tbuckley/cabot-search huggingface dataset:
Quantitative effect of HLA-DRB1 alleles to ACPA levels in Japanese rheumatoid arthritis: no strong genetic impact of shared epitope to ACPA levels after stratification of HLA-DRB1*09:01
Authors: Chikashi Terao, Katsunori Ikari, Koichiro Ohmura, Taku Suzuki, Takuji Iwamoto, Kiyoshi Takasugi, Hiroo Saji, Atsuo Taniguchi, Shigeki Momohara, Hisashi Yamanaka, Fumihiko Matsuda, Tsuneyo Mimori
Journal: Annals of the Rheumatic Diseases (2012)

Anti-citrullinated peptide antibody (ACPA) is a highly specific serological marker for rheumatoid arthritis (RA).1,–,3 Different HLA-DRB1 alleles have been shown to be associated with the susceptibility to ACPA-positive RA.4 5 Former studies demonstrated that HLA-DRB alleles carrying a shared epitope (SE),6 consisting of a conserved amino acid motif at positions 70–74 of the HLA-DRβ chain, were strongly associated with ACPA-positive RA and with higher ACPA levels in European and Japanese populations.7,–,9 On the other hand, HLA-DRB1*09:01 was recently found to be negatively associated with ACPA levels in the Japanese.9 These observations imply that combinations of HLA-DRB1 alleles differentially influence ACPA levels in ACPA-positive RA.

To address this question, we conducted a genetic association study employing 2457 ACPA-positive Japanese RA patients. ACPA was quantified by MESACUP CCP ELISA kit (MBL Co Ltd, Nagoya, Japan) with a cut-off level of 4.5 U/ml. The patients were then divided into three groups …
Inhibiting Stat3 signaling in the hematopoietic system elicits multicomponent antitumor immunity
Authors: Marcin Kortylewski, Maciej Kujawski, Tianhong Wang, Sheng Wei, Shumin Zhang, Shari Pilon-Thomas, Guilian Niu, Heidi Kay, James Mulé, William G Kerr, Richard Jove, Drew Pardoll, Hua Yu
Journal: Nature Medicine (2005)
Re: The Diesel Exhaust in Miners Study: A Nested Case–Control Study of Lung Cancer and Diesel Exhaust
Authors: Lap-Ah Tse, Ignatius Tak-Sun Yu
Journal: JNCI Journal of the National Cancer Institute (2012)

In a recent article in the Journal on diesel exhaust exposure and lung cancer mortality among workers in US non–metal mining facilities, Silverman et al. (1) reported a statistically significantly increasing trend in lung cancer mortality with increasing exposure to cumulative respirable elemental carbon (REC) and average REC intensity, lagged and unlagged 15 years. The major advantage of this nested case–control study over previous epidemiological studies is the ability to obtain lifetime diesel exhaust exposure (represented by REC) of individual workers by incorporating historical industrial hygiene measurements with specific job titles and the calendar year. The overall results regarding the exposure–response relationship between diesel exhaust and lung cancer are generally plausible; however, we have questions about the results and interpretation of the interaction between smoking status/intensity and diesel exhaust exposure. The authors observed an attenuation of the effect of cigarette smoking among workers who were exposed to high levels of diesel exhaust, after adjustment for history of respiratory disease at least 5 years before date of death/reference date, history of a high-risk job for lung cancer for at least 10 years, and mine location (surface only vs ever underground work). The authors had proposed several mechanisms to explain the observed attenuated interactive effect, such as hypotheses about enzyme saturation and enzyme suppression (eg, reduced activity of cytochrome P450, subfamily IIB [CYP2B1]); however, it is possible that the attenuated smoking effect in the presence of high levels of diesel exhaust exposure is the result of a negative residual confounding effect of smoking. We derived the smoking prevalence separately for the surface and underground workers from the data provided in the article and found that the underground workers were more likely to quit smoking compared with the surface-only workers (33.9% vs 42.3%). We suspected that underground workers may have smoked less and had also quit smoking earlier than surface workers because smoking is likely to be prohibited in underground working environments where a high level of diesel exhaust exposure is expected, as is the case in the study of Silverman et al. (eg, ≥304 μg/m
Antibody-Dependent Cellular Cytotoxicity Mediated by Cetuximab against Lung Cancer Cell Lines
Authors: Jun Kurai, Hiroki Chikumi, Kiyoshi Hashimoto, Kosuke Yamaguchi, Akira Yamasaki, Takanori Sako, Hirokazu Touge, Haruhiko Makino, Miyako Takata, Masanori Miyata, Masaki Nakamoto, Naoto Burioka, Eiji Shimizu
Journal: Clinical Cancer Research (2007)

Epidermal growth factor receptor (EGFR) is commonly overexpressed in lung cancer. Cetuximab is a chimeric mouse-human antibody targeted against EGFR. Compared with its inhibitory properties, its immunologic mechanisms have not been well studied. In this study, we investigated the antibody-dependent cellular cytotoxicity (ADCC) activity of cetuximab against lung cancer cell lines.We studied the correlation between EGFR expression in lung cancer cell lines and the ADCC activity of cetuximab as well as the influence of interleukin-2 and chemotherapy on the ADCC activity. EGFR expression was measured by a quantitative flow cytometric analysis and immunohistochemistry. The ADCC activity was assessed by a 4-h (51)Cr release assay. Peripheral blood mononuclear cells, purified T cells, natural killer (NK) cells, and monocytes from healthy donors or lung cancer patients were used as effector cells.Fresh peripheral blood mononuclear cells exhibited cetuximab-mediated ADCC activity against lung cancer cell lines at a low concentration of cetuximab (0.25 microg/mL). A logarithmic correlation was observed between the number of EGFRs and ADCC activity. Even low EGFR expression, which was weakly detectable by immunohistochemistry, was sufficient for maximum ADCC activity, and further increases in EGFR expression on the target cells had no further effect on the ADCC activity. In addition, ADCC activity was enhanced by interleukin-2 mainly through activation of NK cells and was less susceptible to immunosuppression by chemotherapy than NK activity in lung cancer patients.These observations suggest the importance of ADCC activity as an immunologic mechanism of cetuximab in biological therapy for lung cancer patients.
Constitutive and inducible expression of SKALP/elafin provides anti-elastase defense in human epithelia.
Authors: R Pfundt, F van Ruissen, I M van Vlijmen-Willems, H A Alkemade, P L Zeeuwen, P H Jap, H Dijkman, J Fransen, H Croes, P E van Erp, J Schalkwijk
Journal: Journal of Clinical Investigation (1996)

Skin-derived antileukoproteinase (SKALP), also known as elafin, is a serine proteinase inhibitor first discovered in keratinocytes from hyperproliferative human epidermis. In addition to the proteinase inhibiting domain which is directed against polymorphonuclear leukocyte (PMN) derived enzymes such as elastase and proteinase 3, SKALP contains multiple transglutaminase (TGase) substrate domains which enable crosslinking to extracellular and cell envelope proteins. Here we show that SKALP is constitutively expressed in several epithelia that are continuously subjected to inflammatory stimuli, such as the oral cavity and the vagina where it co-localizes with type 1 TGase. All epithelia from sterile body cavities are negative for SKALP. In general, stratified squamous epithelia are positive, whereas pseudostratified epithelia, simple/glandular epithelia and normal epidermis are negative. SKALP was found in fetal tissues of the oral cavity from 17 wk gestation onwards where it continued to be expressed up to adult life. Remarkably, in fetal epidermis SKALP was found from week 28 onwards, but was downregulated to undetectable levels in neonatal skin within three months, suggesting a role during pregnancy in feto-maternal interactions or in the early maturation phase of the epidermis. Immunoelectron microscopy revealed the presence of SKALP in secretory vesicles including the lamellar granules. In culture models for epidermal keratinocytes we found that expression of the endogenous SKALP gene provided protection against cell detachment caused by purified elastase or activated PMNs. Addition of exogenous recombinant SKALP fully protected the keratinocytes against PMN-dependent detachment whereas superoxide dismutase and catalase were only marginally effective. These findings strongly suggest that the constitutive expression of SKALP in squamous epithelia, and the inducible expression in epidermis participate in the control of epithelial integrity, by inhibiting PMN derived proteinases.
N-Myc Regulates Expression of the Detoxifying Enzyme Glutathione Transferase <i>GSTP1</i>, a Marker of Poor Outcome in Neuroblastoma
Authors: Jamie I. Fletcher, Samuele Gherardi, Jayne Murray, Catherine A. Burkhart, Amanda Russell, Emanuele Valli, Janice Smith, André Oberthuer, Lesley J. Ashton, Wendy B. London, Glenn M. Marshall, Murray D. Norris, Giovanni Perini, Michelle Haber
Journal: Cancer Research (2011)

Amplification of the transcription factor MYCN is associated with poor outcome and a multidrug-resistant phenotype in neuroblastoma. N-Myc regulates the expression of several ATP-binding cassette (ABC) transporter genes, thus affecting global drug efflux. Because these transporters do not confer resistance to several important cytotoxic agents used to treat neuroblastoma, we explored the prognostic significance and transcriptional regulation of the phase II detoxifying enzyme, glutathione S-transferase P1 (GSTP1). Using quantitative real-time PCR, GSTP1 gene expression was assessed in a retrospective cohort of 51 patients and subsequently in a cohort of 207 prospectively accrued primary neuroblastomas. These data along with GSTP1 expression data from an independent microarray study of 251 neuroblastoma samples were correlated with established prognostic indicators and disease outcome. High levels of GSTP1 were associated with decreased event-free and overall survival in all three cohorts. Multivariable analyses, including age at diagnosis, tumor stage, and MYCN amplification status, were conducted on the two larger cohorts, independently showing the prognostic significance of GSTP1 expression levels in this setting. Mechanistic investigations revealed that GSTP1 is a direct transcriptional target of N-Myc in neuroblastoma cells. Together, our findings reveal that N-Myc regulates GSTP1 along with ABC transporters that act to control drug metabolism and efflux. Furthermore, they imply that strategies to jointly alter these key multidrug resistance mechanisms may have therapeutic implications to manage neuroblastomas and other malignancies driven by amplified Myc family genes.
Estimating the high risk group for cardiovascular disease in the Norwegian HUNT 2 population according to the 2003 European guidelines: modelling study
Authors: Linn Getz, Johann A Sigurdsson, Irene Hetlevik, Anna Luise Kirkengen, Solfrid Romundstad, Jostein Holmen
Journal: BMJ (2005)

<h3>Abstract</h3> <b>Objective</b> To estimate the high risk group for cardiovascular disease in a well defined Norwegian population according to European guidelines and the systematic coronary risk evaluation system. <b>Design</b> Modelling study. <b>Setting</b> Nord-Tröndelag health study 1995-7 (HUNT 2), Norway. <b>Participants</b> 5548 participants of the Nord-Tröndelag health study 1995-7, aged 40, 50, 55, 60, and 65. <b>Main outcome measures</b> Distribution of risk categories for cardiovascular disease, with emphasis on the high risk group. <b>Main results</b> At age 40, 22.5% (95% confidence interval 19.3% to 25.7%) of women and 85.9% (83.2% to 88.6%) of men were at high risk of cardiovascular disease. Corresponding numbers at age 50 were 39.5% (35.9% to 43.1%) and 88.7% (86.3% to 91.0%) and at age 65 were 84.0% (80.6% to 87.4%) and 91.6% (88.6% to 94.1%). At age 40, one out of 10 women and no men would be classified at low risk for cardiovascular disease. <b>Conclusion</b> Implementation of the 2003 European guidelines on prevention of cardiovascular disease in clinical practice would classify most adult Norwegians at high risk for fatal cardiovascular disease.
Carcinoid lung: diffuse pulmonary infiltration by a multifocal bronchial carcinoid.
Authors: C Skinner, S W Ewen
Journal: Thorax (1976)

A 20-year-old student presented with diarrhoea and miliary mottling in the chest radiograph. Biopsy specimens of lung and cervical lymph node showed diffuse multifocal carcinoid tumour. No deterioration in clinical state, radiographic appearances or lung function has occurred after two years9 treatment with melphalan.
Up-regulation of C-Terminal Tensin-like Molecule Promotes the Tumorigenicity of Colon Cancer through β-Catenin
Authors: Yi-Chun Liao, Nien-Tsu Chen, Yi-Ping Shih, Ying Dong, Su Hao Lo
Journal: Cancer Research (2009)

Abstract C-terminal tensin-like (cten) is a focal adhesion molecule belonging to the tensin family. Previous studies have suggested that cten may function as a prostate-specific tumor suppressor. Here, we show that although cten is expressed at a very low level in normal colon, its expression is significantly up-regulated in colon cancer. Furthermore, a high population of cten is found in the nucleus, where it interacts with β-catenin, a critical player in the canonical Wnt pathway. This interaction may contribute to the role of cten in enhancing the colony formation, anchorage-independent growth, and invasiveness of colon cancer cells. Our studies have identified cten as a novel nuclear partner of β-catenin, showed an oncogenic activity of cten in colon cancers, and revealed cten as a potential biomarker and target for colon cancers. [Cancer Res 2009;69(11):4563–6]
Repetitive Fragmentation Products of Albumin and α1-Antitrypsin in Glomerular Diseases Associated with Nephrotic Syndrome
Authors: Giovanni Candiano, Luca Musante, Maurizio Bruschi, Andrea Petretto, Laura Santucci, Piero Del Boccio, Barbara Pavone, Francesco Perfumo, Andrea Urbani, Francesco Scolari, Gian Marco Ghiggeri
Journal: Journal of the American Society of Nephrology (2006)

Even if nephrotic syndrome is characterized by massive urinary loss of major plasma proteins, a clear structural characterization based on proteomics has never been reported. Urine and plasma of 23 patients with different idiopathic nephrotic syndromes (10 steroid-sensitive minimal-change nephropathy, seven steroid-resistant FSGS, and six membranous glomerulonephritis) were analyzed with two-dimensional electrophoresis in soft gel, Western blot, and matrix-assisted laser desorption/ionization time of flight mass spectrometry; 72 urinary components corresponded to fragments of albumin and/or of alpha1-antitrypsin. Several repetitive fragmentation motives and a few differences among different pathologies were found. Several (21 of 72) urinary albumin fragments also were detected in plasma, although in lower concentration, suggesting a preferential excretion. The bulk of components with low molecular weight were detected only in urine, suggesting an in situ formation; zymograms with albumin as substrate showed the presence in urine of specific proteases. A final but not secondary point was the characterization of albumin adducts that harbor both the COOH and NH2 terminal parts of the protein, suggesting the formation of new covalent chemical groups. Altogether, these new findings reveal unexpected structural and functional aspects of proteinuria that may play a key role in pathogenesis. Characterization of urinary fragmentation patterns should be extended to other renal diseases.
Treatment of HER-2/<b> <i>neu</i> </b> Overexpressing Breast Cancer Xenograft Models with Trastuzumab (Herceptin) and Gefitinib (ZD1839): Drug Combination Effects on Tumor Growth, HER-2/<b> <i>neu</i> </b> and Epidermal Growth Factor Receptor Expression, and Viable Hypoxic Cell Fraction
Authors: Corinna Warburton, Wieslawa H. Dragowska, Karen Gelmon, Stephen Chia, Hong Yan, Dana Masin, Tetyana Denyssevych, Anne E. Wallis, Marcel B. Bally
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The purpose of this research was to assess the effects of single agent and combination treatment with trastuzumab and gefitinib on tumor growth and tumor microenvironment in two HER-2/neu overexpressing breast xenograft models, MDA-MB-435/LCC6HER-2 (LCC6HER-2; estrogen receptor negative) and MCF-7HER-2 (estrogen receptor positive). Experimental Design: LCC6HER-2 and MCF-7HER-2 cells, both in tissue culture and xenografts grown in SCID-Rag 2M mice, were treated with trastuzumab and gefitinib, alone or in combination. The rate of tumor growth was determined. In addition, tumor HER-2/neu and epidermal growth factor receptor expression, cell viability, cell cycle distribution, and proportion of viable hypoxic cells were determined by flow cytometric analyses of single tumor cell suspensions. Results: Both tumor models were very sensitive to trastuzumab and moderately sensitive to gefitinib in vivo. The combination resulted in therapeutic effects, as judged by inhibition of tumor growth, which was greater (albeit not statistically significant) than that observed with trastuzumab administered as a single agent. Trastuzumab was effective in down-regulating HER-2/neu, and gefitinib mediated a reduction in epidermal growth factor receptor expression on tumor cells. In LCC6HER-2 tumors, trastuzumab significantly reduced tumor cell viability, which was not improved by the addition of gefitinib. Gefitinib dramatically reduced the proportion of viable hypoxic cells in LCC6HER-2 and MCF-7HER-2 tumors. This effect was abrogated by the addition of trastuzumab. Conclusions: Although in vivo efficacy studies in two HER-2/neu overexpressing breast xenograft models showed that the combination of trastuzumab and gefitinib was effective, analyses of various cellular parameters failed to reveal beneficial effects and argue that this drug combination may not be favorable.
Invasive Methicillin-Resistant &lt;EMPH TYPE="ITAL"&gt;Staphylococcus aureus&lt;/EMPH&gt; Infections in the United States
Authors: R Monina Klevens, Melissa A Morrison, Joelle Nadle, Susan Petit, Ken Gershman, Susan Ray, Lee H Harrison, Ruth Lynfield, Ghinwa Dumyati, John M Townes, Allen S Craig, Elizabeth R Zell, Gregory E Fosheim, Linda K McDougal, Roberta B Carey, Scott K Fridkin
Journal: JAMA (2007)

ContextAs the epidemiology of infections with methicillin-resistant Staphylococcus aureus (MRSA) changes, accurate information on the scope and magnitude of MRSA infections in the US population is needed.ObjectivesTo describe the incidence and distribution of invasive MRSA disease in 9 US communities and to estimate the burden of invasive MRSA infections in the United States in 2005.Design and SettingActive, population-based surveillance for invasive MRSA in 9 sites participating in the Active Bacterial Core surveillance (ABCs)/Emerging Infections Program Network from July 2004 through December 2005. Reports of MRSA were investigated and classified as either health care–associated (either hospital-onset or community-onset) or community-associated (patients without established health care risk factors for MRSA).Main Outcome MeasuresIncidence rates and estimated number of invasive MRSA infections and in-hospital deaths among patients with MRSA in the United States in 2005; interval estimates of incidence excluding 1 site that appeared to be an outlier with the highest incidence; molecular characterization of infecting strains.ResultsThere were 8987 observed cases of invasive MRSA reported during the surveillance period. Most MRSA infections were health care–associated: 5250 (58.4%) were community-onset infections, 2389 (26.6%) were hospital-onset infections; 1234 (13.7%) were community-associated infections, and 114 (1.3%) could not be classified. In 2005, the standardized incidence rate of invasive MRSA was 31.8 per 100 000 (interval estimate, 24.4-35.2). Incidence rates were highest among persons 65 years and older (127.7 per 100 000; interval estimate, 92.6-156.9), blacks (66.5 per 100 000; interval estimate, 43.5-63.1), and males (37.5 per 100 000; interval estimate, 26.8-39.5). There were 1598 in-hospital deaths among patients with MRSA infection during the surveillance period. In 2005, the standardized mortality rate was 6.3 per 100 000 (interval estimate, 3.3-7.5). Molecular testing identified strains historically associated with community-associated disease outbreaks recovered from cultures in both hospital-onset and community-onset health care–associated infections in all surveillance areas.ConclusionsInvasive MRSA infection affects certain populations disproportionately. It is a major public health problem primarily related to health care but no longer confined to intensive care units, acute care hospitals, or any health care institution.
When Do Microbes Stimulate Rheumatoid Factor?
Authors: David N. Posnett, James Edinger
Journal: The Journal of Experimental Medicine (1997)

Anti–γ-globulins or rheumatoid factors (RF) were first described in the early 1940s. They are present in >70% of patients with rheumatoid arthritis (RA) and high titers are associated with severe disease, but they also appear in a large number of other diseases including viral, bacterial, and parasitic infections (1). In spite of their wide spread occurrence, it is still a puzzle how or why RF are generated.
Correction of DNA Protein Kinase Deficiency by Spliceosome-mediated RNA Trans-splicing and Sleeping Beauty Transposon Delivery
Authors: Hatem Zayed, Lily Xia, Anton Yerich, Stephen R Yant, Mark A Kay, M Puttaraju, Gerard J McGarrity, David L Wiest, R Scott McIvor, Jakub Tolar, Bruce R Blazar
Journal: Molecular Therapy (2007)

Spliceosome-mediated RNA trans-splicing (SMaRT) is an emerging technology for the repair of defective pre-messenger RNA (pre-mRNA) molecules. It is especially useful in the treatment of genetic disorders involving large genes. Although viral vectors have been used for achieving long-lasting expression of trans-splicing molecules, the immunogenicity and suboptimal safety profiles associated with viral-based components could limit the widespread application of SMaRT in the repair of genetic defects. Here, we tested whether the non-viral Sleeping Beauty (SB) transposon system could mediate stable delivery of trans-splicing molecules designed to correct the genetic defect responsible for severe combined immune deficiency (SCID). This immunological disorder is caused by a point mutation within the 12.4 kilobase (kb) gene encoding the DNA protein kinase catalytic subunit (DNA-PKcs) and is associated with aberrant DNA repair, defective T- and B-cell production, and hypersensitivity to radiation-induced injury. Using a novel SB-based trans-splicing vector, we demonstrate stable mRNA correction, proper DNA-PKcs protein production, and conference of a radiation-resistant phenotype in a T-cell thymoma cell line and SCID multipotent adult progenitor cells (MAPCs). These results suggest that SB-based trans-splicing vectors should prove useful in facilitating the correction of endogenous mutated mRNA transcripts, including the DNA-PKcs defect present in SCID cells.