tbuckley/cabot-search huggingface dataset:
PTU-147 Structured gastroenterological evaluation and improved outcomes for patients with chronic gastrointestinal symptoms following pelvic radiotherapy
Authors: C C Henson, J McLaughlin, Y Ang, C Babbs, J Crampton, M Kelly, S Lal, J Limdi, G Whatley, R Swindell, W Makin, S E Davidson
Journal: Gut (2012)

<h3>Introduction</h3> 17 000 patients are treated with radical pelvic radiotherapy per year in the UK. 50% will develop chronic gastrointestinal (GI) symptoms that adversely affect quality-of-life, which have been shown to persist at the same level of severity for at least 3 years following treatment. Despite this, fewer than 20% are referred to a gastroenterologist. We aimed to determine if structured gastroenterological evaluation improves symptoms this patient group. <h3>Methods</h3> 60 patients with GI symptoms ≥6 months after radical pelvic radiotherapy were identified from oncology clinics. Those requiring urgent investigation via the 2-week wait pathway were excluded. They were assessed at baseline using patient-reported symptom-based questionnaires: inflammatory bowel disease questionnaire (IBDQ); Vaizey incontinence questionnaire (VIQ); and the Common Terminology Criteria for Adverse Events (CTCAE) pelvis questionnaire. Participants were then referred to and managed by gastroenterologists using an algorithmic approach, which involves the identification of all GI symptoms and investigation for all potential causes for these symptoms. Further assessments were made at 3 and 6 months using the questionnaires. <h3>Results</h3> 20 men and 36 women were included, with a median age of 58.5 years (range 26.9–81.8). Median time from radiotherapy to baseline gastroenterological assessment was 3.0 years (range 0.6–18.7). Median IBDQ score improved from 168 at baseline to 195 at 6 months (p=0.014). Median IBDQ bowel subset score improved from 41 at baseline to 50 at 6 months (p&lt;0.0005). Significant improvement was also found in the median VIQ score from 11 at baseline to 8 at 6 months (p&lt;0.0005). The median CTCAE rectum bowel mean score for men improved from 1.4 at baseline to 0.9 at 6 months and for women from 1.4 at baseline to 1.3 at 6 months. Pooling male and female data, the CTCAE mean score significantly improved comparing baseline with 6 month scores (p=0.001). <h3>Conclusion</h3> GI symptom questionnaire scores significantly improved from baseline to 6 months. This suggests that structured gastroenterological evaluation using an algorithmic approach may improve GI symptoms in this patient group, although a controlled study is necessary to confirm this. <h3>Competing interests</h3> None declared.
SAT0391 A Diminished Clinical Response at 28 and 52 Weeks of Adalimumab Treatment in Patients with Psoriatic Arthritis is Associated with Anti-Drug Antibodies
Authors: E. Vogelzang, E. Kneepkens, M. Nurmohamed, A. van Kuijk, T. Rispens, G. Wolbink, C. Krieckaert
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Immunogenicity, the formation of anti-drug antibodies (ADA), has important clinical implications for the treatment with adalimumab of patients with rheumatic diseases, since ADA are associated with lower effective drug levels, resulting in an absent or diminished response in some patients. In contrast to rheumatoid arthritis research on immunogenicity and clinical response in patients with psoriatic arthritis (PsA) is scarce. <h3>Objectives</h3> To investigate the relationship between ADA, adalimumab drug levels and clinical response in a large, long-term follow-up cohort of patients with PsA during 52 weeks of follow-up. <h3>Methods</h3> This prospective cohort study included 103 consecutive patients diagnosed with PsA and treated with 40 mg adalimumab subcutaneously every other week. Disease activity score in 28 joints (DAS28), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and psoriasis area and severity index (PASI) were assessed at baseline and after 4, 16, 28, 40 and 52 weeks of treatment. Adalimumab concentrations and ADA were measured in serum trough samples, using an enzyme linked immunosorbent assay (ELISA) and a radio immunoassay (RIA), respectively. <h3>Results</h3> After 52 weeks of treatment, 23 (22%) patients had detectable ADA. Serum adalimumab concentrations were significantly lower at 28 and 52 weeks in patients with detectable ADA compared to patients without detectable ADA (at week 28: 1.3 mg/L [IQR 0.0-3.2] vs 8.7 mg/L [IQR 5.7-11.5], p&lt;0.0001; at week 52: 0.9 mg/L [IQR 0.0-2.9] vs 9.4 mg/L [IQR 5.7-12.1], p=0.0001). DAS28 at 28 weeks (2.16 vs 2.95, p=0.023) and 52 weeks (2.19 vs 2.95, p=0.024) showed a significant difference; patients with detectable ADA had a poorer clinical outcome than patients without (see Table 1). <h3>Conclusions</h3> ADA was detected in 22% of the adalimumab treated PsA patients during 52 weeks of follow-up. These patients had lower adalimumab serum concentrations and a significantly poorer clinical outcome for DAS28 and CRP at week 28 and 52 compared to patients in whom ADA were not detected. <h3>Disclosure of Interest</h3> E. Vogelzang: None declared, E. Kneepkens: None declared, M. Nurmohamed: None declared, A. van Kuijk: None declared, T. Rispens Speakers bureau: Pfizer and Abbvie, G. Wolbink Grant/research support: Pfizer, Speakers bureau: Pfizer and Amgen, C. Krieckaert Speakers bureau: Pfizer and Abbvie <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.2162
Respiratory Syncytial Viral Infection in Children with Compromised Immune Function
Authors: Caroline Breese Hall, Keith R. Powell, Noni E. MacDonald, Christine L. Gala, Marilyn E. Menegus, Stephen C. Suffin, Harvey J. Cohen
Journal: New England Journal of Medicine (1986)

For 10 winters, 608 children five years old or younger who were hospitalized with respiratory syncytial virus (RSV) infection were prospectively studied to evaluate the relation between their immune status and the severity of their infection. Forty-seven had been immunocompromised by chemotherapy, steroid therapy, or a primary immunodeficiency disorder. Among the immunocompromised children, those receiving chemotherapy for cancer and those with immunodeficiency disease had more severe RSV disease, with pneumonia occurring at all ages, and a higher mortality rate. Children receiving long-term steroid therapy did not appear to have more severe clinical manifestations than normal children. Viral shedding, however, was significantly greater and more prolonged in the children receiving steroid therapy, and particularly in those receiving chemotherapy or with an immunodeficiency disease. Giant-cell pneumonia was documented in one child with leukemia. Over half the immunocompromised children acquired the RSV infection nosocomially. These findings indicate that children receiving chemotherapy for cancer and those with immunodeficiency disease are at risk for complicated or fatal infections from RSV and should be considered for antiviral and other therapies as they become available. Efforts should also be made to protect compromised children if hospitalization cannot be avoided.
CHADS2 SCORE PREDICTS ISCHEMIC STROKE AMONG CHRONIC HEART FAILURE PATIENTS WITH SINUS RHYTHM IRRESPECTIVE OF THE LEVEL OF RED CELL DISTRIBUTION WIDTH
Authors: Takumi Kondo, Takahisa Yamada, Takashi Morita, Yoshio Furukawa, Shunsuke Tamaki, Yusuke Iwasaki, Masato Kawasaki, Atsushi Kikuchi, Masashi Ishimi, Hideyuki Hakui, Tatsuhisa Ozaki, Yoshihiro Sato, Masahiro Seo, Iyo Ikeda, Eiji Fukuhara, Masatake Fukunami
Journal: Journal of the American College of Cardiology (2016)
P17 Molecular Complexities Identified Through Targeted Genomic Sequencing Of The Hht3 Locus On Chromosome 5
Authors: C. Shovlin, I. Mollet, A. Giess, E. Thomas, M. Jones, L. Game, F. Govani
Journal: Thorax (2014)

<h3>Introduction and objectives</h3> New methods of high throughput sequencing provide unparalleled access to the human genome and transcriptome. We hypothesised that next generation DNA sequencing technologies would allow us to identify an elusive novel disease gene for a pulmonary vascular disease inherited as an autosomal dominant trait: The <i>HHT3 </i>interval on chromosome 5 is predicted by linkage studies to contain a mutation causing pulmonary arteriovenous malformations and hereditary haemorrhagic telangiectasia.<sup>1,2</sup> <h3>Methods</h3> Published expressed sequence tag (EST) databases and tiling array data were used to supplement sequencing analysis of the <i>HHT3 </i>interval. Sheared, Agilent SureSelect adaptor-ligated genomic DNAs from six related patients and four controls were hybridised to single stranded biotinylated RNA baits. Samples were pooled for multiplexed sequencing on an Illumina HiSeq2000. Sequence data were processed with RTA version 1.7.45, CASAVA Eland pair algorithm, and CASAVA 1.7 demultiplexing algorithms. Validations of sequence variants were performed using conventional PCR and Sanger sequencing. <h3>Results</h3> Conventional exon-based sequencing strategies did not identify the <i>HHT3 </i>causative gene mutation. For individual candidate genes, up to 108 alternatively spliced transcripts per gene were predicted from EST databases. For intergenic regions, tiling array data indicated that up to 44 different transcribed fragments were present in the nucleus and/or cytoplasm of different cell types. For each NextGen sequencing DNA sample, ~8 million reads per sample uniquely mapped to the <i>HHT3 </i>interval which represents ~1/5,000 of the genome. Using a 2:1 threshold, an average of ~4,000 differences to NCBI36/hg18 were identified in each sample. 113 differences to NCBI36/hg18 were present in all six HHT3-affected individuals and absent in all four controls. 60% of novel shared variants were validated by wet lab PCR. Following exclusion in 100 normal chromosomes, and computational predictions of potential function, multiple candidate sequence variants remain. <h3>Conclusions</h3> Genomic sequencing capturing intronic sequences yields challenging numbers of sequence variants for wet lab validations, even when multiple replicate chromosomal strategies are employed. <h3>References</h3> Cole <i>et al</i>. <i>J Med Genet</i> 2005;42(7):577–582 Govani <i>et al</i>. <i>J Angiogen Res</i> 2010;11(2):15
1086 A SUBSTANTIAL PROPORTION OF NAIVE HCV-1 INFECTED PATIENTS WITH CHRONIC INFECTION MAY BENEFIT FROM CURRENT STANDARD THERAPY WITH PEG-INTERFERON AND RIBAVIRIN
Authors: A. Andriulli, M.R. Valvano, F. Spirito, A. Ippolito, A. Iacobellis, F. Bossa, F. Terracciano, G. Niro
Journal: Journal of Hepatology (2012)
Abstract POSTER-BIOL-1323: Elevated MGAT3 expression in ovarian cancer cells is epigenetically regulated and correlates with expression of bisecting GlcNAc-modified proteins
Authors: Francis Jacob, Merrina Anugraham, Reto Kohler, Sheri Nixdorf, Arun Vijay Everest-Dass, André Fedier, Viola Heinzelmann-Schwarz, Nicolle H. Packer
Journal: Clinical Cancer Research (2015)

Abstract Changes in the glycosylation of membrane proteins are a common feature of malignant transformation including ovarian cancer development. Of particular interest are N-linked glycans because these cell surface glycans mediate various cellular functions in cell-cell communication, cell adhesion, and cell motility. However the nature of these changes, their underlying molecular mechanisms, and the biological function of these glycans are poorly understood. In the present study, N-glycans were released from extracted membrane glycoproteins from ovarian cancer and normal ovarian epithelial cell lines and analysed using electrospray ionisation mass spectrometry; RT-qPCR measured gene expression of related glycosyltransferases; bisulfite sequencing analysed DNA methylation of the corresponding genes. We identified characteristic glycan features unique to membrane proteins of ovarian cancer cells. Among those ovarian cancer specific N-glycans were the ‘bisecting N-acetyl-glucosamine (GlcNAc)’ type. The bisecting GlcNAc is the product of the enzyme MGAT3 (beta-1,4-N-acetylglucosaminyltransferase 3) and the expression of the MGAT3 gene was elevated in ovarian cancer cell lines (SKOV3, IGROV1, A2780, OVCAR3) as compared to normal ovary surface epithelial (HOSE) cells. This elevated MGAT3 expression in ovarian cancer cells correlated with DNA hypomethylation at the transcription start site (TSS) of the MGAT3 promotor, which contains a large CpG island with 204 CpG dinucleotides located -600/+800bp relative to the TSS. This finding suggests that MGAT3 expression is epigenetically regulated. This was validated by the finding that the treatment of HOSE cells with the DNA-methyltransferase inhibitor 5-Aza increased MGAT3 expression and corresponded to a reduction in DNA methylation at the TSS. Taken together, we conclude that the elevated MGAT3 expression in ovarian cancer cells correlates with the presence of the resultant specific N-glycan substructures and with the epigenetic regulation of the associated enzymes by DNA methylation. These findings may stimulate the development of novel anti-glycan targeted drugs and clinical diagnostic tools for ovarian cancer Citation Format: Francis Jacob, Merrina Anugraham, Reto Kohler, Sheri Nixdorf, Arun Vijay Everest-Dass, André Fedier, Viola Heinzelmann-Schwarz, Nicolle H. Packer. Elevated MGAT3 expression in ovarian cancer cells is epigenetically regulated and correlates with expression of bisecting GlcNAc-modified proteins [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-BIOL-1323.
New Route for TNF Shows Promise, Saves Limbs
Authors: J. Randal
Journal: JNCI Journal of the National Cancer Institute (1994)

Journal Article New Route for TNF Shows Promise, Saves Limbs Get access Judith Randal Judith Randal Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 86, Issue 14, 20 July 1994, Pages 1044–1046, https://doi.org/10.1093/jnci/86.14.1044 Published: 20 July 1994
Modification of the Association between PM <sub>10</sub> and Lung Function Decline by Cadherin 13 Polymorphisms in the SAPALDIA Cohort: A Genome-Wide Interaction Analysis
Authors: Medea Imboden, Ashish Kumar, Ivan Curjuric, Martin Adam, Gian Andri Thun, Margot Haun, Ming-Yi Tsai, Marco Pons, Robert Bettschart, Alexander Turk, Thierry Rochat, Nino Künzli, Christian Schindler, Florian Kronenberg, Nicole M. Probst-Hensch
Journal: Environmental Health Perspectives (2014)

Both air pollution and genetic variation have been shown to affect lung function. Their interaction has not been studied on a genome-wide scale to date.We aimed to identify, in an agnostic fashion, genes that modify the association between long-term air pollution exposure and annual lung function decline in an adult population-based sample.A two-stage genome-wide interaction study was performed. The discovery (n = 763) and replication (n = 3,896) samples were derived from the multi-center SAPALDIA cohort (Swiss Cohort Study on Air Pollution and Lung Disease in Adults). Annual rate of decline in the forced mid-expiratory flow (FEF25-75%) was the main end point. Multivariate linear regression analyses were used to identify potential multiplicative interactions between genotypes and 11-year cumulative PM10 exposure.We identified a cluster of variants intronic to the CDH13 gene as the only locus with genome-wide significant interactions. The strongest interaction was observed for rs2325934 (p = 8.8 × 10(-10)). Replication of the interaction between this CDH13 variant and cumulative PM10 exposure on annual decline in FEF25-75% was successful (p = 0.008). The interaction was not sensitive to adjustment for smoking or body weight.CDH13 is functionally linked to the adipokine adiponectin, an inflammatory regulator. Future studies need to confirm the interaction and assess how the result relates to previously observed interactions between air pollution and obesity on respiratory function.
SP0110 CD28NULL T cells in myositis
Authors: V. Malmström
Journal: Annals of the Rheumatic Diseases (2013)

Hallmarks of the idiopathic inflammatory myopathies are muscle weakness and abnormal findings in muscle biopsies. Serologically, a growing number of myositis-specific and -associated antibodies have been defined and together with the histological findings patients are subdivided into polymyositis (PM), dermatomyositis (DM) and inclusion body myositis (IBM). The presence of autoantibodies point towards a role for antigen-specific CD4+ T cells, but so far only few studies have addressed adaptive immune responses in myositis. This notion is further supported by associations to HLA. We have during the last years focused on a subset of highly differentiated T helper cells lacking the costimulatory molecule CD28. These cells have been coined CD28null T cells, and are overrepresented in both PM and DM (Fasth et al J Immunol 2009) and IBM (Pandya et al Arthritis Rheum 2010). CD28null T cells are oligoclonally expanded T cells and can be either CD4 or CD8. Irrespective, they are devoted effector T cells making cytokines and being cytotoxic. So far the best described antigen-specificity amongst CD28null T cells is for cytomegalo virus (CMV), but it is likely that other specificities can also be found. Our working hypothesis is that CD28null T cells actively contribute to muscle dysfunction in affected tissue. Indeed, these cells are often persistently found in the biopsies even after aggressive treatment and may thus participate in the chronicity of this syndrome. During the lecture I will summarize our recent data on the functionality and specificity of T cells in patients with inflammatory myopathies. <h3>Disclosure of Interest</h3> None Declared
Abstract 1908: 19q13.2 amplification occurs in a subset of SMAD4-deficient pancreatic cancers.
Authors: Bosun Min, Albert Lai, Nabeel Bardeesy, Vikram Deshpande
Journal: Cancer Research (2013)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease. The PDAC genomes show evidence of high genomic instability leading to complex genomic rearrangements and copy number alterations. Major genetic events involved in PDAC progression have been characterized, but the subsequent alterations that contribute to different tumor behavior or patient outcomes are not well understood. Smad4 tumor suppressor gene mutation or deletion in pancreatic cancer correlates with metastatic disease and poorer patient outcome. We found that in a subset of PDACs with Smad4 expression loss, the chromosomal region 19q13.2 is focally amplified. Genomic amplifications found in cancers have been shown to contain driver genes that contribute to tumorigenesis. We are currently investigating the contribution of 19q13.2 amplicon resident genes in pancreatic cancer cell growth. Our characterization of a cancer amplicon in relation to known major genetic events in pancreatic cancer revealed that the 19q13.2 amplicon is closely associated with a subset of SMAD4-deficient tumors. Through additional in-depth tumor analyses we may better understand the heterogeneity and complexity of PDAC biology. Citation Format: Bosun Min, Albert Lai, Nabeel Bardeesy, Vikram Deshpande. 19q13.2 amplification occurs in a subset of SMAD4-deficient pancreatic cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1908. doi:10.1158/1538-7445.AM2013-1908
Increased 18F-FDG Uptake by a Retroperitoneal Mature Cystic Teratoma in an Infant
Authors: Young Joo Suh, Myung-Joon Kim, Mi-Jung Lee
Journal: Clinical Nuclear Medicine (2013)

A teratoma is a nonseminomatous germ cell tumor composed of well-differentiated derivations from at least 2 of the 3 germ layers. Mature cystic teratomas are known to have low metabolic activity and do not exhibit increased FDG uptake on PET. We report a case of mature cystic teratoma of the retroperitoneum showing increased FDG uptake in the solid portion. Pathologically, the solid portion was composed of abundant central nervous tissue. Increased FDG uptake in a teratoma may be not only due to an immature or malignant component but also to the presence of central nervous tissue.
Abstract 4240: The translocator protein 18kDa in the morphogenesis of breast epithelial cells in 3D culture
Authors: Xiaoting Wu, Kathleen Gallo
Journal: Cancer Research (2012)

Abstract Translocator protein (TSPO) is an 18 kDa mitochondrial membrane protein, first identified as a second binding site for benzodiazepine. Elevated levels of TSPO have been associated with breast cancer progression and with increased proliferation in cancer cells whereas TSPO ligands, PK11195 and Ro5-4864, which may serve as TSPO antagonists, inhibit proliferation in multiple cancer cell lines. Whether TSPO actually contributes to breast cancer progression is not known. In this study, the impact of TSPO up-regulation in breast epithelial cells is being assessed using a 3D Matrigel culture system. MCF10A mammary epithelial cells form well-polarized acini structures with a hollow lumen when grown in 3D Matrigel, whereas expression of oncogenes in MCF10A cells often induces phenotypes such as increased acinar size and filling of the lumen. In this study, a pool of stable TSPO expressing breast epithelial MCF-10A cells has been constructed. TSPO overexpressing MCF-10A cells when grown in 3D matrigel formed larger acini compared with control acini; and displayed abnormal lumen formation. Such a disruption of normal mammary epithelial morphogenesis by TSPO may resemble an early stage breast lesion leading to breast cancer. Immunofluorescent staining revealed increased levels of Ki-67 (a proliferative marker) in TSPO overexpressing acini compared with control acini, suggesting that TSPO promoted proliferation during mammary epithelial morphogenesis. TSPO ligands, including PK11195 and RO5-4864, inhibited proliferation of stable TSPO over-expressing MCF-10A cells in 2D plastic culture. Studies on the impact of TSPO ligands on the morphogenesis of MCF10A and breast cancer cells in 3D culture are being conducted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4240. doi:1538-7445.AM2012-4240