tbuckley/cabot-search huggingface dataset:
P91 Trypsin-like protease activity predicts disease severity and patient mortality in adults with cystic fibrosis
Authors: JA Reihill, KL Moffitt, AM Jones, JS Elborn, SL Martin
Journal: Thorax (2016)

<h3>Introduction</h3> Serine trypsin-like (TL) proteases, which are excessively active in CF airways, promote activation of the epithelial sodium channel (ENaC) and airways dehydration; a key initiating factor for CF lung disease pathogenesis. Furthermore TL-proteases enhance mucin gene expression and mucus hypersecretion, yet whether there is any relationship between the activity of these enzymes and CF pulmonary disease is unknown. <h3>Objectives</h3> The primary objective of the current investigation was to determine whether TL-protease activity, measured in adult CF sputum sol, correlates with lung disease and patient outcome (survival). A secondary objective was to compare the strength of any relationships observed with that of neutrophil elastase (NE), an established protease biomarker. <h3>Methods</h3> In this cross sectional retrospective study we analysed CF sputum sol collected from 30 clinically stable adult CF patients. Protease activity was measured by monitoring the hydrolysis of peptide-based substrates. Biomarkers of inflammation (IL-8 and TNF-α) were measured by ELISA. Lung function was assessed by spirometry (FEV1). Mortality data was retrospectively obtained and time in months until death or transplantation used for subsequent survival analysis. <h3>Results</h3> TL-protease activity inversely correlated with lung function (FEV1) (r = −0.4, p = 0.031) however, no relationship with IL-8 and TNFα was observed. In contrast, NE was found to correlate with IL-8: r = 0.7, p &lt; 0.001 and TNFα: r = 0.7, p &lt; 0.001 but showed no relationship with lung function, indicating that these serine proteases play very distinct roles within the disease process. Kaplan-Meier analysis demonstrated significantly reduced survival for those individuals with above median TL-protease activity. Levels of NE activity showed no relationship with patient survival. Using a multivariate Cox regression analysis (adjusted for age and BMI) a significantly increased mortality hazard (HR 1.028, 95% CI: 1.007–1.049; p = 0.009) was also identified. These findings are supported by analysis of a validation cohort consisting of samples collected from a separate cohort of 33 adult CF patients. <h3>Conclusions</h3> TL-protease activity inversely correlates with lung function and patient survival. As such tryptic activity may warrant consideration when modelling CF survivorship and should be investigated further as a biomarker of CF lung disease and as a potential therapeutic target.
PTH-096 Positive anti-gliadin antibodies with negative anti-endomysial antibodies: prevalence of coeliac disease and other gastrointestinal pathology: Abstract PTH-096
Authors: K M Taylor, K Patel, C Stratton, J Wicking, A McNair
Journal: Gut (2010)

<h3>Introduction</h3> The use of anti-gliadin antibodies (AGA) and anti-endomysial antibodies (EMA) is well established as a means of screening for coeliac disease (CD). Since the presence of EMA is highly specific for CD, a negative EMA result may deter some doctors from referring patients with positive AGA for duodenal (D2) biopsy or gastroenterological assessment. In CD there is a prevalence of IgA deficiency of around 3%, with corresponding negative EMA. In addition, isolated positive AGA are found in other gastrointestinal (GI) conditions, such as Crohn9s disease and chronic liver disease. <h3>Methods</h3> Aims: (1) To determine the proportion of patients with positive IgG AGA and/or IgA AGA but negative EMA who had undergone endoscopy and D2 biopsy. (2) To invite those who had not been investigated to attend either the gastroenterology clinic or for direct endoscopy and duodenal biopsy. (3) To determine the prevalence of CD and other gastrointestinal pathology. We identified patients with positive IgG and/or IgA AGA but negative EMA from the pathology database from February 2007 to August 2008. The medical records were reviewed to determine if there were features of CD on duodenal biopsy if performed, or alternative GI diagnoses. We wrote to the referring doctor and the general practitioner, requesting referral to gastroenterology if D2 biopsy had not been undertaken. If no reply, we contacted the patient directly. <h3>Results</h3> 1597 requests for coeliac serology were made during the 18 months: 186 were both AGA and EMA positive. Forty-six patients were AGA positive with negative EMA: 24 had undergone D2 biopsy; 2 had died prior to further investigation (86 and 89 years old); 1 was ineligible for NHS care; 1 patient had no contact details; and 1 patient had repeat EMA and AGA, which were negative. Of the remaining 17 patients, 8 agreed to undergo OGD and D2 biopsy. <h3>Conclusion</h3> CD is not uncommonly present in patients with isolated positive AGA and all such patients should be referred for OGD and D2 biopsy. Further investigation should also be considered as other gastrointestinal disorders are prevalent in these patients, probably in part reflecting the presence of symptoms or abnormal blood tests that prompted the request for AGA. The majority of requests for coeliac serology originate from primary care or non-GI physicians, many of whom fail to appropriately follow-up positive AGA. Laboratories should consider providing advice on AGA interpretation with test results.
Involvement of the Nervous System in Metastatic Disease of Childhood
Authors: D. P. E. Kingsley, B. Kendall
Journal: Neuro-Oncology (1980)

Metastatic tumours involving the central nervous system are considered to be rare in children (1); this is in marked contrast to adults in which metastases usually from a systemic primary tumour account for between 10 and 20% of intracranial tumours (2, 3, 4). In recent years improved therapy has prolonged life expectancy from many neoplasms which has increased the likelihood of eventual nervous system involve­ment by some tumours. Also the development of the effective and minimally invasive procedure of computed tomography has facilitated the detection of tumours in the nervous system. We considered that it would be of interest to assess the present incidence and the features, especially on computed tomograms, of involvement of the central nervous system by metastatic malignancy in children and have reviewed our material to this end.
Abstract 4539: Nitroxide-aspirin conjugates: A new class of NSAIDs
Authors: Terry W. Moody, Robert T. Jensen, Komba Thomas, Kathryn E. Fairfull-Smith, Steven E. Bottle, Lisa Ridnour, David A. Wink
Journal: Cancer Research (2015)

Abstract Novel nitroxide-aspirin conjugates were synthesized and tested using human lung cancer cell lines. Previously, cyclooxygenase (COX2) was found to be elevated in lung cancer biopsy specimens relative to normal tissue (He et al., 2012; PlosOne 7:e31087). Lung cancer cellular proliferation is inhibited by nonsteroidal anti-inflamatory drugs (NSAIDs) such as indomethacin and aspirin (Hida et al., 1998; Anticancer Res. 18: 775). Dithiolethione-valproate conjugates inhibit COX-2 activity, increase E-cadherin expression and decrease the proliferation of non-small cell lung cancer (NSCLC) cells (Moody et al., 2010, Lung Cancer 68: 154). Here the effects of nitroxide-aspirin conjugates were investigated on NSCLC cells. 1KT121A, a 4-carboxy Tempo-aspirin conjugate, inhibited the proliferation of NCI-H1299 or A549 cells with IC50 values of 125 uM using the MTT assay whereas aspirin and tempol had IC50 values of 750 and &amp;gt;1000 uM, respectively. 1KT121A, which has an ester link, was approximately 5-fold more potent at inhibiting NSCLC cellular proliferation than aspirin plus tempol or 2KT106A, which is a Tempo-aspirin conjugate with an amide link. 1KT121A was more potent than 2KT106A or tempol plus aspirin at reducing prostaglandin E2 levels in A549 cells. Similar results were obtained if the nitroxide moiety was changed from 4-carboxy Tempo to 3-carboxy proxyl or 5-carboxy-1,1,3,3-tetramethylisoindolin-yloxyl (CTMIO). 1KT121A potentiated the ability of gefitinib, an EGF receptor tyrosine kinase inhibitor, to kill NSCLC cells. Because 1KT121A increased E-cadherin and reduced vimentin, it may impair epithelial-mesenchymal transitions of NSCLC cells. All of the nitoxide analogues were antioxidants based on the ability to inhibit reactive oxygen species in NSCLC cells treated with hydrogen peroxide. Nitroxide-aspirin conjugates represent a novel class of NSAIDs which are antioxidants that inhibit NSCLC proliferation. Citation Format: Terry W. Moody, Robert T. Jensen, Komba Thomas, Kathryn E. Fairfull-Smith, Steven E. Bottle, Lisa Ridnour, David A. Wink. Nitroxide-aspirin conjugates: A new class of NSAIDs. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4539. doi:10.1158/1538-7445.AM2015-4539
Survivin inhibition by si-RNA induces apoptosis and increases sensitivity to adriamycin in human lung cancer cells with p53 mutation
Authors: Kimio Yonesaka, Kenji Tamura, Tarou Satoh, Takayasu Kurata, Toshiji Nogami, Kazuhiko Nakagawa, Masahiro Fukuoka
Journal: Cancer Research (2004)

2933   Survivin is a novel member of the inhibitor of apoptosis protein (IAP) family that is specifically overexpressed in cancer tissues/cells but not in normal adult tissues/cells. Survivin gene expression is downregulated in G1 and upregulated in G2/M phase in a cell cycle-dependent manner. Overexpression of Survivin has been found in many human cancers, including lung, colon, pancreas, prostate and breast, and correlates with poor prognosis. p53 is one of the tumor suppressor genes, frequently mutates in cancer tissues/cells. p53 induction and check points control in response to DNA damage induce apoptosis and correlates with drug sensitivity. Generally, cancer tissues/cells with mutated p53 have a tendency to be resistant to anti-cancer drug. Recent report suggests that wild type (wt) p53 downregulates Survivin expression in ALL cell lines. To investigate the possible regulation of Survivin by p53, we examined the Survivin expression level in lung cancer cell lines in response to DNA-damaging stimulus by adriamycin. mRNA and protein expression level of Survivin in 3 cell lines with (wt) p53, were dramatically decreased following p53 inductions. In contrast, in other 3 cell lines with mutated or null p53, no induction of p53 and no reduction of survivin (both mRNA and protein level) were observed after the treatment of adriamycin. To evaluate the direct downregulation of Survivin by (wt) p53, we have inhibited the (wt) p53 in A549 by short interfering (si) RNA technique. Administration of siRNA targeting p53 has significantly reduced p53 protein expression and comparatively increased Survivin protein expression. To investigate differences of sensitivity to adriamycin in cancer cells by inhibition of Survivin, we have inhibited Survivin by siRNA in PC9 which has mutated p53. After 48h siRNA administration to PC9 which has significantly inhibited the Survivin expression, we replaced the medium and added to IC 50  dose of adriamycin. Additional 48h incubation with adriamycin, the cell proliferation was significant repressed in the cell treated by siRNA targeting survivin, in comparison with in the cell treated by anti-scramble. Furthermore, we observed a significant increase of apoptosis after the treatment of adriamycin and siRNA targeting survivin in comparison with adriamycin and anti-scramble, by pro-caspase3 expression assay and TUNEL assay. Our results demonstrate that Survivin is transcriptionally downregulated by p53, and the siRNA targeting survivin increase a sensitivity to adriamycin and promotes apoptosis. The siRNA targeting survivin could be a potential approach to increase sensitivity to anti-cancer drug especially in the drug resistant cells which has mutated p53.
Prechemotherapy hemoglobin levels and survival in patients with advanced urothelial carcinoma who received a first-line gemcitabine/platinum(GP)-based regimen: Results of a single center retrospective study.
Authors: S. Park, S. Lee, J. Kong, J. Yun, J. Kim, J. Park, Y. Park, H. Lim, W. Kang
Journal: Journal of Clinical Oncology (2010)

e15123 Background: The aim of this retrospective study was to assess whether the pre-chemotherapy hemoglobin (Hb) levels have any impact on the clinical outcome of patients with advanced urothelial carcinoma who received a first-line GP-based regimen. Methods: A total of 181 evaluable patients with recurrent locally advanced or metastatic urothelial carcinoma received GP between 2001 and 2009 in a single institution. The relationship of pretreatment variables including Hb levels and response was evaluated with logistic regression, and prognostic factors for survival were analyzed with Cox's multivariate model. All the patients had ECOG performance status 0-2 at presentation. Results: The overall median survival was 42.8 months (95% CI: 34.13-51.53) with a 21.0% censoring rate at a follow-up time 71.7 months (range, 15.9-157.4 months). Response was achieved in 74.6% of the patients with a complete response rate of 17.1%. Gross hematuria, disease status before palliative first line GP chemotherapy (metastasis vs locally advanced status) were independent prognostic variables for overall survival. Conversely, albumin levels (<3.5 versus ≥3.5) and Hb levels (<12.1 g/dl versus ≥12.1) were inversely related to overall survival at multivariated analysis. Conclusions: This investigation showed that Hb levels before starting first-line GP-based chemotherapy is an independent prognostic factor for overall survival in patients with advanced urothelial carcinoma. No significant financial relationships to disclose.
140. Point Mutation Correction for ADA SCID
Authors: Miguel Calero-Garcia, Marlene Carmo, Adrian Thrasher, H Bobby Gaspar
Journal: Molecular Therapy (2016)

Adenosine deaminase (ADA) deficiency is a rare genetic disease characterised by the absence of the ADA enzyme (EC 3.5.4.4) involved in purine salvage and degradation. Patients lacking ADA build up adenosine and deoxyadenosine metabolites in the organism, something that in turn leads to an accumulation of other deoxynucleotides and gives rise to functional defects in all lymphocyte lineages and severe combined immunodeficiency (ADA SCID). This SCID phenotype can be corrected by hematopoietic stem cell transplant, enzyme replacement therapy, and integrative gene therapy protocols employing autologous CD34+ cells. ADA deficiency confers a positive selective advantage to corrected lymphocytes over deficient cells, thus offering a great system for the study of novel molecular therapies such as gene editing. The advent of the CRISPR/Cas9 system has allowed for the swift tailoring of novel gene editing strategies in laboratories without access to advanced cloning platforms. We believe this democratisation of gene editing has also made more practicable the therapeutic reversal of genetic mutations into wild type sequences, the ultimate form of genetic correction. We have designed a CRISPR/Cas9 strategy that can target the nonsense Q3X (ADA c7C>T) point mutation endemic to ADA SCID patients of Somali origin residing in the UK, as well as its equivalent site in wild type sequences. In the present work we show evidence of the Q3X site non-homologous end joining (NHEJ) gene ablation in Jurkat cells by means of DNA sequencing and ADA protein readouts (approximately 70% efficiency). Moreover, we have designed a donor for the Q3X repair step that contains an adjacent traceable silent mutation in order to track any homology directed repair (HDR) when working with wild type cells. Here we show preliminary evidence of Q3X site HDR in wild type Jurkat cells in DNA sequencing results by detection of the aforementioned traceable mutation, albeit with low efficiency (less than 3% efficiency). We are currently attempting the translation of this approach into human CD34+ cells, the ultimate target cell population for the correction of the SCID phenotype in ADA deficient patients.
Abstract 3146: T cell therapy targeting a neoantigen reduces <i>in vivo</i> tumour growth
Authors: Else M. Inderberg-Suso, Sebastien Wälchli, Marit R. Myhre, Mengyu Wang, Hilde Almåsbak, Gunnar Kvalheim, Gustav Gaudernack
Journal: Cancer Research (2015)

Abstract T-cell receptor (TCR) transfer is an attractive strategy to increase the number of cancer-specific T cells in adoptive cell therapy. However, recent clinical and pre-clinical findings indicate that careful consideration of the target antigen is required to avoid on-target, off-site toxicity. A safer alternative to targeting tumour-associated self-antigens may be to direct engineered T cells against mutated proteins such as frequently occurring frameshift mutations. Furthermore, such frameshift mutations result in novel polypeptides allowing selection of TCRs from the non-tolerant T-cell repertoire circumventing the problem of low affinity TCRs due to central tolerance. The transforming growth factor β Receptor II frameshift mutation (TGFβRIImut) is found in Lynch syndrome cancer patients and in around 15% of sporadic colorectal and gastric cancers displaying microsatellite instability. The -1A mutation within a stretch of 10 adenine bases (nucleotides 709-718) of the TGFβRII gene gives rise to immunogenic peptides previously used for vaccination of MSI+ colorectal cancer patients in a Phase I clinical trial. From a clinically responding patient we isolated a CD8neg/CD4neg CTL clone from which we cloned an HLA-A2-restricted TGFβRIImut-specific TCR. We showed that both CD8+ and CD4+ T cells transiently redirected with this TGFβRIImut-TCR recognised colon carcinoma cell lines harbouring the frameshift mutation, indicating CD8+ co-receptor independency. Cysteine modification of the TCR enhanced its expression and function and we have demonstrated that these TCR-redirected T cells significantly enhanced survival and reduced tumour growth in a NOD/SCID xenograft mouse model of colorectal cancer. Citation Format: Else M. Inderberg-Suso, Sebastien Wälchli, Marit R. Myhre, Mengyu Wang, Hilde Almåsbak, Gunnar Kvalheim, Gustav Gaudernack. T cell therapy targeting a neoantigen reduces in vivo tumour growth. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3146. doi:10.1158/1538-7445.AM2015-3146
Abstract 4971: Detection of receptor and non receptor tyrosine kinases in the culture filtrates of astrocytes and cancer cells
Authors: Venkateswara Rao Gogineni
Journal: Cancer Research (2015)

Abstract As demonstrated in our previous work, meningioma cells shed their membrane receptors and these receptors function in a cell-free environment. The purpose of this study was to determine if receptor and non-receptor kinases were similarly being released in different cancers. Using antibody arrays, cell culture filtrates from glioma and prostate cancer cell lines were assessed to determine if solubilized receptors and kinases were present. Supernatants from cells treated with Brefeldin-A were analyzed similarly. Further, culture filtrates concentrated by ultrafiltration were subjected to luminescence based kinase assays and western blotting to assess the active forms. Cell viability was measured with Trypan blue staining in all the experiments. Our results demonstrate that an array of receptors are solubilized into culture filtrates of brain and prostate cancer cell lines within the first 24 hours. Simultaneously, soluble receptors in the culture filtrates of astrocytes within 48 hours of culture were also detected. Compared to astrocytes, cancer cells showed elevated levels of receptors and kinases released at 48 hours. As many as 15 receptor or non-receptor tyrosine kinases including Src family of kinases were found in the culture filtrates of the brain and prostate cancer cell lines. Treatment with Brefeldin-A inhibited the release of receptors and kinases partially, but markedly, within first 24 hours suggesting a secretory pathway for their release. Additionally, phosphorylation of tyrosine kinases was detected in the western blots within 24 hours. Kinase assays further confirmed active nature of the extracellular kinases, particularly, when checked for the active form of Lyn kinase in the culture filtrates, phosphorylation on Tyrosine-507 was detected along with the total forms. Cell viability assays on the cultured cells revealed more than 98% viability, thus eliminating the possibility of the release of detected kinases from dead cells. In light of this study, we propose a new niche for solubilized receptor and tyrosine kinase functioning that might have a role in intercellular signaling in cell-free conditions both in disease and physiological statuses. Note: This abstract was not presented at the meeting. Citation Format: Venkateswara Rao Gogineni. Detection of receptor and non receptor tyrosine kinases in the culture filtrates of astrocytes and cancer cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4971. doi:10.1158/1538-7445.AM2015-4971
Abstract 2042: Low Slit2 expression is associated with the aggressiveness of papillary thyroid carcinoma
Authors: MinJi Jeon, Won Gu Kim, Seonhee Lim, Eun Kyung Jang, Tae Yong Kim, Young Kee Shong, Won Bae Kim
Journal: Cancer Research (2015)

Abstract Context: Slits, representative axon guidance molecules, and their Roundabout (Robo) transmembrane receptors are identified as key regulators of many cancers. One genome-wide liknage analysis suggested Slit-Robo Rho GTPase activating protein 1 gene as a candidate gene in papillary thyroid carcinoma (PTC) susceptibility. Objective: To identify the role of Slit-Robo signaling in PTC. Results : Slits(Slit 1-3) and Robos (Robo 1-4) were expressed in all of thyroid cancer cells and Slit2, Slit3, Robo1 and Robo4 presented higher expression than others. The mRNA expression of Slits and Robos was higher in fresh frozen PTC tissues than matched normal tissues. When we conducted immunohistochemical staining of Slit2 and Robo1 in thyroid tissues, the positivity of Slit2 and Robo1 were higher in PTC tissues than benign or normal tissues. However, negative Slit2 expression was significantly associated with cervical lymph node (LN) metastasis, distant metastasis and cervical recurrence of PTC (P &amp;lt;.001) irrespective of BRAF mutation status. In cellular assays, Slit2 treatment inhibited proliferation of thyroid cancer cells as dose dependent manner and also significantly suppressed cell migration by inhibiting activation of beta-catenin and inducing E-cadherin. Slit2 treatment also significantly suppressed beta-catenin activation induced by Wnt3A in luciferase reporter assay. Conclusions : Low expression of Slit2 was associated with poor prognostic factors in PTC. This present study demonstrated the potential of Slit2 as a novel prognostic and therapeutic factor in PTC. Citation Format: MinJi Jeon, Won Gu Kim, Seonhee Lim, Eun Kyung Jang, Tae Yong Kim, Young Kee Shong, Won Bae Kim. Low Slit2 expression is associated with the aggressiveness of papillary thyroid carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2042. doi:10.1158/1538-7445.AM2015-2042