tbuckley/cabot-search huggingface dataset:
Interaction of Integrin-Linked Kinase and Miniature Chromosome Maintenance 7–Mediating Integrin α7 Induced Cell Growth Suppression
Authors: Yu-Chen Han, Yan P. Yu, Joel Nelson, Chuanyue Wu, Hui Wang, George K. Michalopoulos, Jian-Hua Luo
Journal: Cancer Research (2010)

Abstract Mutation of integrin α7 (ITGA7) was previously identified in multiple human malignancies. Restoration of ITGA7 expression in prostate cancer and leiomyosarcoma cell lines suppressed tumor growth and cell motility both in vitro and in vivo. In this study, we showed that integrin-linked kinase (ILK) binds with miniature chromosome maintenance 7 (MCM7), a DNA replication licensing protein. A 58–amino acid ILK binding motif was identified in the NH2-terminus of MCM7. The expression of ITGA7 induced the phosphorylation of MCM7. Knocking down of ILK abrogated ITGA7-induced MCM7 phosphorylation. ANK, the dominant-negative mutant of ILK, also blocked the phosphorylation of MCM7 induced by ITGA7. The phosphorylation of MCM7 reduced MCM7 chromatin association and inhibited cell growth. A MCM7 mutant that does not bind with ILK did not respond to ITGA7 stimulation, and behaved similarly to a dominant MCM7-negative mutant and neutralized the effect of ITGA7. We conclude that ILK interaction with MCM7 and MCM7 phosphorylation may be a critical event in ITGA7 signaling pathway, leading to tumor suppression. Cancer Res; 70(11); 4375–84. ©2010 AACR.
Clinical phenotypes of Italian and Spanish patients with α<sub>1</sub>-antitrypsin deficiency
Authors: Barbara Piras, Ilaria Ferrarotti, Beatriz Lara, Maria Teresa Martinez, Ana Bustamante, Stefania Ottaviani, Pietro Pirina, Maurizio Luisetti, Marc Miravitlles
Journal: European Respiratory Journal (2012)

With the aim of providing better clinical characterisation of patients with α 1 -antitrypsin deficiency (AATD), we analysed the data of adult patients with severe AATD enrolled in the Spanish and Italian national registries. We assessed 745 subjects, 416 of whom were enrolled in the Spanish registry and 329 in the Italian registry. 57.2% were male and 64.9% were smokers or former smokers with a mean± sd age of 49.9±13.8 years. Most (81.2%) were index cases, mainly having the PI*ZZ genotype (73.4%), and the mean± sd diagnostic delay was 9.0±12.1 years. Patients with chronic bronchitis were younger, had better preserved lung function and lower tobacco consumption. Overlap patients (chronic obstructive pulmonary disease with asthma) were mainly females, more frequently never-smokers and received respiratory medications more often. 48% of emphysema, 27.5% of chronic bronchitis and 44.8% of overlap subjects were receiving augmentation therapy. Compared with PI*ZZ patients (n=547), the PI*SZ (n=124) subjects were older at diagnosis and had more preserved lung function, despite a higher mean smoking consumption. Early diagnosis of AATD is still an unmet need. Augmentation therapy is administered to similar proportions of patients with different clinical phenotypes. PI*ZZ patients in both registries had more severe respiratory disease than those with PI*SZ, despite lower smoking levels.
Cost-effectiveness Analysis of a Rotavirus Immunization Program for the United States
Authors: Andrew W. Tucker
Journal: JAMA (1998)

Context.—Rotavirus is the most common cause of severe diarrhea in children, and a live, oral vaccine may soon be licensed for prevention.Objective.—To estimate the economic impact of a national rotavirus immunization program in the United States.Design.—Cost-effectiveness was analyzed from the perspectives of the health care system and society. A decision tree used estimates of disease burden, costs, vaccine coverage, efficacy, and price obtained from published and unpublished sources.Intervention.—The proposed vaccine would be administered to infants at ages 2, 4, and 6 months as part of the routine schedule of childhood immunizations.Main Outcome Measures.—Total costs, outcomes prevented, and incremental cost-effectiveness.Results.—A routine, universal rotavirus immunization program would prevent 1.08 million cases of diarrhea, avoiding 34000 hospitalizations, 95000 emergency department visits, and 227000 physician visits in the first 5 years of life. At $20 per dose, the program would cost $289 million and realize a net loss of $107 million to the health care system—$103 per case prevented. The program would provide a net savings of $296 million to society. Threshold analysis identified a break-even price per dose of $9 for the health care system and $51 for the societal perspective. Greater disease burden and greater vaccine efficacy and lower vaccine price increased cost-effectiveness.Conclusions.—A US rotavirus immunization program would be cost-effective from the perspectives of society and the health care system, although the cost of the immunization program would not be fully offset by the reduction in health care cost of rotavirus diarrhea unless the price fell to $9 per dose.
Characteristics and clinical correlates of MPL 515W&gt;L/K mutation in essential thrombocythemia
Authors: Alessandro M. Vannucchi, Elisabetta Antonioli, Paola Guglielmelli, Alessandro Pancrazzi, Vittoria Guerini, Giovanni Barosi, Marco Ruggeri, Giorgina Specchia, Francesco Lo-Coco, Federica Delaini, Laura Villani, Silvia Finotto, Emanuele Ammatuna, Renato Alterini, Valentina Carrai, Gloria Capaccioli, Simonetta Di Lollo, Vincenzo Liso, Alessandro Rambaldi, Alberto Bosi, Tiziano Barbui
Journal: Blood (2008)
Genetic determination of the cellular basis of the sympathetic regulation of bone mass accrual
Authors: Daisuke Kajimura, Eiichi Hinoi, Mathieu Ferron, Aruna Kode, Kyle J. Riley, Bin Zhou, X. Edward Guo, Gerard Karsenty
Journal: The Journal of Experimental Medicine (2011)

The sympathetic nervous system, whose activity is regulated by leptin signaling in the brain, is a major regulator of bone mass accrual. To determine the identity of the cell type in which the sympathetic tone signals to inhibit bone mass accrual, we performed a systematic, cell-specific analysis of the function of the β2 adrenergic receptor (Adrβ2) and various genes implicated in the pathway in the mouse. This was followed by leptin intracerebroventricular (ICV) infusion and bone histomorphometric analyses of bone parameters. We show that the sympathetic tone signals in the osteoblasts to inhibit CREB (cAMP-responsive element-binding protein) phosphorylation and thus decrease osteoblast proliferation and to promote ATF4 phosphorylation and thus increase RANKL (receptor activator of NF-κB ligand) expression, which then stimulates osteoclast differentiation. Leptin ICV infusion in various mouse models established that leptin-dependent inhibition of bone mass accrual relies on both transcriptional events taking place in osteoblasts. Thus, this study formally identifies the osteoblast as the major cell type in which the molecular events triggered by the sympathetic regulation of bone mass accrual take place. As such, it suggests that inhibiting sympathetic signaling could be beneficial in the treatment of low bone mass conditions.
The B7 Family of Ligands and Its Receptors: New Pathways for Costimulation and Inhibition of Immune Responses
Authors: Beatriz M. Carreno, Mary Collins
Journal: Annual Review of Immunology (2002)

T cell activation is dependent upon signals delivered through the antigen-specific T cell receptor and accessory receptors on the T cell. A primary costimulatory signal is delivered through the CD28 receptor after engagement of its ligands, B7-1 (CD80) or B7-2 (CD86). Engagement of CTLA-4 (CD152) by the same B7-1 or B7-2 ligands results in attenuation of T cells responses. Recently, molecular homologs of CD28 and CTLA-4 receptors and their B7-like ligands have been identified. ICOS is a CD28-like costimulatory receptor with a unique B7-like ligand. PD-1 is an inhibitory receptor, with two B7-like ligands. Additional members of B7 and CD28 gene families have been proposed. Integration of signals through this family of costimulatory and inhibitory receptors and their ligands is critical for activation of immune responses and tolerance. Understanding these pathways will allow development of new strategies for therapeutic intervention in immune-mediated diseases.
OxLDL Triggers Retrograde Translocation of Arginase2 in Aortic Endothelial Cells via ROCK and Mitochondrial Processing Peptidase
Authors: Deepesh Pandey, Anil Bhunia, Young Jun Oh, Fumin Chang, Yehudit Bergman, Jae Hyung Kim, Janna Serbo, Tatiana N. Boronina, Robert N. Cole, Jennifer Van Eyk, Alan T. Remaley, Dan E. Berkowitz, Lewis H. Romer
Journal: Circulation Research (2014)

Increased arginase activity contributes to endothelial dysfunction by competition for l-arginine substrate and reciprocal regulation of nitric oxide synthase (NOS). The rapid increase in arginase activity in human aortic endothelial cells exposed to oxidized low-density lipoprotein (OxLDL) is consistent with post-translational modification or subcellular trafficking.To test the hypotheses that OxLDL triggers reverse translocation of mitochondrial arginase 2 (Arg2) to cytosol and Arg2 activation, and that this process is dependent on mitochondrial processing peptidase, lectin-like OxLDL receptor-1 receptor, and rho kinase.OxLDL-triggered translocation of Arg2 from mitochondria to cytosol in human aortic endothelial cells and in murine aortic intima with a concomitant rise in arginase activity. All of these changes were abolished by inhibition of mitochondrial processing peptidase or by its siRNA-mediated knockdown. Rho kinase inhibition and the absence of the lectin-like OxLDL receptor-1 in knockout mice also ablated translocation. Aminoterminal sequencing of Arg2 revealed 2 candidate mitochondrial targeting sequences, and deletion of either of these confined Arg2 to the cytoplasm. Inhibitors of mitochondrial processing peptidase or lectin-like OxLDL receptor-1 knockout attenuated OxLDL-mediated decrements in endothelial-specific NO production and increases in superoxide generation. Finally, Arg2(-/-) mice bred on an ApoE(-/-) background showed reduced plaque load, reduced reactive oxygen species production, enhanced NO, and improved endothelial function when compared with ApoE(-/-) controls.These data demonstrate dual distribution of Arg2, a protein with an unambiguous mitochondrial targeting sequence, in mammalian cells, and its reverse translocation to cytoplasm by alterations in the extracellular milieu. This novel molecular mechanism drives OxLDL-mediated arginase activation, endothelial NOS uncoupling, endothelial dysfunction, and atherogenesis.
Induction of Cell Cycle Arrest and Apoptosis by the Proteasome Inhibitor PS-341 in Hodgkin Disease Cell Lines Is Independent of Inhibitor of Nuclear Factor-κB Mutations or Activation of the CD30, CD40, and RANK Receptors
Authors: Bei Zheng, Georgios V. Georgakis, Yang Li, Alok Bharti, David McConkey, Bharat B. Aggarwal, Anas Younes
Journal: Clinical Cancer Research (2004)

The malignant Hodgkin and Reed-Sternberg cells of Hodgkin disease (HD) are known to constitutively express high levels of activated nuclear factor kappaB (NF-kappaB), which plays an important role in their survival. The proteasome inhibitor PS-341 has been recently shown to modulate tumor cell proliferation and survival by inhibiting NF-kappaB and modulating critical cellular regulatory proteins, but its activity in cells carrying IkappaBalpha gene mutations has not been reported previously.The activity of PS-341 in four well-characterized, HD-derived cell lines. Cell proliferation and apoptosis were determined by the 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfonyl)-2H-tetrazolium (MTS) and Annexin-V binding methods, respectively. Cell cycle analysis was determined by flow cytometry. Intracellular protein levels were determined by Western blot.PS-341 demonstrated a strong antiproliferative activity, which was irrespective of the status of mutations in IkappaBalpha and even the presence of CD30, CD40, or RANK receptor activation. This effect was attributable to the induction of apoptosis and cell cycle arrest at the G(2)-M phase. PS-341 not only inhibited nuclear localization of NF-kappaB but also activated the caspase cascade, increased p21 and Bax levels, and decreased Bcl-2 levels. Furthermore, PS-341 enhanced the effect of gemcitabine chemotherapy and potentiated the effect of tumor necrosis factor-related apoptosis-inducing ligand/APO2L and two agonistic antibodies to tumor necrosis factor-related apoptosis-inducing ligand death receptors R1 and R2.The in vitro activity of PS-341 against HD-derived cell lines suggests that PS-341 may have a therapeutic value for the treatment of HD.
Allergic bronchopulmonary aspergillosis in cystic fibrosis. A European epidemiological study
Authors: G. Mastella, M. Rainisio, H.K Harms, M.E Hodson, C Koch, J Navarro, B Strandvik, S.G McKenzie, on behalf of the investigators of the Epidemiologic Registry of Cystic Fibrosis
Journal: European Respiratory Journal (2000)

Allergic bronchopulmonary aspergillosis (ABPA) is a disease resulting from a hypersensitivity response to Aspergillus fumigatus, although the pathogenesis of the disease is unknown and its prevalence in cystic fibrosis (CF) is still poorly defined. Data from the Epidemiologic Registry of Cystic Fibrosis (ERCF) on 12,447 CF patients gathered from 224 CF centres in nine European countries were analysed. The ERCF definition of ABPA diagnosis is a positive skin test and serum precipitins to A. fumigatus, together with serum immunoglobulin (Ig)E levels &gt;1,000 U x mL(-1) and additional clinical or laboratory parameters. The overall prevalence of ABPA in the ERCF population was 7.8% (range: 2.1% in Sweden to 13.6% in Belgium). Prevalence was low &lt;6 yrs of age but was almost constant approximately 10% thereafter. No sex differences were observed. ABPA affected 8.0% of patients with a deltaF508/deltaF508 genotype and 5-6% with deltaF508/G551D, deltaF508/G542X and deltaF508/N1303K genotypes. ABPA patients presented a lower forced expiratory volume in one second (FEV1) than those without ABPA at any age and the prevalence ranged from 6.6% in patients with FEV1 &gt; or =20-12.9% in those with FEV1 &lt;40%. ABPA was associated with higher rates of microbial colonization, pneumothorax and massive haemoptysis, and with higher IgG serum levels and poorer nutritional status. A mixed model regression analysis of lung function showed that FEVI decline during the follow-up period was not substantially different in ABPA patients compared with non-ABPA patients for any subgroups based on age or disease severity at enrollment. To conclude, allergic bronchopulmonary aspergillosis is a frequent complication in cystic fibrosis patients, particularly after the age of 6 yrs, and it is generally associated with a poorer clinical condition. However, any clear independent influence of allergic bronchopulmonary aspergillosis on the rate of lung function decline in the short term was not shown.
Immunoglobulin G Responses Against Human Papillomavirus Type 16 Virus-Like Particles in a Prospective Nonintervention Cohort Study of Women With Cervical Intraepithelial Neoplasia
Authors: T. D. d. Gruijl, H. J. Bontkes, J. M. M. Walboomers, J. T. Schiller, M. J. Stukart, B. S. Groot, M. M. R. Chabaud, A. J. Remmink, R. H. M. Verheijen, C. J. L. M. Meijer, R. J. Scheper
Journal: JNCI Journal of the National Cancer Institute (1997)

Infection with cancer-linked human papillomavirus (HPV) types such as HPV type 16 (HPV16) is the most important risk factor in the development of cervical cancer. It has been shown that immunoglobulin G (IgG) antibody responses against HPV16 virus-like particles (VLPs) are specifically associated with genital HPV16 infection.The aim of this study was to determine the temporal relationships between the presence of HPV16 VLP-specific IgGs, HPV16 infection patterns, and the course of premalignant cervical disease.Plasma samples from 133 women who had been diagnosed originally with mild to moderate cervical dyskaryosis and enrolled in a prospective non-intervention cohort study conducted in Amsterdam, The Netherlands, from 1991 through 1996 were analyzed for the presence of HPV16 VLP-specific IgGs by use of an enzyme-linked immunosorbent assay. A detailed analysis was performed on 43 women with different HPV16 infection patterns during a follow-up period of 10-34 months. Progression or regression of cervical intraepithelial neoplasia (CIN) lesions was monitored by cytologic and colposcopic testing at intervals of 3-4 months. HPV typing in cervical smears was performed by use of a polymerase chain reaction-based assay. Statistical analysis of the serologic data was performed by use of the Mann-Whitney U test or 2 x 2 table analyses.The presence of HPV16 VLP-specific IgGs in the plasma of the patients was found to be associated with the presence of HPV16 DNA in the cervical smear. Significantly higher proportions of patients with persistent HPV16 infections (i.e., who were polymerase chain reaction positive in three to 11 consecutive tests) than of patients with cleared HPV16 infections were found to be positive for the presence of HPV16 VLP-specific IgGs (18 [69.2%] of 26 versus nine [28.1%] of 32, respectively; P = .003). HPV16 VLP-specific IgGs were consistently detected in all women (n = 11) who were persistently HPV16 DNA positive during follow-up and whose disease ultimately progressed to CIN III (histologically diagnosed severe dysplasia or carcinoma in situ).HPV16 VLP-specific IgG responses are present in the plasma of a majority of patients with persistent HPV16 infections and histologically confirmed high-grade lesions but only in a smaller subset of patients with cleared HPV16 infections and either normal cervical histology or low-grade CIN lesions.These results suggest that HPV16 VLP-specific antibodies are not responsible for the clearance of virally induced CIN lesions but that they might, in patients with persistent HPV16 infections, be indicative of an increased cervical cancer risk.
Autoregulation of Th1-mediated inflammation by <i>twist1 </i>
Authors: Uwe Niesner, Inka Albrecht, Marko Janke, Cornelia Doebis, Christoph Loddenkemper, Maria H. Lexberg, Katharina Eulenburg, Stephan Kreher, Juliana Koeck, Ria Baumgrass, Kerstin Bonhagen, Thomas Kamradt, Philipp Enghard, Jens Y. Humrich, Sascha Rutz, Ulf Schulze-Topphoff, Orhan Aktas, Sina Bartfeld, Helena Radbruch, Ahmed N. Hegazy, Max Löhning, Daniel C. Baumgart, Rainer Duchmann, Martin Rudwaleit, Thomas Häupl, Inna Gitelman, Veit Krenn, Joachim Gruen, Jochen Sieper, Martin Zeitz, Bertram Wiedenmann, Frauke Zipp, Alf Hamann, Michal Janitz, Alexander Scheffold, Gerd R. Burmester, Hyun D. Chang, Andreas Radbruch
Journal: The Journal of Experimental Medicine (2008)

The basic helix-loop-helix transcriptional repressor twist1, as an antagonist of nuclear factor κB (NF-κB)–dependent cytokine expression, is involved in the regulation of inflammation-induced immunopathology. We show that twist1 is expressed by activated T helper (Th) 1 effector memory (EM) cells. Induction of twist1 in Th cells depended on NF-κB, nuclear factor of activated T cells (NFAT), and interleukin (IL)-12 signaling via signal transducer and activator of transcription (STAT) 4. Expression of twist1 was transient after T cell receptor engagement, and increased upon repeated stimulation of Th1 cells. Imprinting for enhanced twist1 expression was characteristic of repeatedly restimulated EM Th cells, and thus of the pathogenic memory Th cells characteristic of chronic inflammation. Th lymphocytes from the inflamed joint or gut tissue of patients with rheumatic diseases, Crohn's disease or ulcerative colitis expressed high levels of twist1. Expression of twist1 in Th1 lymphocytes limited the expression of the cytokines interferon-γ, IL-2, and tumor necrosis factor-α, and ameliorated Th1-mediated immunopathology in delayed-type hypersensitivity and antigen-induced arthritis.
Somatic APC mosaicism: an underestimated cause of polyposis coli
Authors: F J Hes, M Nielsen, E C Bik, D Konvalinka, J T Wijnen, E Bakker, H F A Vasen, M H Breuning, C M J Tops
Journal: Gut (2007)

<h3>Background:</h3> The patient with 10 or more adenomas in the colon poses a diagnostic challenge. Beside germline mutations in the <i>APC</i> and <i>MUTYH</i> genes, only four cases of mosaic <i>APC</i> mutations have been reported. <h3>Aim:</h3> Given the relatively high frequency of de novo <i>APC</i> mutations in familial adenomatous polyposis (FAP), an investigation was carried out into whether the proportion of somatic mosaic <i>APC</i> mutations is currently underestimated. <h3>Methods:</h3> Between 1 January 1994 and 31 December 2005 germline mutation analysis was performed in 599 consecutive index patients with polyposis coli referred for diagnostic <i>APC</i> scanning using a combination of denaturing gradient gel electrophoresis (DGGE) and protein truncation test (PTT). Variants were analysed by direct sequencing with primers flanking those used for DGGE and PTT, and quantified using pyrosequencing. <h3>Results:</h3> Scrutinising the molecular genetic results and family data of 242 index patients with pathogenic <i>APC</i> mutations led to the identification of 10 mosaic cases (4%). C&gt;T transitions were observed in CGA sites in four of the 10 cases with somatic mosaicism, which is significantly more than 26 of the 232 non-mosaic cases (p = 0.02). Phenotypes of patients with somatic mosaicism ranged from an attenuated form of polyposis coli to florid polyposis with major extracolonic manifestations. <h3>Conclusions:</h3> Mosaicism occurs in a significant number of <i>APC</i> mutations and it is estimated that one-fifth of the de novo cases of FAP are mosaic. Clinically, the severity of manifestations in offspring and the recurrence risk for siblings of apparently sporadic polyposis patients may be underestimated due to parental <i>APC</i> mosaicism.
Impact of COPD in patients with coronary heart disease submitted to coronary heart bypass graft
Authors: Filipe Leite, Pedro Antunes, Manuel Antunes
Journal: European Respiratory Journal (2014)

Introduction: The association between COPD and coronary heart disease (CHD) as long been recognized and is included in most risk models. Still the extent of such association remains mostly unknown.  Objectives: To analyze the impact COPD in CHD and in the outcome of coronary heart bypass graft (CABG).  Material and Methods: Search the center9s database for CABG patients with COPD from January 1st 1990 to December 31st 2013.  Results: During this period 10791 patients were submitted to CABG (9327 male/1464 female), 356 with the diagnosis of COPD.  Considering CHD risk factors, no difference was found in terms of diabetes or hypertension. There was a difference in the incidence of tobacco (P  Postoperatively there was no difference in the overall mortality, nor in the number of cardiopulmonary arrests. No difference was found in the number of acute coronary syndromes, in the time of assisted ventilation, inotropes used or the number of reoperations due to haemorrhage.  A significant difference existed in the number of neurological complications, arrythmias and acute renal damage. Further the incidence of acute respiratory failure was greater in COPD patients (P  Conclusion: COPD patients presented with worse CHD, more risk factors and complications. This warrants a better preoperative optimization, a more careful surgery and postoperative period. Further, a stratification of COPD might reveal significant differences between the groups.