tbuckley/cabot-search huggingface dataset:
Evaluation of 21st-Century Risks of Smallpox Vaccination and Policy Options
Authors: J. Michael Lane, Joel Goldstein
Journal: Annals of Internal Medicine (2003)

The United States stopped vaccinating against smallpox in 1972 because the risks were judged to outweigh the benefits. The possibility of a terrorist attack using smallpox has led to renewed interest in a vaccination program. Smallpox vaccination carries considerable risks, which may be of greater concern today than in the late 1960s because of the increased prevalence of immunosuppression and atopy in the population. This paper reviews the clinical presentations of major adverse events after vaccination and the rates of occurrence of these events observed in the 1960s. The normal dynamics of the spread of smallpox is slow, and usually only persons who have had close personal contact with an overtly ill patient are affected. There are several preattack vaccination policy options, but immunization of medical workers, especially those who might have close contact with infected patients, is sufficient in the absence of a known threat of a bioterrorist attack or the identification of a smallpox-infected person.
Effect of interferon gamma-1b on survival in patients with idiopathic pulmonary fibrosis (INSPIRE): a multicentre, randomised, placebo-controlled trial
Authors: Talmadge E King, Carlo Albera, Williamson Z Bradford, Ulrich Costabel, Phil Hormel, Lisa Lancaster, Paul W Noble, Steven A Sahn, Javier Szwarcberg, Michiel Thomeer, Dominique Valeyre, Roland M du Bois
Journal: The Lancet (2009)
<i>In vivo</i> Imaging and Quantitation of Adoptively Transferred Human Antigen-Specific T Cells Transduced to Express a Human Norepinephrine Transporter Gene
Authors: Mikhail M. Doubrovin, Ekaterina S. Doubrovina, Pat Zanzonico, Michel Sadelain, Steven M. Larson, Richard J. O'Reilly
Journal: Cancer Research (2007)

Sequential imaging of genetically marked effector cells after adoptive transfer in vivo has greatly enhanced analyses of their biodistribution, growth, and activity both in animal models and in clinical trials of cellular immunotherapy. However, the immunogenicity of cells expressing xenogeneic reporter constructs limits their survival and clinical utility. To address this limitation, we have evaluated a human norepinephrine transporter (hNET) permitting imaging of transduced cells in vivo with a previously approved clinical grade radiolabeled probe, metaiodobenzylguanidine (MIBG). The hNET gene cDNA was cloned from the SK-N-SH cell line and inserted into a bicistronic retroviral vector also encoding green fluorescent protein. Following transfection, human EBV-specific T lymphocytes seemed fully functional in vitro and also selectively accumulated [(123)I]MIBG. In nonobese diabetic/severe combined immunodeficient mice bearing human EBV lymphoma xenografts, as few as 10(4) transduced T cells injected into the tumors could be imaged by single-photon emission computed tomography (SPECT) or positron emission tomography (PET) after i.v. infusion of [(123)I]MIBG or [(124)I]MIBG, respectively. When hNET(+) EBV-specific T cells were infused i.v., their migration and specific accumulation in EBV(+) tumors expressing their restricting HLA allele could be imaged by SPECT or PET over 28 days. Image intensity was closely correlated with the number of T cells accumulated in targeted tumors. The use of two reporter probes (MIBG and 2'-deoxy-2'-fluoro-beta-d-arabinofuranosyl-5-iodouracil) permitted independent contemporaneous tracking of two distinct EBV-specific T-cell subpopulations expressing different reporter genes (hNET-CD4(+) T cells and HSV-TK-CD8(+) T cells) in the same animal using three-dimensional nuclear modalities (SPECT and PET). The hNET-based system described may thus have significant potential as a nonimmunogenic reporter for extended repeated quantitative in vivo imaging of transduced cells in man.
MHC Class I Genes in the Tuatara (Sphenodon spp.): Evolution of the MHC in an Ancient Reptilian Order
Authors: H. C. Miller
Journal: Molecular Biology and Evolution (2006)

The major histocompatibility complex (MHC) is an extremely dynamic region of the genome, characterized by high polymorphism and frequent gene duplications and rearrangements. This has resulted in considerable differences in MHC organization and evolution among vertebrate lineages, particularly between birds and mammals. As nonavian reptiles are ancestral to both mammals and birds, they occupy an important phylogenetic position for understanding these differences. However, little is known about reptile MHC genes. To address this, we have characterized MHC class I sequences from the tuatara (Sphenodon spp.), the last survivor of an ancient order of reptiles, Sphenodontia. We isolated two different class I cDNA sequences, which share 93% sequence similarity with each other but are highly divergent from other vertebrate MHC genes. Southern blotting and polymerase chain reaction amplification of class I sequences from seven adult tuatara plus a family group indicate that these sequences represent at least two to three loci. Preliminary analysis of variation among individuals from an island population of tuatara indicates that these loci are highly polymorphic. Maximum likelihood analysis of reptile MHC class I sequences indicates that gene duplication has occurred within reptilian orders. However, the evolutionary relationships among sequences from different reptilian orders cannot be resolved, reflecting the antiquity of the major reptile lineages.
Growth Inhibition of Human Ovarian Cancers by Cytotoxic Analogues of Luteinizing Hormone-Releasing Hormone
Authors: M. Miyazaki, A. Nagy, A. V. Schally, N. Lamharzi, G. Halmos, K. Szepeshazi, K. Groot, P. Armatis
Journal: JNCI Journal of the National Cancer Institute (1997)

Background: Receptors for luteinizing hormone-releasing hormone (LH-RH) are found in nearly 80% of human ovarian cancers. The chemotherapeutic agent doxorubicin can be linked to [ d -lysine 6 ]LH-RH to form a cytotoxic analogue (AN-152) that may have greater specificity for tumor cells. This study was conducted to investigate the effects of AN-152 on the growth of LHRH receptor-positive OV-1063 human epithelial ovarian cancers. Methods: Nude mice bearing human ovarian tumors, OV-1063 or UCI-107 (LH-RH receptor negative), were injected intraperitoneally with saline (control) or with equimolar doses of AN-152 or doxorubicin; experiments involving mice with OV-1063 tumors also included groups that were administered [ d -lysine 6 ]LH-RH either alone or in combination with doxorubicin. Tumor volume, weight, doubling time, and burden (i.e., tumor weight/body weight) as well as tumor apoptotic and mitotic indices were determined. The levels of receptors for LH-RH and epidermal growth factor (EGF) and their messenger RNAs were measured by use of radioreceptor and reverse transcription-polymerase chain reaction assays, respectively. Results: The growth of OV-1063 ovarian tumors in nude mice, as based on reduction in tumor volume, was inhibited significantly (all P<.05, two-sided) 4 weeks after treatment with AN-152, even at the lowest dose tested (413 nmol/20 g weight); the toxic effects of an equivalent dose of doxorubicin caused substantial mortality. Highaffinity receptors for LH-RH and EGF were found on cell membranes of OV1063 cancers; however, after in vivo treatment with AN-152, LH-RH receptor-binding sites were not detectable and EGF receptors were reduced in number. The growth of UCI-107 ovarian cancers was not inhibited by AN-152. Conclusions: In nude mice bearing LH-RH receptor positive OV-1063 epithelial ovarian cancers, systemic administration of AN-152 is less toxic and inhibits tumor growth better than equimolar doses of doxorubicin.
The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak
Authors: Andrew M Tager, Peter LaCamera, Barry S Shea, Gabriele S Campanella, Moisés Selman, Zhenwen Zhao, Vasiliy Polosukhin, John Wain, Banu A Karimi-Shah, Nancy D Kim, William K Hart, Annie Pardo, Timothy S Blackwell, Yan Xu, Jerold Chun, Andrew D Luster
Journal: Nature Medicine (2007)
Exon skipping during splicing of dystrophin mRNA precursor due to an intraexon deletion in the dystrophin gene of Duchenne muscular dystrophy kobe.
Authors: M Matsuo, T Masumura, H Nishio, T Nakajima, Y Kitoh, T Takumi, J Koga, H Nakamura
Journal: Journal of Clinical Investigation (1991)

Recent molecular studies have shown that in a patient with Duchenne muscular dystrophy (DMD) Kobe, the size of exon 19 of the dystrophin gene was reduced to 36 bp due to the deletion of 52 bp out of 88 bp of the exon. The consensus sequences at the 5' and 3' splice sites of exon 19 were unaltered (Matsuo, M., et al. 1990. Biochem. Biophys. Res. Commun. 170:963-967). To further elucidate the molecular nature of the defect, we examined the primary structure of cytoplasmic dystrophin mRNA of the DMD Kobe patient across the junctions of exons 18, 19, and 20 by gel electrophoresis and sequencing of polymerase chain reaction-amplified cDNA. The mRNA coding for dystrophin was reverse transcribed using random primers, and the cDNA was then enzymatically amplified in vitro. The targeted fragment was smaller than expected from the genomic DNA analysis. By sequencing of the amplified product, we found that exon 18 was joined directly to exon 20, so that exon 19 was completely absent, suggesting that this exon was skipped during processing of the dystrophin mRNA precursor. All other bases in the amplified product were unaltered. Therefore, the data strongly suggest that the internal exon deletion generates an abnormally spliced mRNA in which the sequence of exon 18 is joined to the sequence of exon 20. We propose that the deletion is responsible for abnormal processing of the DMD Kobe allele. This finding has important implications regarding the determinants of a functional splice site.
Fungal Exposure Modulates the Effect of Polymorphisms of Chitinases on Emergency Department Visits and Hospitalizations
Authors: Ann Chen Wu, Jessica Lasky-Su, Christine A. Rogers, Barbara J. Klanderman, Augusto A. Litonjua
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Chitinases are enzymes that cleave chitin, which is present in fungal cells. Two types of human chitinases, chitotriosidase and acidic mammalian chitinase, and the chitinase-like protein, YKL-40, seem to play an important role in asthma. We hypothesized that exposure to environmental fungi may modulate the effect of chitinases in individuals with asthma.To explore whether interactions between high fungal exposure and common genetic variants in the two chitinases in humans, CHIT1 and CHIA, and the chitinase 3-like 1 gene, CHI3L1, are associated with severe asthma exacerbations and other asthma-related outcomes.Forty-eight single nucleotide polymorphisms (SNPs) in CHIT1, CHIA, and CHI3L1 and one CHIT1 duplication were genotyped in 395 subjects and their parents as part of the Childhood Asthma Management Program. Household levels of mold (an index of fungal exposure) were determined on house dust samples. We conducted family-based association tests with gene-environment interactions. Our outcome was severe exacerbation, defined as emergency department visits and hospitalizations from asthma over a 4-year period, and our secondary outcomes included indices of lung function and allergy-related phenotypes.Of the 395 subjects who had mold levels at randomization, 24% (95 subjects) had levels that were greater than 25,000 units per gram of house dust (high mold exposure). High mold exposure significantly modified the relation between three SNPs in CHIT1 (rs2486953, rs4950936, and rs1417149) and severe exacerbations (P for interaction 0.0010 for rs2486953, 0.0008 for rs4950936, and 0.0005 for rs1417149). High mold exposure did not significantly modify the relationship between any of the other variants and outcomes.Environmental exposure to fungi, modifies the effect of CHIT1 SNPs on severe asthma exacerbations.
Obesity and Social Class
Authors: Trevor Silverstone
Journal: Psychotherapy and Psychosomatics (1970)

A random sample of patients aged twenty to fifty-nine on the lists of two general practitioners in the London area was weighed and measured. It was found that thirty-seven per cent of the men and forty-nine per cent of the women were at least twenty per cent above the desirable weight for their height, and eighteen per cent of the men and twenty-five per cent of the women were at least thirty per cent above this desirable weight. The prevalence of obesity was related to age and to social class, particulary among the women. Seventy-two per cent of women in the lower socio-economic group were overweight compared to thirty-nine per cent of upper class women. There was also a greater prevalence of obesity among the older subjects in the sample. These findings are discussed in relation to the pathogenesis of obesity.
609 SMALL INTESTINE INFLAMMATION IN RATS WITH CCL4 CIRRHOSIS: ROLE OF ENTERIC BACTERIA
Authors: L. Muñoz, M.J. Borrero, M. Ubeda, M. Lario, D. Díaz, J. Monserrat, L. Lledó, M. Álvarez-Mon, A. Albulos
Journal: Journal of Hepatology (2011)
The angiotensin AT2-receptor mediates inhibition of cell proliferation in coronary endothelial cells.
Authors: M Stoll, U M Steckelings, M Paul, S P Bottari, R Metzger, T Unger
Journal: Journal of Clinical Investigation (1995)

Angiotensin II (ANG II) is known to be a potent growth promoting factor for vascular smooth muscle cells and fibroblasts but little is known about its influence on growth in endothelial cells. We studied the effects of ANG II on endothelial growth and the role of the angiotensin receptor subtypes involved. Proliferation of rat coronary endothelial cells (CEC) and rat vascular smooth muscle cells (VSMC) was determined by [3H]thymidine incorporation, the MTT-test and by directly counting cells in a coulter counter. Angiotensin AT1- and AT2-receptors were demonstrated by binding studies and by the presence of their respective mRNA through reverse transcription polymerase chain reaction (RT-PCR). In contrast to VSMC, which in culture only express the AT1-receptor, CEC express both, AT1- and AT2-receptors simultaneously up to the third passage. Whereas ANG II stimulated growth of quiescent VSMC, an effect abolished by pretreatment with the AT1-receptor antagonist, losartan, ANG II did not induce proliferation in quiescent CEC. However, after pretreatment of quiescent endothelial cells (< passage 4) with the AT2-receptor antagonist, PD 123177, ANG II induced proliferation. This effect was reversed by additional pretreatment with losartan. ANG II significantly inhibited the proliferation of bFGF-stimulated CEC in a dose-dependent manner by maximally 50%. This effect was prevented by PD 123177 while losartan was ineffective. The AT2-receptor agonist, CGP 42112, mimicked the antiproliferative actions of ANG II, confirming the specificity of the effect. Our results show that the growth modulating actions of ANG II depend on the type of angiotensin receptor present on a given cell. In coronary endothelial cells, the antiproliferative actions of the AT2-receptor offset the growth promoting effects mediated by the AT1-receptor.
Performance of the Prostate Cancer Antigen 3 (PCA3) Gene and Prostate-Specific Antigen in Prescreened Men: Exploring the Value of PCA3 for a First-line Diagnostic Test
Authors: Monique J. Roobol, Fritz H. Schröder, Pim van Leeuwen, Tineke Wolters, Roderick C.N. van den Bergh, Geert J.L.H. van Leenders, Daphne Hessels
Journal: European Urology (2010)
Autoimmune Thyroid Disease
Authors: G F Bottazzo, D Doniach
Journal: Annual Review of Medicine (1986)

The concept of thyroid autoimmune disease now includes the following clinical entities: 1 degree thyrotoxicosis and goitrous thyroiditis (Hashimoto) with their variants, and 1 degree myxedema (atrophic thyroiditis); some cases of sporadic nontoxic goiters; most cases of neonatal hyperthyroidism; and a proportion of congenital athyreotic cretinism. Endocrine exophthalmos, though clinically associated with Graves' disease, is now considered a separate immunological entity.
Inequalities in outcomes for non-small cell lung cancer: the role of the MDT: Table 1
Authors: Paul Beckett, Ian Woolhouse
Journal: Thorax (2012)

Inequalities in outcomes for nonsmall cell lung cancer: the role of the MDT Rich et al 1 report that non-small cell lung cancer patients first seen in a hospital which has on-site thoracic surgical services are more likely to have surgical treatment of their tumour.However, it is not clear what aspects of 'being a surgical centre' are crucial to increasing resection rates.Numerous reports have documented a volumeoutcome relationship for complex surgical and medical care and one hypothesis to explain this relationship is higher case load since surgical units tend to be located in large hospitals serving large populations.To assess this, we analysed all 129 052 cases submitted to the NLCA (England
Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes
Authors: Shinji Kondo, Brian C. Schutte, Rebecca J. Richardson, Bryan C. Bjork, Alexandra S. Knight, Yoriko Watanabe, Emma Howard, Renata L.L. Ferreira de Lima, Sandra Daack-Hirsch, Achim Sander, Donna M. McDonald-McGinn, Elaine H. Zackai, Edward J. Lammer, Arthur S. Aylsworth, Holly H. Ardinger, Andrew C. Lidral, Barbara R. Pober, Lina Moreno, Mauricio Arcos-Burgos, Consuelo Valencia, Claude Houdayer, Michel Bahuau, Danilo Moretti-Ferreira, Antonio Richieri-Costa, Michael J. Dixon, Jeffrey C. Murray
Journal: Nature Genetics (2002)
Molecular cloning of the complementary DNA and gene that encode mouse brain natriuretic peptide and generation of transgenic mice that overexpress the brain natriuretic peptide gene.
Authors: Y Ogawa, H Itoh, N Tamura, S Suga, T Yoshimasa, M Uehira, S Matsuda, S Shiono, H Nishimoto, K Nakao
Journal: Journal of Clinical Investigation (1994)

Brain natriuretic peptide (BNP) is a cardiac hormone that occurs predominantly in the ventricle. To study the roles of BNP in chronic cardiovascular regulation, we isolated mouse BNP cDNA and genomic clones, and generated transgenic mice with elevated plasma BNP concentration. The mouse BNP gene was organized into three exons and two introns. Two BNP mRNA species were identified, which were generated by the alternative mRNA splicing. The ventricle was a major site of BNP production in mice. Mouse preproBNP was a 121- (or 120-) residue peptide, and its COOH-terminal 45-residue peptide was the major storage form in the heart. Transgenic mice carrying the human serum amyloid P component/mouse BNP fusion gene were generated so that the hormone expression is targeted to the liver. In the liver of these mice, considerable levels of BNP mRNA and peptide were detected, reaching up to 10-fold greater than in the ventricle. These animals showed 10- to 100-fold increase in plasma BNP concentration accompanied by elevated plasma cyclic GMP concentration, and had significantly lower blood pressure than their nontransgenic littermates. The present study demonstrates that these mice provide a useful model system with which to assess the roles of BNP in cardiovascular regulation and suggests the potential usefulness of BNP as a long-term therapeutic agent.
Insulin Therapy for Type 2 Diabetes
Authors: Sanne G. Swinnen, Joost B. Hoekstra, J. Hans DeVries
Journal: Diabetes Care (2009)

A number of landmark randomized clinical trials established that insulin therapy reduces microvascular complications (1,2). In addition, recent follow-up data from the U.K. Prospective Diabetes Study (UKPDS) suggest that early insulin treatment also lowers macrovascular risk in type 2 diabetes (3). Whereas there is consensus on the need for insulin, controversy exists on how to initiate and intensify insulin therapy. The options for the practical implementation of insulin therapy are many. In this presentation, we will give an overview of the evidence on the various insulin regimens commonly used to treat type 2 diabetes.

Secondary analyses of the aforementioned landmark trials endeavored to establish a glycemic threshold value below which no complications would occur. The UKPDS found no evidence for such a threshold for A1C, but instead showed that better glycemic control was associated with reduced risks of complications over the whole glycemic range (“the lower the better”) (4). For the management of type 2 diabetes, this resulted in the recommendation to “maintain glycemic levels as close to the nondiabetic range as possible” (5). However, in contrast to the UKPDS, the Kumamoto study observed a threshold, with no exacerbation of microvascular complications in patients with type 2 diabetes whose A1C was <6.5%, suggesting no additional benefit in lowering A1C below this level (2). Moreover, the intensive glycemia treatment arm of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, targeting A1C <6.0%, was discontinued because of higher mortality in this group compared with the standard therapy group targeting A1C from 7.0 to 7.9% (6). Therefore, the American Diabetes Association (ADA) recommendation of an A1C target <7.0% seems the most balanced compromise at present (7).

Another important conclusion of the UKPDS was that the risk reductions in long-term complications were related to the levels of glycemic control …
DOG1 Regulates Growth and IGFBP5 in Gastrointestinal Stromal Tumors
Authors: Susanne Simon, Florian Grabellus, Loretta Ferrera, Luis Galietta, Benjamin Schwindenhammer, Thomas Mühlenberg, Georg Taeger, Grant Eilers, Juergen Treckmann, Frank Breitenbuecher, Martin Schuler, Takahiro Taguchi, Jonathan A. Fletcher, Sebastian Bauer
Journal: Cancer Research (2013)

Gastrointestinal stromal tumors (GIST) are characterized by activating mutations of KIT or platelet-derived growth factor receptor α(PDGFRA), which can be therapeutically targeted by tyrosine kinase inhibitors (TKI) such as imatinib. Despite long-lasting responses, most patients eventually progress after TKI therapy. The calcium-dependent chloride channel DOG1 (ANO1/TMEM16A), which is strongly and specifically expressed in GIST, is used as a diagnostic marker to differentiate GIST from other sarcomas. Here, we report that loss of DOG1 expression occurs together with loss of KIT expression in a subset of GIST resistant to KIT inhibitors, and we illustrate the functional role of DOG1 in tumor growth, KIT expression, and imatinib response. Although DOG1 is a crucial regulator of chloride balance in GIST cells, we found that RNAi-mediated silencing or pharmacologic inhibition of DOG1 did not alter cell growth or KIT signaling in vitro. In contrast, DOG1 silencing delayed the growth of GIST xenografts in vivo. Expression profiling of explanted tumors after DOG1 blockade revealed a strong upregulation in the expression of insulin-like growth factor-binding protein 5 (IGFBP5), a potent antiangiogenic factor implicated in tumor suppression. Similar results were obtained after selection of imatinib-resistant DOG1- and KIT-negative cells derived from parental DOG1 and KIT-positive GIST cells, where a 5,000-fold increase in IGFBP5 mRNA transcripts were documented. In summary, our findings establish the oncogenic activity of DOG1 in GIST involving modulation of IGF/IGF receptor signaling in the tumor microenvironment through the antiangiogenic factor IGFBP5.