tbuckley/cabot-search huggingface dataset:
G-Protein–Coupled Receptor Mas Is a Physiological Antagonist of the Angiotensin II Type 1 Receptor
Authors: Evi Kostenis, Graeme Milligan, Arthur Christopoulos, Carlos F. Sanchez-Ferrer, Silvia Heringer-Walther, Patrick M. Sexton, Florian Gembardt, Elaine Kellett, Lene Martini, Patrick Vanderheyden, Heinz-Peter Schultheiss, Thomas Walther
Journal: Circulation (2005)

We previously identified the G-protein-coupled receptor Mas, encoded by the Mas proto-oncogene, as an endogenous receptor for the heptapeptide angiotensin-(1-7); however, the receptor is also suggested to be involved in actions of angiotensin II. We therefore tested whether this could be mediated indirectly through an interaction with the angiotensin II type 1 receptor, AT1.In transfected mammalian cells, Mas was not activated by angiotensin II; however, AT1 receptor-mediated, angiotensin II-induced production of inositol phosphates and mobilization of intracellular Ca2+ was diminished by 50% after coexpression of Mas, despite a concomitant increase in angiotensin II binding capacity. Mas and the AT1 receptor formed a constitutive hetero-oligomeric complex that was unaffected by the presence of agonists or antagonists of the 2 receptors. In vivo, Mas acts as an antagonist of the AT1 receptor; mice lacking the Mas gene show enhanced angiotensin II-mediated vasoconstriction in mesenteric microvessels.These results demonstrate that Mas can hetero-oligomerize with the AT1 receptor and by so doing inhibit the actions of angiotensin II. This is a novel demonstration that a G-protein-coupled receptor acts as a physiological antagonist of a previously characterized receptor. Consequently, the AT1-Mas complex could be of great importance as a target for pharmacological intervention in cardiovascular diseases.
Smooth-Muscle Myosin Light-Chain Kinase Content Is Increased in Human Sensitized Airways
Authors: ALAINA J. AMMIT, CAROL L. ARMOUR, JUDITH L. BLACK
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

We have previously reported that contractile reactivity of human airway preparations in vitro depends on sensitization status. The aim of this study was to examine whether this could be associated with differences in the content and/or expression pattern of myosin light-chain kinase (MLCK) isoforms in airway smooth muscle (ASM). Macroscopically normal lung tissue was obtained from subjects undergoing lung transplantation, and smooth-muscle bundles were dissected from nonsensitized (n = 5) and sensitized (n = 5) bronchi. MLCK isoform expression was then assessed by immunoblotting. The major MLCK isoform in ASM was smooth-muscle MLCK (smMLCK; 136 kD). Nonmuscle MLCK isoforms (nmMLCK; 210 to 220 kD) were not present. The smMLCK content was significantly higher in ASM from sensitized bronchi (p = 0.049) than in ASM from nonsensitized tissue (11.9 ± 3.3 versus 4.1 ± 0.7 arbitrary units [a.u.] smMLCK/mg ASM, respectively). In contrast, there was no significant difference (p = 0.636) in the content of myosin heavy chain (MHC) in tissue collected from sensitized and nonsensitized bronchi (1.33 ± 0.33 versus 1.09 ± 0.37 μ g MHC/mg ASM, respectively). This study is the first to examine MLCK isoforms in human ASM, and suggests that increased smMLCK content may be one of the mechanisms responsible for enhanced contractile reactivity in sensitized tissue. Ammit AJ, Armour CL, Black JL. Smooth-muscle myosin light-chain kinase content is increased in human sensitized airways.
TRANSFER OF AN AUTOIMMUNE NEPHROSIS IN THE RAT BY MEANS OF LYMPH NODE CELLS
Authors: Evelyn V. Hess, Charles T. Ashworth, Morris Ziff
Journal: The Journal of Experimental Medicine (1962)

An autoimmune nephrosis produced in rats by repeated injections of kidney extract with Freund's adjuvant has been transferred by means of lymph node cells to recipient animals rendered tolerant by neonatal injection with spleen cells from prospective donors. Transfer of the disease was manifested in the recipients by the development of proteinuria, hypoalbuminemia, hypercholesterolemia,and histological changes. The latter consisted of glomerular epithelial swelling, increase in basement membrane material and the presence of protein droplets in the glomerular and tubular epithelium. Appropriate control experiments were negative. Attempts to transfer with serum were unsuccessful. The transfer described is believed to provide evidence for an immunological mechanism for kidney and adjuvant induced nephrosis in the rat.
Reductase Enzyme Expression Across the National Cancer Institute Tumor Cell Line Panel: Correlation With Sensitivity to Mitomycin C and EO9
Authors: S. A. Fitzsimmons, P. Workman, M. Grever, K. Paull, R. Camalier, A. D. Lewis
Journal: JNCI Journal of the National Cancer Institute (1996)

BackgroundMany antitumor drugs require metabolic activation to exert their cytotoxic or cytostatic effects. The socalled bioreductive compounds, whose conversion into active antitumor agents is catalyzed by reductase enzymes, are examples of such drugs. The identification of specific enzymes involved in the activation of these compounds is important in understanding cellular factors that may influence drug antitumor activity.
THE FORMATION OF ANTIBODIES IN THE POPLITEAL LYMPH NODE IN RABBITS
Authors: W. E. Ehrich, T. N. Harris
Journal: The Journal of Experimental Medicine (1942)

Typhoid vaccine and sheep erythrocytes were injected subcutaneously into the feet of rabbits, and the subsequent formation of agglutinins and hemolysins in the popliteal lymph node was compared with the output of lymphocytes through the efferent lymph and with changes in the lymph node. Antibodies began to appear in the efferent lymph 2 to 4 days after the injection of the antigen and reached their highest titer after 6 days. This was preceded by a sharp rise in the output of lymphocytes through the efferent lymph, while in the lymph node there was lymphatic hyperplasia after preliminary infiltration of granulocytes and monocytes. This hyperplasia was first of a diffuse type, but was later superseded by large so called germinal centers, the latter lagging somewhat behind the rise in antibody titer. The fact that the tissue response accompanying the formation of antibodies was chiefly a lymphocytic one points to the lymphocyte as a factor in the formation of antibodies.
Prolonged measurement of lower oesophageal sphincter function in patients with intestinal metaplasia at the oesophagogastric junction
Authors: C Wolf
Journal: Gut (2001)

<h3>BACKGROUND AND AIMS</h3> It has been shown that gastro-oesophageal reflux plays a role in the pathogenesis of intestinal metaplasia (IM) limited to the oesophagogastric junction (OGJ), similar to the pathogenesis of IM in long segments of columnar lined oesophagus. The aim of this study was to examine lower oesophageal sphincter (LOS) function by means of prolonged recording in patients with IM limited to a normal appearing OGJ. <h3>PATIENTS AND METHODS</h3> Eighteen patients with IM at the OGJ (five females, 13 males; mean age 55.4 years) and 22 patients without IM (nine females, 13 males; mean age 53.9 years) underwent conventional stationary oesophageal manometry. Thereafter, seven hour water perfused manometry with simultaneous pH measurement (probe 5 cm proximal to the LOS) was performed. Swallowing was monitored with a pharyngeal sidehole and LOS pressure was recorded with a Dent sleeve. Patients were studied in the fasted state (three hours) and after a standardised meal (four hours). LOS pressure was analysed using customised software, and the incidence of reflux episodes (pH &lt;4 for at least five seconds) and transient LOS relaxations (TLOSRs) were examined. TLOSRs were judged to be accompanied by reflux if a decrease of 1 pH unit occurred during relaxation. <h3>RESULTS</h3> Patients with IM at the OGJ had a higher prevalence of postprandial acid reflux compared with patients without IM. No differences were observed in LOS pressure (pre- and postprandially) or in the prevalence of TLOSRs. However, in the postprandial phase, the rate of TLOSRs accompanied by acid reflux was increased in patients with IM. <h3>CONCLUSION</h3> Patients with IM at the OGJ have a higher prevalence of postprandial acid reflux. This is not associated with a higher prevalence of TLOSRs or a decreased LOS pressure but with a higher rate of TLOSRs accompanied by reflux.
P123 The Benefits Of Pulmonary Rehabilitation (pr) In Interstitial Lung Disease (ild): Observations From Oxfordshire's Mixed Respiratory Disease, Community Based Pr Programme
Authors: R. Lardner, S. Bolton, R. Hoyles
Journal: Thorax (2014)

<h3>Introduction</h3> The benefits of increased exercise capacity and health related quality of life after PR are well documented in chronic obstructive pulmonary disease (COPD). Interest is growing in whether other respiratory diseases benefit from PR interventions. Limited research is available to demonstrate benefit to patients with ILD (Holland <i>et al</i>., 2008). No published studies examine the relative performance of ILD patients in a PR programme compared with a mixed disease cohort. <h3>Objective</h3> To establish whether ILD patients benefit from participation in an established PR programme. <h3>Methods</h3> Pre- and post-PR data for patients with ILD who took part in a 6-week PR programme compliant with BTS guidelines (Bolton <i>et al</i>., 2013), were examined alongside similar data for all patients who had participated in the PR programmes over an 18 month period. <h3>Results</h3> Data was available for 21 patients with ILD, and 344 patients with other respiratory diseases. Median MRC grade of both groups of patients was 4. Mean baseline lung function of ILD patients was FEV<sub>1</sub> 2.06 (84.6% predicted), FVC 2.59 (82.81% predicted), FEV<sub>1</sub> /FVC 78.37, TL<sub>CO</sub> 46% predicted. Incremental Shuttle Walk Test (ISWT) and St Georges Respiratory Questionnaire (SGRQ) data for ILD patients, and the whole cohort is shown in the attached table. <h3>Discussion</h3> Examination of data available demonstrates that patients with ILD achieve the minimum important difference of the ISWT (&gt;47.5 m) and were close to achieving the minimum important difference of the SGRQ (&gt;4). ILD patients have a greater benefit in terms of reduction in symptoms as measured by SGRQ, than the cohort as a whole. Limitations to generalisation of conclusions due to small sample size are acknowledged. <h3>Conclusion</h3> ILD patients who completed a 6-week community based, PR programme within a mixed respiratory disease cohort demonstrate a clinically significant improvement in exercise capacity and make gains in health related quality of life. <h3>References</h3> Bolton C, Bevan-Smith E, Blakey J, <i>et al</i>. British Thoracic Society guideline on pulmonary rehabilitation in adults. <i>Thorax</i>. 2013;68:ii1–ii130 Holland A, Hill C, Conron M, Munro P, McDonald C. Short term improvement in exercise capacity and symptoms following exercise training in interstitial lung disease. <i>Thorax</i>, 2008;63:549–554
Gastric Recurrence of Extramedullary Granulocytic Sarcoma After Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia
Authors: E Ryoung Choi, Young Hye Ko, Seok Jin Kim, Jun Ho Jang, Kihyun Kim, Won Ki Kang, Chul Won Jung, Dong Hwan Kim
Journal: Journal of Clinical Oncology (2009)
<i>CASP3</i> Polymorphisms and Risk of Squamous Cell Carcinoma of the Head and Neck
Authors: Kexin Chen, Hui Zhao, Zhibin Hu, Li-E Wang, Wei Zhang, Erich M. Sturgis, Qingyi Wei
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Caspase-3 plays a central role in executing cell apoptosis and thus in carcinogenesis, but little is known about the role of CASP3 variants in susceptibility to SCCHN. Experimental Design: Genotype and haplotypes of the first intron (rs4647601:G&amp;gt;T and rs4647602:C&amp;gt;A) and 5′-untranslated region (UTR; rs4647603:G&amp;gt;A) of CASP3 (NT_022792.17) were determined for 930 SCCHN patients and 993 cancer-free controls in a U.S. non-Hispanic white population. Odds ratio (OR) and 95% confidence interval (95% CI) were calculated in multivariate logistic regression analysis. Results: We found that the CASP3 rs4647601:TT variant genotype was associated with an increased risk of SCCHN (adjusted OR, 1.32; 95% CI, 1.00-1.73) compared with the GG genotype. This risk was more evident in the subgroups of younger (≤56 years) subjects, males, and never smokers with a significant trend for increased risk with increased number of variant T allele (P &amp;lt; 0.05 for all). However, these risks were not found for other two SNPs. Furthermore, individuals with two copies of haplotypes TCG or GCA were found to have a significant increased risk of SCCHN (OR, 1.31; 95% CI, 1.07-1.61) compared with the other haplotypes, and this risk was more evident in less advanced diseases (OR, 1.45; 95% CI, 1.11-1.89) than in the advanced diseases (OR, 1.22; 95% CI, 0.96-1.54). Conclusions: These results suggested that genetic variation in CASP3 may contribute to SCCHN risk. Larger studies are needed to confirm our findings.
A genetically determined insertion/deletion related polymorphism in human T cell receptor beta chain (TCRB) includes functional variable gene segments.
Authors: T M Zhao, S E Whitaker, M A Robinson
Journal: The Journal of Experimental Medicine (1994)

Polymorphism in the human T cell receptor beta chain (TCRB) gene complex includes haplotypes with different numbers of TCRBV genes. An insertion/deletion related polymorphism (IDRP) in the human TCRBV region was found to involve TCRBV gene segments. Inserted TCRB haplotypes contain an additional 21.5 kb in which three TCRBV genes are encoded, members of the TCRBV7, TCRBV9, and TCRBV13 families. Two TCRBV gene segments were present only in inserted haplotypes; one of these, TCRBV7S3, is a functional gene and the other, TCRBV9S2(P), is a pseudogene because of an inframe termination colon. In addition, inserted haplotypes contain two identical copies of the TCRBV13S2 gene, whereas deleted haplotypes have only one copy. Deleted haplotypes could be subdivided into two types, deleted*1 and deleted*2, on the basis of sequence variations in TCRBV6S7 and TCRBV13S2 genes. Both deleted*1 and deleted*2 haplotypes contained the same number of TCRBV genes; both contain 60 genes of which 50 are functional, whereas, inserted haplotypes contained 63 genes of which 52 are functional. Comparisons of inserted region sequences with the homologous region in a deleted haplotype, and with sequences surrounding related TCRBV genes, revealed patterns of similarity that suggest insertion as well as deletion events have occurred in the evolution of the TCRBV gene complex. These data indicate that the genomic TCR repertoire is expanded in individuals who have inserted TCRBV haplotypes. The presence of additional TCRBV genes or, alternatively, the absence of certain TCRBV genes may have an impact upon immune responses and susceptibility to autoimmune diseases.
Prospective long term follow-up of a cohort of patients with giant cell arteritis screened for aortic structural damage (aneurysm or dilatation)
Authors: Ana García-Martínez, Pedro Arguis, Sergio Prieto-González, Georgina Espígol-Frigolé, Marco A Alba, Montserrat Butjosa, Itziar Tavera-Bahillo, José Hernández-Rodríguez, Maria C Cid
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Aortic structural damage (ASD) may complicate the course of patients with giant cell arteritis (GCA). However the frequency and outcome of ASD has not been assessed in long term prospective studies. <h3>Methods</h3> In a previous screening of 54 biopsy proven GCA patients, significant ASD was detected in 12 (22.2%) after a median follow-up of 5.4 years. These patients were periodically evaluated (every 4 years) over a median of 10.3 years (range 4–16.6 years) in order to investigate the development of new ASD and the outcome of previously detected abnormalities. <h3>Results</h3> 18 of the 54 patients abandoned the study due to death or other reasons. The remaining 36 patients were subjected to a second screening and 14 to a third screening. 12 (33.3%) of the 36 patients re-screened and 16 (29.6%) of the initial cohort developed ASD, all but one in the thoracic aorta. Aortic diameters at the ascending and descending aorta significantly increased over time. One patient (1.9% of the initial cohort) died from aortic dissection. Surgery was advised in eight (50%) patients with ASD but could only be performed in three patients (37.7%). The development of ASD was not associated with persistence of detectable disease activity. <h3>Conclusions</h3> The incidence of ASD is maximal within the first 5 years after diagnosis but continues developing over time, affecting up to 33.3% of individuals after long term follow-up. Once ASD occurs, dilatation increases over time, underlining the need for periodic evaluation. Surgical repair is feasible in about one-third of candidates.
Loss of Caspase-8 Expression Does Not Correlate with <i>MYCN</i> Amplification, Aggressive Disease, or Prognosis in Neuroblastoma
Authors: Simone Fulda, Christopher Poremba, Bernd Berwanger, Sabine Häcker, Martin Eilers, Holger Christiansen, Barbara Hero, Klaus-Michael Debatin
Journal: Cancer Research (2006)

Abstract Inactivation of caspase-8 because of aberrant gene methylation has been associated with amplification of the MYCN oncogene and aggressive disease in neuroblastoma, suggesting that caspase-8 may function as tumor suppressor. However, the prognostic effect of caspase-8 in neuroblastoma has remained obscure. Therefore, we investigated caspase-8 expression and its correlation with established prognostic markers and survival outcome in a large cohort of neuroblastoma patients. Here, we report that loss of caspase-8 protein expression occurs in the majority (75%) of neuroblastoma and is not restricted to advanced disease stages. Surprisingly, no correlation was observed between caspase-8 expression and MYCN amplification. Similarly, ectopic expression of MYCN or antisense-mediated down-regulation of MYCN had no effect on caspase-8 expression in neuroblastoma cell lines. In addition, caspase-8 expression did not correlate with other variables of high-risk disease (e.g., 1p36 aberrations, disease stage, age at diagnosis, or tumor histology). Most importantly, loss of caspase-8 protein had no effect on event-free or overall survival in the overall study population or in distinct subgroups of patients. By revealing no correlation between caspase-8 expression and MYCN amplification or other established variables of aggressive disease, our findings in a large cohort of neuroblastoma patients show that inactivation of caspase-8 is not a characteristic feature of aggressive neuroblastoma. Thus, our study provides novel insight into the biology of this tumor, which may have important clinical implications. (Cancer Res 2006; 66(20): 10016-23)
Interaction between the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) pathways: a rational approach for multi-target anticancer therapy
Authors: F. Ciardiello, T. Troiani, R. Bianco, M. Orditura, F. Morgillo, E. Martinelli, M.P. Morelli, T. Cascone, G. Tortora
Journal: Annals of Oncology (2006)

Over the last decade, the concept of targeted biological therapy for the treatment of cancer has emerged. However, a better understanding of these targets and their role in tumor cells and in the surrounding stromal cells is required. Two interesting biological targets are the epidermal growth factor receptor (EGFR) and the vascular endothelia growth factor (VEGF) and its receptors. A number of agents that target these pathways have been described. Many of these are currently in clinical trials and a few have recently been approved by the regulatory authorities in USA and in the European Union. The molecular pathways involved in the proliferation of cancer cells and in tumor-related angiogenesis are very complex and the interference with only a single step of these pathways may often reveal an insufficient therapeutic approach. Moreover, cancer cells have an inherent ability to harness different growth factor signaling pathways for growth advantage and cell survival, a process that may even be facilitated by the use of selective targeted agents. Because of these escape mechanisms, monotherapy with selective targeted agents is unlikely to be a fully effective cancer treatment. For these reasons, targeting different pathways is an attractive and effective therapeutic strategy with a strong rationale for investigating this approach in the clinic. This review focuses on the preclinical rationale of combining targeted agents such as EGFR and VEGF inhibitors in the treatment of cancer and on the clinical trials that have emerged from these studies.
Gastrointestinal and liver diseases: genetic and epigenetic markers
Authors: H. E. Blum
Journal: Gut (2011)

The basic aspects of molecular, cell and stem cell biology are central to biomedical research and are increasingly becoming part of patient care in clinical practice (‘translational medicine’). The genetic material of humans is made up of DNA that in its entirety makes up an individual's genome that is structurally organised into 46 chromosomes (44 autosomes and two sex chromosomes XX or XY, defining the female or male phenotype). A seminal scientific achievement was deciphering the complete nucleotide sequence of the human genome by the concerted effort of the international human genome organisation project 10 years ago.1 2 This was followed by the era of ‘genomics’ that aim at unravelling the complete genetic information of an individual.3 In order to use the sequence information from genomics for research as well as for clinical applications and to define the function(s) of newly identified genes, strategies were developed to analyse globally genomic DNA sequences as well as their cell-, tissue- or organ-specific expression profiles that are collectively termed, ‘functional genomics’.

An important tool of functional genomics are array analyses, which are based on the complementary base pairing of single-stranded DNA or RNA (genes) to form a double-stranded hybrid (hybridisation). This principle has been used for several decades for the characterisation of DNA and RNA sequences, termed Southern or northern blot analyses, respectively. In contrast to these analytical tools which allow the simultaneous analysis of only a very limited number of DNA or RNA species, the recently developed array technologies now make it possible to simultaneously analyse huge numbers of DNA species or gene products (mRNA and proteins). Using chips, also termed ‘microarrays’ with a surface of about 0.5 cm2, thousands to tens of thousands of single-stranded DNA or reverse transcribed RNA (cDNA) species or oligonucleotides of known sequence can be …