tbuckley/cabot-search huggingface dataset:
Major histocompatibility complex-specific recognition of Mls-1 is mediated by multiple elements of the T cell receptor.
Authors: D L Woodland, H P Smith, S Surman, P Le, R Wen, M A Blackman
Journal: The Journal of Experimental Medicine (1993)

We have recently shown that recognition of the mouse mammary tumor virus 9-associated superantigen (vSAG-9) by murine V beta 17+ T cells is strongly influenced by the major histocompatibility complex (MHC) class II haplotype of the presenting cells, resulting in a form of MHC-restricted recognition. This finding was unexpected, because T cell recognition of another well-characterized retroviral superantigen, minor lymphocyte-stimulating antigen 1 (Mls-1), had been shown to be independent of the MHC haplotype of the presenting cell. To determine whether recognition of vSAG-9 and Mls-1 is fundamentally different, we undertook an extensive analysis of MHC haplotype influences on vSAG-9 and Mls-1 recognition by panels of T cell hybridomas. Our results show that, although most hybridomas recognized Mls-1 regardless of the MHC haplotype of the presenting cells, as previously described by others, some hybridomas exhibited unique patterns of MHC fine specificity. Thus, T cell recognition of vSAG-9 and Mls-1 is not fundamentally different, but the apparent differences can be explained in terms of frequency. The MHC fine specificity of individual Mls-1-reactive hybridomas was influenced by both V beta and non-V beta T cell receptor (TCR) elements. First, the influence of the V beta element was apparent from the observation that V beta 8.2+ hybridomas were significantly more MHC specific in their recognition of Mls-1 than V beta 8.1 hybridomas. Second, a role for the TCR alpha chain was implicated from the distinct patterns of fine specificity of Mls-1 reactivity among a panel of transgenic hybridomas that expressed an identical beta chain (V beta 8.1D beta 2J beta 2.3C beta 2). Sequence analysis revealed that junctional residues of the TCR alpha chain and/or V alpha/J alpha combinations influenced the MHC haplotype fine specificity for Mls-1. Third, D beta J beta influences were implicated, in that the transgenic hybridomas expressed distinctive patterns of Mls-1 fine specificity not represented among V beta 8.1+ nontransgenic hybridomas. The findings that T cell recognition of endogenous superantigen is MHC specific, and that this specificity correlates with non-V beta elements of the TCR, support the hypothesis that there is a direct interaction between the TCR and either polymorphic residues of the MHC class II molecule or haplotype-specific dominant peptides presented by class II.
Elevation of sulfatides in ovarian cancer: An integrated transcriptomic and lipidomic analysis including tissue-imaging mass spectrometry
Authors: Ying Liu, Yanfeng Chen, Amin Momin, Rebecca Shaner, Elaine Wang, Nathan J Bowen, Lilya V Matyunina, L DeEtte Walker, John F McDonald, M Cameron Sullards, Alfred H Merrill
Journal: Molecular Cancer (2010)

Abstract Background Sulfatides (ST) are a category of sulfated galactosylceramides (GalCer) that are elevated in many types of cancer including, possibly, ovarian cancer. Previous evidence for elevation of ST in ovarian cancer was based on a colorimetric reagent that does not provide structural details and can also react with other lipids. Therefore, this study utilized mass spectrometry for a structure-specific and quantitative analysis of the types, amounts, and tissue localization of ST in ovarian cancer, and combined these findings with analysis of mRNAs for the relevant enzymes of ST metabolism to explore possible mechanisms. Results Analysis of 12 ovarian tissues graded as histologically normal or having epithelial ovarian tumors by liquid chromatography electrospray ionization-tandem mass spectrometry (LC ESI-MS/MS) established that most tumor-bearing tissues have higher amounts of ST. Because ovarian cancer tissues are comprised of many different cell types, histological tissue slices were analyzed by matrix-assisted laser desorption ionization-tissue-imaging MS (MALDI-TIMS). The regions where ST were detected by MALDI-TIMS overlapped with the ovarian epithelial carcinoma as identified by H &amp; E staining and histological scoring. Furthermore, the structures for the most prevalent species observed via MALDI-TIMS (d18:1/C16:0-, d18:1/C24:1- and d18:1/C24:0-ST) were confirmed by MALDI-TIMS/MS, whereas, a neighboring ion( m/z 885.6) that was not tumor specific was identified as a phosphatidylinositol. Microarray analysis of mRNAs collected using laser capture microdissection revealed that expression of GalCer synthase and Gal3ST1 (3'-phosphoadenosine-5'-phosphosulfate:GalCer sulfotransferase) were approximately 11- and 3.5-fold higher, respectively, in the ovarian epithelial carcinoma cells versus normal ovarian stromal tissue, and they were 5- and 2.3-fold higher in comparison with normal surface ovarian epithelial cells, which is a likely explanation for the higher ST. Conclusions This study combined transcriptomic and lipidomic approaches to establish that sulfatides are elevated in ovarian cancer and should be evaluated further as factors that might be important in ovarian cancer biology and, possibly, as biomarkers.
Happiness to be gained in paediatric asthma care
Authors: B. C. T. Flapper, E. J. Duiverman, J. Gerritsen, K. Postema, C. P. van der Schans
Journal: European Respiratory Journal (2008)

The aim of the present study was to establish the efficacy in terms of morbidity and health-related quality of life (HRQoL) of a group asthma education-exercise programme to children with low (below 10th percentile value) quality-of-life scores. A controlled, randomised, open, clinical trial was conducted. In total, 36 out of 53 unhappy children, among 204 (68%) respondents, treated in four paediatric practices, enrolled (mean age 10 yrs; range: 8–12 yrs), after random allocation in control and intervention groups (child, parent, teacher). Measurements were taken at baseline (T0) and after 3, 6 (T6) and 9 months (T9; intervention group only at 9 months). All but four controls completed the study. From T0–T6, changes (Δ) in HRQoL were clinically important and significantly greater in the intervention group than in the control group, both for generic HRQoL (effect size (ES) 0.95; Δ 16%±12% <i>versus</i> -1±4%) and for asthma-specific HRQoL (ES 0.58; Δ 15%±17% <i>versus</i> 1.5±14%). T9 measurements were consistent with T6 findings. Changes in sick days (ES 0.78), oral prednisone courses (ES 0.71) and doctor visits (ES 0.74) over a 6-month period were greater in the intervention group than in the control group. Changes could not be ascribed to change in lung function or medication. In unhappy children, quality of life and morbidity may improve with a low intensity asthma education-exercise programme, even without gains in pulmonary function or exercise tolerance.
Therapeutic Drug Monitoring of Imatinib—New Data Strengthen the Case
Authors: Ian Judson
Journal: Clinical Cancer Research (2012)

A population pharmacokinetic study of imatinib in patients with gastrointestinal stromal tumor by Eechoute and colleagues has shown a significant increase in drug clearance over the first 3 months of treatment, resulting in a 30% decrease in drug exposure. This finding clearly shows the possibility of pharmacokinetic resistance in this disease.
Tumor fibroblast–derived epiregulin promotes growth of colitis-associated neoplasms through ERK
Authors: Clemens Neufert, Christoph Becker, Özlem Türeci, Maximilian J. Waldner, Ingo Backert, Katharina Floh, Imke Atreya, Moritz Leppkes, Andre Jefremow, Michael Vieth, Regine Schneider-Stock, Patricia Klinger, Florian R. Greten, David W. Threadgill, Ugur Sahin, Markus F. Neurath
Journal: Journal of Clinical Investigation (2013)

Molecular mechanisms specific to colitis-associated cancers have been poorly characterized. Using comparative whole-genome expression profiling, we observed differential expression of epiregulin (EREG) in mouse models of colitis-associated, but not sporadic, colorectal cancer. Similarly, EREG expression was significantly upregulated in cohorts of patients with colitis-associated cancer. Furthermore, tumor-associated fibroblasts were identified as a major source of EREG in colitis-associated neoplasms. Functional studies showed that Ereg-deficient mice, although more prone to colitis, were strongly protected from colitis-associated tumors. Serial endoscopic studies revealed that EREG promoted tumor growth rather than initiation. Additionally, we demonstrated that fibroblast-derived EREG requires ERK activation to induce proliferation of intestinal epithelial cells (IEC) and tumor development in vivo. To demonstrate the functional relevance of EREG-producing tumor-associated fibroblasts, we developed a novel system for adoptive transfer of these cells via mini-endoscopic local injection. It was found that transfer of EREG-producing, but not Ereg-deficient, fibroblasts from tumors significantly augmented growth of colitis-associated neoplasms in vivo. In conclusion, our data indicate that EREG and tumor-associated fibroblasts play a crucial role in controlling tumor growth in colitis-associated neoplasms.
Does National Bowel Cancer Screening Programme (NBCSP) affect colonoscopists' performance over time?
Authors: T. R. Lim, M. Thian, C. Grimley
Journal: Gut (2011)

<h3>Introduction</h3> The South Lancashire Bowel Cancer Screening Programme (BCSP) went ‘live’ in June 2008. All colonoscopists enrolled in the BCSP are required to undergo a validated endoscopic accreditation process to become bowel cancer screeners. However, it is uncertain whether participation in the BCSP affects colonoscopists9 performance over time. <h3>Methods</h3> The performances of five bowel cancer screeners in the South Lancashire BCSP was analysed. 320 colonoscopies performed during month 1–6 were compared to 486 colonoscopies performed during month 13–18. Performances were scored using caecal intubation rates, duration of procedure, adenoma and cancer detection rates. <h3>Results</h3> All screeners were accredited at the beginning of the BCSP. There was no difference in caecal intubation rate or polyp/cancer detection rate amongst the colonoscopists over time. Caecal intubation rate was high in the first half of the audit period (96.24%), as well as in the latter half of the audit period (95.45%). Adenoma detection rate also remained above the national target (35%) at 51.22% (month 1–6) and 52.89% (month 13–18). <h3>Conclusion</h3> Bowel cancer screeners who underwent validated accreditation process continue to perform at a consistently high standard, above the national target over time. The high standard expected of a bowel cancer screener prior to joining the programme may explain the consistent performance shown in this audit.
The health of Gulf War veterans * Authors' reply
Authors: A H Wilson-Ing, H. A Lee, R. Gabriel, J P. G Bolton, A. J Bale, M. Jackson
Journal: Journal of the Royal Society of Medicine (2003)

How objective are systematic reviews?Dr Linde and Dr Willich (January 2003 JRSM 1 ) have done a great service to the medical community by showing us how systematic reviews (SRs) can differ confusingly regarding a range of methodological aspects.As they point out, SRs are designed to avoid biases and make conclusions as objective as possible.Given the diversity of the SRs analysed, I was impressed with the level of agreement many of them reached in their conclusions.Table 1 summarizes five subject areas where our own SRs were cited.The concordance of the conclusions is stunning.
Menatetrenone, a Vitamin K2 Analogue, Inhibits Hepatocellular Carcinoma Cell Growth by Suppressing Cyclin D1 Expression through Inhibition of Nuclear Factor κB Activation
Authors: Iwata Ozaki, Hao Zhang, Toshihiko Mizuta, Yasushi Ide, Yuichiro Eguchi, Tsutomu Yasutake, Toshiyuki Sakamaki, Richard G. Pestell, Kyosuke Yamamoto
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Menatetrenone, a vitamin K2 analogue, plays an important role in the production of blood coagulation factors. Menatetrenone has also bee shown to have antineoplastic effects against several cancer cell lines including hepatocellular carcinoma (HCC) cells. However, the mechanisms by which vitamin K2 inhibits HCC cell growth have not bee fully clarified, and we therefore investigated the molecular basis of vitamin K2–induced growth inhibition of HCC cells. Experimental Design: HCC cells were treated with vitamin K2 and the expression of several growth-related genes including cyclin-dependent kinase inhibitors and cyclin D1 was examined at the mRNA and protein levels. A reporter gene assay of the cyclin D1 promoter was done under vitamin K2 treatment. The regulation of nuclear factor κB (NF-κB) activation was investigated by a NF-κB reporter gene assay, an electrophoretic mobility shift assay, a Western blot for phosphorylated IκB, and an in vitro kinase assay for IκB kinase (IKK). We also examined the effect of vitamin K2 on the growth of HCC cells transfected with p65 or cyclin D1. Results: Vitamin K2 inhibited cyclin D1 mRNA and protein expression in a dose-dependent manner in the HCC cells. Vitamin K2 also suppressed the NF-κB binding site-dependent cyclin D1 promoter activity and suppressed the basal, 12-O-tetradecanoylphorbol-13-acetate (TPA)–, TNF-α–, and interleukin (IL)-1–induced activation of NF-κB binding and transactivation. Concomitant with the suppression of NF-κB activation, vitamin K2 also inhibited the phosphorylation and degradation of IκBα and suppressed IKK kinase activity. Moreover, HCC cells overexpressing cyclin D1 and p65 became resistant to vitamin K2 treatment. Conclusion: Vitamin K2 inhibits the growth of HCC cells via suppression of cyclin D1 expression through the IKK/IκB/NF-κB pathway and might therefore be useful for treatment of HCC.
Safety and immunogenicity of a recombinant live attenuated tetravalent dengue vaccine (DENVax) in flavivirus-naive healthy adults in Colombia: a randomised, placebo-controlled, phase 1 study
Authors: Jorge E Osorio, Ivan D Velez, Cynthia Thomson, Liliana Lopez, Alejandra Jimenez, Aurelia A Haller, Shawn Silengo, Jaclyn Scott, Karen L Boroughs, Janae L Stovall, Betty E Luy, John Arguello, Mark E Beatty, Joseph Santangelo, Gilad S Gordon, Claire Y-H Huang, Dan T Stinchcomb
Journal: The Lancet Infectious Diseases (2014)
Identification of nuclear-enriched miRNAs during mouse granulopoiesis
Authors: Justin JL Wong, William Ritchie, Dadi Gao, Katherine A Lau, Maria Gonzalez, Anupma Choudhary, Ryan J Taft, John EJ Rasko, Jeff Holst
Journal: Journal of Hematology & Oncology (2014)

MicroRNAs (miRNAs) are coordinators of cellular differentiation, including granulopoiesis. Although differential expression of many miRNAs is associated with the maturation of granulocytes, analysis of differentially expressed miRNAs and their cellular localization across all stages of granulopoiesis, starting from hemopoietic stems cells, is not well characterized.We analyzed whole cell miRNA and mRNA expression during granulopoiesis using Taqman low-density and Affymetrix arrays respectively. We also performed nuclear and cytoplasmic fractionation followed by Taqman low-density array and/or quantitative PCR to identify nuclear-enriched miRNAs in hemopoietic stem/progenitor cells, promyelocytes, myelocytes, granulocytes and several hemopoietic cell lines. Anti-correlation between the expression of miRNA and target pairs was used to determine putative miRNA targets.Analyses of our array data revealed distinct clusters of differentially expressed miRNAs that are specific to promyelocytes and granulocytes. While the roles of many of these miRNAs in granulopoiesis are not currently known, anti-correlation of the expression of miRNA/mRNA target pairs identified a suite of novel target genes. Clusters of miRNAs (including members of the let-7 and miR-17-92 families) are downregulated in hemopoietic stem/progenitor cells, potentially allowing the expression of target genes known to facilitate stem cell proliferation and homeostasis. Additionally, four miRNAs (miR-709, miR-706, miR-690 and miR-467a*) were found to be enriched in the nucleus of myeloid cells and multiple hemopoietic cell lines compared to other miRNAs, which are predominantly cytoplasmic-enriched. Both miR-709 and miR-706 are nuclear-enriched throughout granulopoiesis and have putative binding sites of extensive complementarity downstream of pri-miRNAs. Nuclear enrichment of miR-467a* is specific to hemopoietic stem/progenitors and promyelocytes. These miRNAs are also nuclear-enriched in other hemopoietic cell lines, where nuclear sequestering may fine-tune the expression of cytoplasmic mRNA targets.Overall, we have demonstrated differentially expressed miRNAs that have not previously been associated with hemopoietic differentiation and provided further evidence of regulated nuclear-enrichment of miRNAs. Further studies into miRNA function in granulocyte development may shed light on fundamental aspects of regulatory RNA biology and the role of nuclear miRNAs.
Sex, drugs and arrhythmia: are gender differences in risk of torsades de pointes simply a matter of testosterone?
Authors: A James
Journal: Cardiovascular Research (2002)

See article by Liu et al. \[4\] (pages 28–36) in this issue. 

As highlighted by a recent ‘Spotlight’ issue of Cardiovascular Research [1], the existence of major differences between men and women in the function and pathophysiology of the cardiovascular system implicates the need for gender-specific optimisation of patient treatment. One key gender difference resides in the electrocardiogram: it has long been known that women have higher resting heart rates than men, but that the rate-corrected QT interval (QTc) is longer in women (by 2–6%) [2,3]. As will be discussed below, this difference is an important factor in sex-linked differences in pro-arrhythmic risk, and its basis is the subject of an article in this edition of the journal by Liu et al. [4].

Women are at significantly greater risk than men of developing the potentially lethal ventricular tachyarrhythmia torsades de pointes in response to certain drugs that prolong ventricular repolarisation [3,5–7]. Excessive prolongation of ventricular repolarisation, known as the long QT syndrome owing to the increase in duration of the QTc interval, is thought to favour the generation of early after depolarisations (EADs), cellular proarrythmic events that, with the appropriate dispersion of repolarisation, in turn may initiate torsades de pointes [8–10]. Long QT syndrome can be either inherited through mutations in ion channels or, as alluded to above, acquired through administration of drugs that block cardiac K+ channels (in particular channels responsible for the rapid delayed rectifier current, I Kr) [8,9,11,12]. Female gender is also an independent risk factor for the incidence of syncope and sudden death in the inherited long QT syndrome [3].

The basis for the gender difference in risk of torsades de pointes is unclear, but is likely to reflect the influence of sex hormones on ventricular repolarisation. In … 

* Corresponding author. Tel.: +44-117-928-9187; fax: +44-117-928-8923.
Intracardiac echocardiographic quantification of atrial wall thickness changes associated with rediofrequency ablation
Authors: J.F. Ran, D. Schwartzman, J.J. Michele, S.E. Brode, C.T. Trankiem, K.S. Li, S.M. Dillon, D. Callans, F.A. Chaudhry
Journal: Journal of the American College of Cardiology (1998)
Targeting ER stress–induced autophagy overcomes BRAF inhibitor resistance in melanoma
Authors: Xiao-Hong Ma, Sheng-Fu Piao, Souvik Dey, Quentin Mcafee, Giorgos Karakousis, Jessie Villanueva, Lori S. Hart, Samuel Levi, Janice Hu, Gao Zhang, Rossitza Lazova, Vincent Klump, John M. Pawelek, Xiaowei Xu, Wei Xu, Lynn M. Schuchter, Michael A. Davies, Meenhard Herlyn, Jeffrey Winkler, Constantinos Koumenis, Ravi K. Amaravadi
Journal: Journal of Clinical Investigation (2014)

Melanomas that result from mutations in the gene encoding BRAF often become resistant to BRAF inhibition (BRAFi), with multiple mechanisms contributing to resistance. While therapy-induced autophagy promotes resistance to a number of therapies, especially those that target PI3K/mTOR signaling, its role as an adaptive resistance mechanism to BRAFi is not well characterized. Using tumor biopsies from BRAFV600E melanoma patients treated either with BRAFi or with combined BRAF and MEK inhibition, we found that BRAFi-resistant tumors had increased levels of autophagy compared with baseline. Patients with higher levels of therapy-induced autophagy had drastically lower response rates to BRAFi and a shorter duration of progression-free survival. In BRAFV600E melanoma cell lines, BRAFi or BRAF/MEK inhibition induced cytoprotective autophagy, and autophagy inhibition enhanced BRAFi-induced cell death. Shortly after BRAF inhibitor treatment in melanoma cell lines, mutant BRAF bound the ER stress gatekeeper GRP78, which rapidly expanded the ER. Disassociation of GRP78 from the PKR-like ER-kinase (PERK) promoted a PERK-dependent ER stress response that subsequently activated cytoprotective autophagy. Combined BRAF and autophagy inhibition promoted tumor regression in BRAFi-resistant xenografts. These data identify a molecular pathway for drug resistance connecting BRAFi, the ER stress response, and autophagy and provide a rationale for combination approaches targeting this resistance pathway.
Republished editorial: London's Olympic public health legacy: Will it turn to dust?
Authors: Denis Campbell
Journal: British Journal of Sports Medicine (2013)

London won the Olympic bid on the back of a promise to increase young people's participation in sport.

Denis Campbell assesses the likelihood of success

For years cities and countries vying to host mega sports events like the World Cup and Olympic Games competed on the basis of who had the best venues, most robust security systems, most imaginative legacy plans, and other similarly technical aspects. But in 2005, London rewrote the rulebook in its quest to win what some call sport's greatest prize—the right to stage the summer Olympics. If London got the Games, it would use them to inspire young people to play sport.

In early July that year bid teams from the five cities vying to host the event in 2012—London, Paris, Madrid, Moscow, and New York—gathered in Singapore to make a final presentation to the International Olympic Committee (IOC). Not even the key figures in London's team, headed by Sebastian Coe, a double Olympic gold medal winner turned politician, expected to be first across the line.

Where the other four pitches embodied perspiration, London's went for inspiration. Its 100 strong team inside the Raffles City Convention Centre's ballroom gave a clue to its intentions. Among its contingent were 30 pupils from Langdon secondary school in Newham, east London, near where the Games would be held if London won.

In an evocative address, Coe tapped into a fear inside the IOC and the wider global concern about many children's increasingly sedentary lifestyles: “We can no longer take it for granted that young people will choose sport. Some may lack the facilities, or the coaches and role models to teach them. Others, in an age of 24 hour entertainment and instant fame, may simply lack the desire.” But Coe added, “We are determined that a London Games will …