, adhesion molecule/chemokine expression and pro-thrombotic activation are thought to contribute to the pathophysiology of atherosclerosis and coronary-artery-disease (CAD) with its clinical complications, such as acute coronary syndromes. High-density lipoproteins (HDL) from healthy subjects or reconstituted HDL have been observed to exert potential direct anti-atherogenic effects by modulating these endothelial cell functions. Importantly, endothelial effects of HDL have now been reported to be highly heterogeneous, and are modulated as part of immune responses. More recently, this has also been observed for HDL of patients with CAD, where HDL becomes potentially pro-inflammatory and endothelial-protective properties are markedly altered. Several mechanisms may lead to these altered endothelial effects of HDL in patients with CAD, including oxidative modification of HDL-associated lipids and proteins, such as apoA-I and paraoxonase-1, and alterations of HDL-proteome. These findings have to be considered with respect to interpretation of recent clinical studies failing to demonstrate reduced cardiovascular events by HDL-cholesterol raising strategies in patients with CAD. Both clinical and genetic studies suggest that HDL-cholesterol levels alone are not a sufficient therapeutic target in patients with CAD. The focus of this review is to summarize the role of HDL onto endothelial homeostasis and to describe recently characterized molecular pathways involved. We highlight how structural and functional modifications of HDL particles in patients with CAD may perturb the physiological homeostasis and lead to a loss of endothelial-protective properties of HDL in patients with CAD.
Distinct B-Cell and T-Cell Lymphoproliferative Disease Prevalence among Dog Breeds Indicates Heritable Risk
Authors: Jaime F. Modiano, Matthew Breen, Robert C. Burnett, Heidi G. Parker, Seidu Inusah, Rachael Thomas, Paul R. Avery, Kerstin Lindblad-Toh, Elaine A. Ostrander, Gary C. Cutter, Anne C. Avery
Journal: Cancer Research (2005)

Abstract Immunophenotypes in lymphoproliferative diseases (LPD) are prognostically significant, yet causative factors for these conditions, and specifically those associated with heritable risk, remain elusive. The full spectrum of LPD seen in humans occurs in dogs, but the incidence and lifetime risk of naturally occurring LPD differs among dog breeds. Taking advantage of the limited genetic heterogeneity that exists within dog breeds, we tested the hypothesis that the prevalence of LPD immunophenotypes would differ among different breeds. The sample population included 1,263 dogs representing 87 breeds. Immunophenotype was determined by the presence of clonal rearrangements of immunoglobulin heavy chain or T-cell receptor γ chain. The probability of observing the number of B-cell or T-cell tumors in a particular breed or breed group was compared with three reference populations. Significance was computed using χ2 test, and logistic regression was used to confirm binomial predictions. The data show that, among 87 breeds tested, 15 showed significant differences from the prevalence of LPD immunophenotypes seen across the dog population as a whole. More significantly, elevated risk for T-cell LPD seems to have arisen ancestrally and is retained in related breed groups, whereas increased risk for B-cell disease may stem from different risk factors, or combinations of risk factors, arising during the process of breed derivation and selection. The data show that domestic dogs provide a unique and valuable resource to define factors that mediate risk as well as genes involved in the initiation of B-cell and T-cell LPD.
Phospholipase Cγ1 Is Required for Metastasis Development and Progression
Authors: Gianluca Sala, Francesco Dituri, Claudio Raimondi, Sara Previdi, Tania Maffucci, Marco Mazzoletti, Cosmo Rossi, Manuela Iezzi, Rossano Lattanzio, Mauro Piantelli, Stefano Iacobelli, Massimo Broggini, Marco Falasca
Journal: Cancer Research (2008)

Abstract Cell motility and invasion play an essential role in the development of metastasis. Evidence suggests that the enzyme phospholipase Cγ1 (PLCγ1) may be involved in tumor progression and possibly development of metastasis. In this study, we show that down-regulation of PLCγ1 expression severely impairs activation of the small GTP-binding protein Rac and cell invasion in breast cancer cell lines and U87 in vitro. Experimental metastasis assays in nude mice show that inducible knockdown of PLCγ1 strongly inhibits development of MDA-MB-231–derived lung metastasis and reverts metastasis formation. In addition, analysis of 60 breast cancer patients' tissues revealed an increase of PLCγ1 expression in metastasis compared with the primary tumor in 50% of tissues analyzed. These data show a critical role of PLCγ1 in the metastatic potential of cancer cells, and they further indicate that PLCγ1 inhibition has a therapeutic potential in the treatment of metastasis dissemination. [Cancer Res 2008;68(24):10187–96]
Gulf War Veterans' Health: Medical Evaluation of a U.S. Cohort
Authors: Seth A. Eisen
Journal: Annals of Internal Medicine (2005)

Background: United States military personnel reported various symptoms after deployment to the Persian Gulf during the 1991 Gulf War. However, the symptoms' long-term prevalence and association with deployment remain controversial. Objective: To assess and compare the prevalence of selected medical conditions in a national cohort of deployed and nondeployed Gulf War veterans who were evaluated by direct medical and teledermatologic examinations. Design: A cross-sectional prevalence study performed 10 years after the 1991 Gulf War. Setting: Veterans were examined at 1 of 16 Veterans Affairs medical centers. Participants: Deployed (n = 1061) and nondeployed (n = 1128) veterans of the 1991 Gulf War. Measurements: Primary outcome measures included fibromyalgia, the chronic fatigue syndrome, dermatologic conditions, dyspepsia, physical health–related quality of life (Short Form-36 [SF-36]), hypertension, obstructive lung disease, arthralgias, and peripheral neuropathy. Results: Of 12 conditions, only 4 conditions were more prevalent among deployed than nondeployed veterans: fibromyalgia (deployed, 2.0%; nondeployed, 1.2%; odds ratio, 2.32 [95% CI, 1.02 to 5.27]); the chronic fatigue syndrome (deployed, 1.6%; nondeployed 0.1%; odds ratio, 40.6 [CI, 10.2 to 161]); dermatologic conditions (deployed, 34.6%; nondeployed, 26.8%; odds ratio, 1.38 [CI, 1.06 to 1.80]), and dyspepsia (deployed, 9.1%; nondeployed, 6.0%; odds ratio, 1.87 [CI, 1.16 to 2.99]). The mean physical component summary score of the SF-36 for deployed and nondeployed veterans was 49.3 and 50.8, respectively. Limitations: Relatively low participation rates introduce potential participation bias, and deployment-related illnesses that resolved before the research examination could not, by design, be detected. Conclusions: Ten years after the Gulf War, the physical health of deployed and nondeployed veterans is similar. However, Gulf War deployment is associated with an increased risk for fibromyalgia, the chronic fatigue syndrome, skin conditions, dyspepsia, and a clinically insignificant decrease in the SF-36 physical component score. *For a list of the Gulf War Study Participating Investigators, see the Appendix.
Activity of fulvestrant in HER2-overexpressing advanced breast cancer
Authors: J.F.R. Robertson, G.G. Steger, P. Neven, S. Barni, F. Gieseking, F. Nolè, K.I. Pritchard, F.P. O'Malley, S.D. Simon, B. Kaufman, L. Petruzelka
Journal: Annals of Oncology (2009)
Multifocal epithelial tumors and field cancerization: stroma as a primary determinant
Authors: G. Paolo Dotto
Journal: Journal of Clinical Investigation (2014)

It is increasingly evident that cancer results from altered organ homeostasis rather than from deregulated control of single cells or groups of cells. This applies especially to epithelial cancer, the most common form of human solid tumors and a major cause of cancer lethality. In the vast majority of cases, in situ epithelial cancer lesions do not progress into malignancy, even if they harbor many of the genetic changes found in invasive and metastatic tumors. While changes in tumor stroma are frequently viewed as secondary to changes in the epithelium, recent evidence indicates that they can play a primary role in both cancer progression and initiation. These processes may explain the phenomenon of field cancerization, i.e., the occurrence of multifocal and recurrent epithelial tumors that are preceded by and associated with widespread changes of surrounding tissue or organ "fields."
The pathogenesis of duodenal gastric metaplasia: the role of local goblet cell transformation
Authors: R Shaoul
Journal: Gut (2000)

<h3>BACKGROUND AND AIMS</h3> Gastric metaplasia is frequently seen in biopsies of the duodenal cap, particularly when inflamed or ulcerated. In its initial manifestation small patches of gastric foveolar cells appear near the tip of a villus. These cells contain periodic acid-Schiff (PAS) positive neutral mucins in contrast with the alcian blue (AB) positive acidic mucins within duodenal goblet cells. Previous investigations have suggested that these PAS positive cells originate either in Brunner9s gland ducts or at the base of duodenal crypts and migrate in distinct streams to the upper villus. To investigate the origin of gastric metaplasia in superficial patches, we used the PAS/AB stain to distinguish between neutral and acidic mucins and in addition specific antibodies to immunolocalise foveolar cell mucin MUC5AC, the foveolar cell secretory product, gastric trefoil factor (TFF1), the mature goblet cell mucin MUC2, and MUC2 core antigen. <h3>RESULTS</h3> Cells in focal patches of gastric metaplasia contained secretory granules of both gastric and goblet cell phenotypes. MUC5AC and TFF1 were present as expected in gastric foveolar cells but in addition, MUC2 core antigen, normally present only in the Golgi of intestinal goblet cells, was expressed in secretory granules. Goblet cells in the vicinity of metaplastic patches also expressed both gastric and intestinal antigens. MUC5AC/MUC2 containing goblet cells were most common near the villus tip but were also seen at the base of crypts. Where crypts and Brunner9s gland ducts merged they were always seen on the crypt side of the junction. Goblet cells were the only cells to express gastric antigens in these areas. In advanced metaplastic lesions, dual phenotype goblet cells were less evident and fewer cells expressed intestinal mucin antigens. <h3>CONCLUSIONS</h3> We suggest that goblet cells that express both intestinal and gastric antigens may represent local precursors of gastric metaplasia undergoing a transition to foveolar-like cells of mixed phenotype at the site of early metaplastic patches. As metaplasia becomes more widespread, a more pure gastric phenotype emerges. This progression is likely to be controlled by local inflammatory signals.
Re-emergence of epidemic Venezuelan equine encephalomyelitis in South America
Authors: Scott C Weaver, Rosalba Salas, Rebeca Rico-Hesse, George V Ludwig, M Steven Oberste, Jorge Boshell, Robert B Tesh
Journal: The Lancet (1996)

BackgroundVenezuelan equine encephalomyelitis (VEE) virus has caused periodic epidemics among human beings and equines in Latin America from the 1920s to the early 1970s. The first major outbreak since 1973 occurred in Venezuela and Colombia during 1995, and involved an estimated 75 000 to 100 000 people. We report an epidemiological and virological investigation of this epidemic.MethodsVirus isolates were made in cell culture from human serum, human throat swabs, and brain tissue from aborted and stillborn human fetuses, as well as from horse brain tissue and pooled mosquito collections. Human sera were also tested for VEE-specific antibodies. The serotypes of VEE isolates were identified by antigen assays, and viruses were characterised genetically by sequencing PCR products generated from the E3 and E2 genes. Phylogenetic analyses were done to determine evolutionary relations with respect to previous epidemic/epizootic and enzootic VEE virus isolates. Mosquito collections were made to identify possible vectors, and clinical findings were determined by direct observation of patients visiting hospitals and clinics in affected regions, and by inspecting patient records. Equine vaccination and vector control were used in an attempt to halt the spread of the outbreak.FindingsMost affected people had an acute, self-limited febrile illness of 3 to 4 days duration. However, convulsions were often seen in children, and abortions and fetal deaths occurred in pregnant women infected with VEE virus. Antigenic characterisation of 12 virus isolates spanning the temporal and spatial range of the outbreak indicated that all are VEE serotype IC. Phylogenetic analysis revealed that all of the 1995 viruses were closely related to serotype IC viruses isolated during a large VEE outbreak that occurred in the same regions of Colombia and Venezuela from 1962–1964. A 1983 mosquito isolate from north central Venezuela was also closely related to the 1995 isolates.InterpretationThis outbreak was remarkably similar to one that occurred in same regions of Venezuela and Colombia during 1962–1964. Symptoms of infected patients, estimated mortality rates, meteorological conditions preceding the epidemic, and seasonal patterns of transmission were all very similar to those reported in the previous outbreak. In addition, viruses isolated during 1995 were antigenically and genetically nearly identifical to those obtained during 1962–1964. These findings suggest that the epidemic resulted from the re-emergence of an epizootic serotype IC VEE virus. Identification of a similar virus isolate in mosquitoes in Venezuela in 1983, 10 years after epidemic/epizootic VEE activity ceased, raises the possibility of a serotype IC enzootic transmission cycle in northern Venezuela.
A 52-Week Trial Comparing Briakinumab with Methotrexate in Patients with Psoriasis
Authors: Kristian Reich, Richard G. Langley, Kim A. Papp, Jean-Paul Ortonne, Kristina Unnebrink, Martin Kaul, Joaquin M. Valdes
Journal: New England Journal of Medicine (2011)

Briakinumab is a monoclonal antibody against the p40 molecule shared by interleukin-12 and interleukin-23, which is overexpressed in psoriatic skin lesions. We assessed the efficacy and safety of briakinumab as compared with methotrexate in patients with psoriasis.In this 52-week trial, we randomly assigned 317 patients with moderate-to-severe psoriasis to briakinumab, at a dose of 200 mg at weeks 0 and 4 and 100 mg at week 8 and every 4 weeks thereafter (154 patients), or methotrexate, at a dose of 5 to 25 mg weekly (163 patients). The primary end points were the percentages of patients with at least 75% improvement in the score on the psoriasis area-and-severity index (PASI) at weeks 24 and 52 and a score on the physician's global assessment of 0 (clear; i.e., no apparent disease) or 1 (minimal disease) at weeks 24 and 52. A total of 248 patients were enrolled in an ongoing 160-week open-label continuation study.At week 24, a total of 81.8% of the patients in the briakinumab group versus 39.9% in the methotrexate group had at least 75% improvement in the PASI score, and 80.5% versus 34.4% had a score of 0 or 1 on the physician's global assessment. The corresponding percentages at week 52 were 66.2% versus 23.9% with at least a 75% improvement in the PASI score and 63.0% versus 20.2% with a score of 0 or 1 on the physician's global assessment (P<0.001 for all comparisons). During the 52-week study, serious adverse events occurred in 9.1% of the patients in the briakinumab group (12.9 events per 100 patient-years) and in 6.1% in the methotrexate group (10.6 events per 100 patient-years). Serious infections occurred in 2.6% of the patients in the briakinumab group (4.1 events per 100 patient-years) and in 1.8% in the methotrexate group (2.7 events per 100 patient-years); cancers occurred in 1.9% (2.0 events per 100 patient-years) versus 0%.Briakinumab showed higher efficacy than methotrexate in patients with moderate-to-severe psoriasis. Serious infections and cancers occurred more frequently with briakinumab, but the differences were not significant. (Funded by Abbott Laboratories; ClinicalTrials.gov number, NCT00679731.).
Activation of Hedgehog Signaling by the Environmental Toxicant Arsenic May Contribute to the Etiology of Arsenic-Induced Tumors
Authors: Dennis Liang Fei, Hua Li, Courtney D. Kozul, Kendall E. Black, Samer Singh, Julie A. Gosse, James DiRenzo, Kathleen A. Martin, Baolin Wang, Joshua W. Hamilton, Margaret R. Karagas, David J. Robbins
Journal: Cancer Research (2010)

Exposure to the environmental toxicant arsenic, through both contaminated water and food, contributes to significant health problems worldwide. In particular, arsenic exposure is thought to function as a carcinogen for lung, skin, and bladder cancer via mechanisms that remain largely unknown. More recently, the Hedgehog signaling pathway has also been implicated in the progression and maintenance of these same cancers. Based on these similarities, we tested the hypothesis that arsenic may act in part through activating Hedgehog signaling. Here, we show that arsenic is able to activate Hedgehog signaling in several primary and established tissue culture cells as well as in vivo. Arsenic activates Hedgehog signaling by decreasing the stability of the repressor form of GLI3, one of the transcription factors that ultimately regulate Hedgehog activity. We also show, using tumor samples from a cohort of bladder cancer patients, that high levels of arsenic exposure are associated with high levels of Hedgehog activity. Given the important role Hedgehog signaling plays in the maintenance and progression of a variety of tumors, including bladder cancer, these results suggest that arsenic exposure may in part promote cancer through the activation of Hedgehog signaling. Thus, we provide an important insight into the etiology of arsenic-induced human carcinogenesis, which may be relevant to millions of people exposed to high levels of arsenic worldwide.
Case of spontaneous haemothorax associated with an endodermal sinus tumour.
Authors: M Karabocuoglu, S Ugur, N Uzel, E Dayioglu, D Yilmazbayhan, R Ilhan
Journal: Thorax (1993)

Abstract Spontaneous haemothorax is rare in infants. A case is reported of a nine month old infant who was found to have an endodermal sinus tumour.
Antiangiogenic gene therapy for hepatocellular carcinoma using angiostatin gene
Authors: Hiroki Ishikawa, Kazuhiko Nakao, Kojiro Matsumoto, Tatsuki Ichikawa, Keisuke Hamasaki, Keisuke Nakata, Katsumi Eguchi
Journal: Hepatology (2003)

Recent studies have reported that antiangiogenic gene delivery into cancer cells inhibits growth of certain tumors in vivo. Hepatocellular carcinoma (HCC) is a hypervascular cancer, and antiangiogenic gene therapy might be suitable for HCC. In the present study, we investigated the antiangiogenic effects of angiostatin gene transduction into HCC both in vitro and in vivo. Angiostatin gene was cloned into a pSecTag2B mammalian expression vector to construct pSecTag2B-ANG. pSecTag2B or pSecTag2B-ANG were transfected into an HCC cell line, PLC/PRF/5, and then stable transfectants were obtained by Zeocin selection. pSecTag2B or pSecTag2B-ANG transfection did not alter the expression of vascular endothelial growth factor (VEGF), a potent angiogenic stimulator, or pigment epithelium-derived factor (PEDF), an angiogenic inhibitor, in PLC/PRF/5 cells. However, conditioned media (CM) derived from pSecTag2B-ANG-transfected PLC/PRF/5 cells (CM-ANG) suppressed the proliferation and migration of human umbilical vein endothelial cells (HUVEC) by 35% and 50%, respectively, relative to their effects on nontransfected cells. In in vivo experiments, pSecTag2B-ANG stable transfected (CM-Mock) and nontransfected cells (CM-N) were mixed at various proportions and the mixed cells were subcutaneously implanted into athymic mice. Suppression of tumor growth was noted in mice implanted with angiostatin gene-transfected cells, and such suppression was proportional with the percentage of transfected cells. Analysis of the vascular density in these tumors showed that the tumor growth suppression effect of angiostatin gene correlated with suppression of tumor vascularity. In conclusion, antiangiogenic gene therapy using angiostatin gene is potentially suitable for the treatment of patients with HCC.
Identification, characterization and comparative genomics of chimpanzee endogenous retroviruses
Authors: Nalini Polavarapu, Nathan J Bowen, John F McDonald
Journal: Genome biology (2006)

Retrotransposons, the most abundant and widespread class of eukaryotic transposable elements, are believed to play a significant role in mutation and disease and to have contributed significantly to the evolution of genome structure and function. The recent sequencing of the chimpanzee genome is providing an unprecedented opportunity to study the functional significance of these elements in two closely related primate species and to better evaluate their role in primate evolution.We report here that the chimpanzee genome contains at least 42 separate families of endogenous retroviruses, nine of which were not previously identified. All but two (CERV 1/PTERV1 and CERV 2) of the 42 families of chimpanzee endogenous retroviruses were found to have orthologs in humans. Molecular analysis (PCR and Southern hybridization) of CERV 2 elements demonstrates that this family is present in chimpanzee, bonobo, gorilla and old-world monkeys but absent in human, orangutan and new-world monkeys. A survey of endogenous retroviral positional variation between chimpanzees and humans determined that approximately 7% of all chimpanzee-human INDEL variation is associated with endogenous retroviral sequences.Nine families of chimpanzee endogenous retroviruses have been transpositionally active since chimpanzees and humans diverged from a common ancestor. Seven of these transpositionally active families have orthologs in humans, one of which has also been transpositionally active in humans since the human-chimpanzee divergence about six million years ago. Comparative analyses of orthologous regions of the human and chimpanzee genomes have revealed that a significant portion of INDEL variation between chimpanzees and humans is attributable to endogenous retroviruses and may be of evolutionary significance.
Sarcoidosis: immunopathogenetic concepts and their clinical application
Authors: J Muller-Quernheim
Journal: European Respiratory Journal (1998)

Our understanding of the immunopathogenesis of sarcoidosis has been advanced by studies of bronchoalveolar lavage cells. Activated macrophages and T-cells have been identified in different compartments of the sarcoid lung and the characteristics of the activation suggest that the cells become activated in the course of a normal immune response. The immune cells communicate via a cytokine network and the measuring of cytokine levels yields subgroups of sarcoidosis patients with different courses of the disease indicating different states of activation of the disease-mediating immune cells. The causative agent of sarcoidosis has not yet been identified; however, some of the described mechanisms can be clinically applied either to detect patients at risk of deterioration or to develop new therapeutic strategies. Using these approaches methotrexate, pentoxifylline and thalidomide have been identified as drugs which effectively suppress sarcoid inflammation and the serum level of soluble interleukin-2 receptors has been delineated to be a serum marker of sarcoid inflammation. Furthermore, analysing the pulmonary cytokine network in sarcoidosis will yield new staging parameters possibly supplying prognostic information and guiding therapeutic intervention.