tbuckley/cabot-search huggingface dataset:
Abstract 2239: Buthionine sulfoximine enhanced melphalan cytotoxic activity against multiple myeloma cell lines
Authors: Ashujit Tagde, C Patrick Reynolds
Journal: Cancer Research (2011)

Abstract Multiple myeloma (MM) is a neoplasm of terminally differentiated antibody secreting B cells commonly treated with myeloablative doses of the alkylating agent melphalan (L-PAM) and supported by stem cell transplantation (SCT). Relapse after SCT is common and a second SCT with L-PAM for patients achieving less than a complete response or at time of relapse is usually only modestly effective. Glutathione (GSH) is ubiquitous intracellular tripeptide that acts as antioxidant and protects cells against reactive oxygen species (ROS) and xenobiotics. Conjugation of GSH to alkylating agents is known to be one mechanism of melphalan resistance. Buthionine sulfoximine (BSO) inhibits synthesis of GSH and enhances the activity of melphalan in preclinical and clinical studies of neuroblastoma. The potent hematopoietic toxicity of BSO + L-PAM led us to conduct an ongoing phase I trial in recurrent neuroblastoma of escalating L-PAM + BSO given with SCT. To explore the potential for a similar trial in MM, we have undertaken preclinical studies of BSO + L-PAM in MM. We determined if buthionine sulfoximine (BSO) enhanced the activity of melphalan (L-PAM) against MM cell lines. In-vitro cytotoxicity mediated by BSO (0-400 micro molar) alone and in combination with L-PAM (0-50 micro molar) was assessed in a panel of six MM cell lines in both “standard cell culture conditions” (20% O2) and “bone marrow level hypoxia” (5% O2) using the DIMSCAN digital image fluorescence assay. Single-strand DNA (ssDNA) damage by F7-26 antibody, apoptosis by TdT labeling (TUNEL) and mitochondrial depolarization by JC-1 were measured by flow cytometry. At clinically achievable concentrations, BSO consistently caused two to four logs synergistic enhancement of L-PAM cytotoxicity (combination index &amp;lt; 1) in all six multiple myeloma cell lines at both 5% and 20% O2. BSO + L-PAM caused a significant increase in single strand DNA damage (p&amp;lt;0.001), mitochondrial depolarization (p&amp;lt;0.001), and apoptosis (p&amp;lt;0.001) compared with L-PAM alone. Thus BSO can enhance L-PAM activity and overcome L-PAM resistance in multiple myeloma cell lines and BSO/L-PAM synergy is also achieved in bone marrow level hypoxia. Obtaining additional data on this novel combination approach to therapy of multiple myeloma is warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2239. doi:10.1158/1538-7445.AM2011-2239
Abstract LB-313: Development of a non-invasive, multi-analyte assay for the triage of patients presenting with hematuria
Authors: Cecilia A. Fernandez, John M. Millholland, Ellen C. Zwarthoff, Kevin R. Loughlin, Adam Feldman, R. Jeffrey Karnes, Anthony P. Shuber
Journal: Cancer Research (2011)

Abstract Introduction The presence of blood in the urine (hematuria) is one of the hallmark symptoms of bladder cancer. Thus, the current best practice policy suggests that patients with hematuria undergo cystoscopic examination. However, hematuria can be present in healthy individuals as well as in individuals with various non-life threatening conditions such that a majority of patients with blood in the urine (∼95%) who are screened by cystoscopy do not have bladder cancer. In addition, recent studies have found that a majority of patients with hematuria are not referred on to a specialist for further invasive tests, despite the guidelines. This suggests that the prevalence of cancer in this population may be lower than 5%, making screening by cystoscopy inefficient and, in a large number of cases, unnecessary. We are developing a non-invasive diagnostic assay utilizing urinary protein and DNA biomarkers to triage those patients who do not have cancer from those who should go on to be existing invasive screening modalities. Methods Urine samples were obtained from 48 cancer patients and 256 patients who were evaluated for hematuria but who did not have cancer upon cystoscopic evaluation (Hem+/Cysto−). Twist1 and Nid2 methylation status was assessed using methylation-specific PCR primers and FGFR3 mutational status was determined by quantitative PCR. Matrix Metalloproteinases (MMPs) levels were determined by ELISA. Results Using a novel combination of these DNA and protein markers we identified with high confidence (99% negative predictive value) those patients who do not have cancer and who could be excluded from further testing. Cutoffs could be adjusted such that at 94% sensitivity, 65% of patients who do not have cancer could be excluded. Conclusions The Multi-Analyte Diagnostic Readout (MADR) assay described here combines the best performance characteristics of protein and DNA biomarkers into one assay for optimal clinical performance. Using this approach, the detection of FGFR3 mutations and Twist1 and Nid2 methylation in the urine of hematuria patients undergoing screening for bladder cancer effectively increases the sensitivity and negative predictive value at an established MMP protein cutoff. This non-invasive urinary diagnostic assay could lead to the more efficient triage of hematuria patients by identifying those patients who do not have cancer and could be excluded from receiving invasive procedures. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-313. doi:10.1158/1538-7445.AM2011-LB-313
Abstract 1562: The G protein-coupled receptor mFPR2 promotes antitumor host defense
Authors: Ying Liu, Keqiang Chen, Xiaohong Yao, Wanghua Gong, Teizo Yoshimura, Jill Ford, Daniel McVicar, Ji Ming Wang
Journal: Cancer Research (2011)

Abstract mFPR2 is a G protein-coupled receptor interacting with chemotactic agonists produced by bacteria and the host. In vivo, mFPR2 plays a major role in innate and adaptive immune responses as shown by reduced severity of allergic airway inflammation and diminished production of Th1 and Th2 cytokines in mFPR2-deficient mice. These defects were associated with impaired trafficking of antigen presenting dendritic cells into the inflammatory sites and the draining lymph nodes. The aim of this study is to examine the role of mFPR2 in tumor progression. We found that mFPR2-deficient mice bearing subcutaneously implanted Lewis Lung Cancer cells (LLC) exhibited significantly shortened survival rate due to more rapidly growing tumors. In contrast, in mFPR2-transgenic (Tg) mice, subcutaneously implanted LLC tumors grew more slowly than those in wild type (WT) littermates. We further observed a decrease in the proportion of CD11b+ and Gr1+ myeloid cells accompanied by reduced infiltration of CD11b+Gr1low myeloid-derived suppressor cells and CD4+Foxp3+ regulatory T cells in LLC tumors in mFPR2-Tg mice. These results suggest that mFPR2 may play an important role in anti-tumor host defense by down-regulating immune suppressive cell infiltration in tumor tissues. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1562. doi:10.1158/1538-7445.AM2011-1562
THU0001 Variation in granzyme-b is associated with progression of joint destruction in rheumatoid arthritis
Authors: R. Knevel, A. Krabben, G. Wilson, E. Brouwer, E. Lindqvist, D. de Rooy, N. Daha, M. van der Linden, R. Tsonaka, S. Zhernakova, H.-J. Westra, L. Franke, J. Houwing-Duistermaat, R. Toes, T. Huizinga, T. Saxne, A. van der Helm-van Mil
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> The severity of joint destruction in Rheumatoid Arthritis (RA) is highly variable between patients and 45-58% of the variance is estimated to be explained by genetic factors. The serine proteinase Granzyme-B (GZMB) is important for the rapid induction of target cell apoptosis by cytotoxic T-cells and several in vitro studies suggested that GZMB is involved in apoptosis of chondrocytes. GZMB serum levels are increased in RA and the height of these levels are associated with higher risk of radiographic erosions. <h3>Objectives</h3> To investigate <i>GZMB</i> as a candidate gene for the severity of the rate of joint destruction in RA. <h3>Methods</h3> 1,418 patients with 4,885 X-ray sets of both hands and feet of four independent datasets were studied. First, explorative analyses were performed on 600 RA-patients enrolled in the Leiden-Early-Arthritis-Clinic. 16 SNPs tagged <i>GZMB</i> and were tested. Significantly associated SNPs were genotyped in datasets from Groningen (NL), Sheffield (UK) and Lund (Sw). In each dataset the relative increase of the progression rate per year in the presence of a genotype was assessed. Subsequently, data were summarized in a meta-analysis. To assess the functional potential of <i>GZMB</i>, the association of the identified SNPs with RNA-expression level of the genomic region of <i>GZMB</i> was tested, by mapping expression quantitative trait locus (eQTL) on 1,469 whole blood samples. <h3>Results</h3> In the discovery cohort, patients homozygous for the minor allele of rs8192916 had a 1.05 (95%CI 1.02-1.08) fold rate of joint destruction per year compared to other patients (<i>P</i>=1.2×10<sup>-3</sup>). Thisassociation remained significant in the meta-analysis on all datasets (<i>P</i>=7.8×10<sup>-4</sup>). eQTL of <i>GZMB</i> tested a higher expression in the presence of the minor allele of rs8192916 (<i>P</i>=2.2×10<sup>-5</sup>). <h3>Conclusions</h3> Rs8192916 located in <i>GZMB</i> is associated with the progression of joint destruction in RA as well as with RNA expression levels in whole blood. Future studies are needed to evaluate whether rs8291916, or a genetic variant linked to this SNP, is associated with an enhanced destructive process or with propagation of the immune response, to further explain the observations done on DNA and RNA levels in RA. <h3>Disclosure of Interest</h3> None Declared
TCT-794 Percutaneous clousure of para valvular mitral prosthetic regurgitation with AVPIII device
Authors: jorge enrique sandoval berrocal, Manuel Paulo, Rosana Hernandez-Antolin, Carlos Almería, Carlos Ramon Rodas, Patricia Martin, Jaime Dutary, Fernando Federico Fernandez-Viña, Eulogio Garcia
Journal: Journal of the American College of Cardiology (2012)
Abstract LB-187: Identification of CIT-0665, a novel inhibitor of LSD1
Authors: Bret J. Stephens, Steven L. Warner, Hari Vankayalapati, David J. Bearss, Sunil Sharma
Journal: Cancer Research (2011)

Abstract Lysine-specific demethylase 1 (LSD1/AOF2/KDM1A) is a flavin-dependent histone demethylase that catalyzes the posttranslational oxidative demethylation of mono- and dimethylated lysines on histones. Methylation of lysine residues on histones can signal transcriptional activation or repression depending on the specific residue involved. H3K4me2 is a transcription-activating chromatin mark at gene promoters, and demethylation of this mark by LSD1 is thought to prevent expression of tumor suppressor genes important in human cancer. In contrast, methylation of H3K9 is a repressive mark and LSD1 activity has been shown to upregulate tumor promoting pathways. Thus, LSD1 is emerging as an important target for the development of specific inhibitors as a new class of antitumor drugs. Currently, only a few existing compounds, such as monoamine oxidase inhibitors, have been shown to act as inhibitors of LSD1. More potent and specific inhibitors of LSD1 are needed to advance LSD1 biology and test for potential efficacy in tumor models. We utilized the 3-D crystal structure of LSD1 to computationally dock more than 10 million virtual compounds into the active site of the protein. From the docking experiments, we physically screened 52 compounds in an LSD1 biochemical assay (resorufin-based assay measuring the amount of hydrogen peroxide generated by LSD1). The compound CIT-0665 was identified as a potent inhibitor of LSD1 enzymatic activity, with an IC50 of 290nM. Additionally, cell lines treated with CIT-0665 show increased levels of H3K4 methylation. A large panel of cancer cell lines was also tested for sensitivity to CIT-0665, using a cell viability assay. We are currently engaged in determining possible mechanisms of sensitivity from the cell line panel and making analogs of CIT-0665 with improved drug-like qualities. In conclusion, CIT-0665 is a novel LSD-1 inhibitor with activity in biochemical and cell-based assays. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-187. doi:10.1158/1538-7445.AM2011-LB-187
THU0059 Decreased Expression of Neuropilin-1 in Systemic Sclerosis: Potential Contribution to Impaired Angiogenesis
Authors: E. Romano, M. Manetti, C. Mazzotta, I. J. da Silva Cora, S. Bellando-Randone, L. Ibba-Manneschi, M. Matucci-Cerinic, S. Guiducci
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Systemic sclerosis (SSc) is a chronic, multisystem connective tissue disorder characterised by widespread microangiopathy, fibrosis and autoimmunity. Vascular damage is a primary event in SSc and is characterised by vascular tone dysfunction and increased circulating levels of vascular endothelial growth factor (VEGF). Neuropilins (NRPs) were origi­nally identified as adhesion molecules in the nervous system and subse­quently rediscovered as receptors for the class-3 semaphorin (sema) family of axon guidance molecules and as blood vessel receptors for VEGF. NRP1 is required for optimal VEGF/VEGFR-2 signalling, and NRP1–deficient mice exhibit vascular defects including disorganised blood vessels, lack of normal branching and missing capillary networks. Soluble NRP1 (sNRP1) may regulate VEGF/VEGFR-2 interactions. Sema3a is reported to control physiological and pathological angiogenesis. <h3>Objectives</h3> To investigate the possible involvement of the sema3a/NRP1 axis in SSc. <h3>Methods</h3> Circulating levels of soluble NRP1 (sNRP1) and sema3a were measured by sandwich ELISA in serum samples from SSc patients (n=49, mean±SDage: 64<b>±</b>10years) and age- and sex-matched healthy controls (n=39, mean±SDage: 58<b>±</b>14years). sNRP1 and sema3a levels were expressed as median and range and compared by Mann-Whitney U test. Differences were considered significant for p values less than 0.05. NRP1 protein expression was evaluated by immunohistochemistry in skin biopsies from SSc patiens (n=10) and healthy controls (n=8). Western blot was used to measure NRP1 expression in human dermal microvascular endothelial cells (H-MVECs) isolated from 3 healthy subjects at basal condition and after stimulation with recombinant human VEGF165 (10 ng/ml), SSc sera (n=3) and healthy sera (n=3) for 24h. <h3>Results</h3> Serum levels of sNRP1 were significantly higher in healthy controls (median 0.69 ng/ml, range 0.00-2.49 ng/ml) than in SSc patients (median0.22 ng/ml, range 0.00-3.12 ng/ml) (p=0.005). No significant differences in serum levels of sema3a were detected between SSc patients (median2.07 ng/ml, range 0.13-16.4 ng/ml) and healthy controls (median 3.86 ng/ml, range 0.03-11.69 ng/ml). The expression of NRP1 was decreased in clinically affected skin biopsies from SSc patients compared with healthy skin, especially in dermal endothelial cells and stromal cells. Stimulation with VEGF165 strongly upregulated NRP1 expression in H-MVECs. The expression of NRP1 in H-MVECs was higher after treatment with healthy sera compared with basal condition, while it was decreased after challenging with SSc sera. <h3>Conclusions</h3> Our findings suggest that NRP1 might play a role in the vascular damage and impaired angiogenic process characteristic of SSc. <h3>Disclosure of Interest</h3> None Declared
Abstract 4249: Development of Champions Tumorgraft models in rare cancer types for preclinical investigation and drug discovery
Authors: Jay A. Friedman, Christine Kilonzo, Lee Albee, Meredith James, Bin Lu, Elizabeth Bruckheimer
Journal: Cancer Research (2012)

Abstract Little progress has been achieved in the treatment of the rare cancers such as Ewing Sarcoma (ES), Merkel cell carcinoma (MCC), and osteosarcoma. ES is a rare bone malignancy that affects children and young adults and there has been little improvement in survival rates for patients with metastatic or recurrent disease despite aggressive treatment. MCC is a rare malignant cutaneous tumor of the elderly and optimal treatment strategies remains unclear for these patients. Poor clinical outcome is seen especially those MCC patients with regional lymph node metastases and distant metastases. Osteosarcoma arises in bone and affects adolescents and young adults. There has been no significant improvement in prognosis since the advent of multi-agent chemotherapy. A significant limitation in sorting out the complexities of these rare tumors and evaluating therapeutic strategies is the lack of preclinical models. To overcome this challenge, we have embarked on a mission to establish and characterize Champions TumorgraftTM models within these rare tumor indications. The Champions Tumorgraft utilizes the implantation of primary human tumors in immune-deficient mice in a manner that preserves the biological properties of the original human tumor. In this preliminary work, we reveal several new Champion TumorgraftTM models of ES, MCC, and osteosarcoma along with their tumor histology, mutational status, and chemosensitivity profiles to several standard of care compounds. These rare Champion TumorgraftTM models represent invaluable tools for preclinical research and drug discovery to find promising new therapies for this high unmet clinical need. 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 4249. doi:1538-7445.AM2012-4249
PMO-098 Diagnostic yield of ERCP and EUS FNA in a tertiary pancreatic cancer centre
Authors: D McClements, H Smart, P Whelan
Journal: Gut (2012)

<h3>Introduction</h3> Patients with suspected pancreatic malignancy on cross sectional imaging are often referred for endoscopic investigations with a view to obtaining a definitive histological diagnosis. We aimed to assess the diagnostic yield of brushings and biopsies taken at endoscopic retrograde cholangiopancreatography (ERCP) and endoscopic ultrasound with fine needle aspiration (EUS FNA) in patients with pancreatic malignancy proven by operative histology. <h3>Methods</h3> A retrospective audit of 125 patients undergoing surgery for pancreatic malignancy at the Royal Liverpool University Hospital (RLUH) from January 2009 to December 2011 was carried out. Of these patients, 35 underwent investigation at RLUH and are included in this analysis, two of these required two investigations. Fifty patients had ERCP at an external Trust and 40 patients went straight to surgery without endoscopic intervention. Data were extracted from the pancreatic surgery database and electronic patient records for demographics and histology reports taken at the time of endoscopy and surgery. <h3>Results</h3> Overall 123 patients had operative histology confirming pancreatic adenocarcinoma, two patients had neuroendocrine tumour (NET) of the pancreas. Of the 35 patients undergoing investigation at RLUH, 34 had pancreatic adenocarcinoma and one had NET of the pancreas. Fifteen of 29 (52%) patients had brushings confirmatory of malignancy at ERCP, 9 of 29 (31%) had no malignant cells seen on brushings at ERCP, 3 of 29 (10%) had equivocal results suggestive but not diagnostic of malignancy. Brush cytology was not obtained in two patients, one patient suffered a perforation at ERCP requiring emergency surgery and one patient had failed cannulation of the CBD. Five of eight patients had an EUS FNA confirmatory of malignancy, two of eight had no malignant cells seen and 1 had equivocal results. In our cohort the sensitivity of ERCP alone is 56% (95% CI 36% to 74%) the combined sensitivity for ERCP and EUS 57% (95% CI 40% to 73%). <h3>Conclusion</h3> The sensitivity of brush cytology at ERCP for has previously been reported to be between 50% and 65%<sup>1–3</sup> for pancreatic malignancies. This is comparable to our findings in this cohort of patients with proven pancreatic malignancy. Positive histology from ERCP to EUS FNA can be confirmatory of pancreatic malignancy, but caution should be used when interpreting negative histology results given the intermediate sensitivity of these investigations. <h3>Competing interests</h3> None declared. <h3>References</h3> 1. <b>Mansfield JC</b>, Griffin SM, Wadehra V, <i>et al.</i> A prospective evaluation of cytology from biliary strictures. <i>Gut</i> 1997;<b>40</b>:671–7. 2. <b>Macken E</b>, <i>et al.</i> Brush cytology of ductal strictures during ERCP. <i>Acta Gastroenterol Belg</i> 2000;<b>63</b>:254–9. 3. <b>Temino Lopez-Jurado R</b>, <i>et al.</i> Diagnostic yeild of brush cytology for biliary stenosis during ERCP. <i>Rev Esp Enferm Digest</i> 2009;<b>101</b>:385–94.
Abstract 4118: Expression of CD133 as a prognostic marker of non-small cell lung cancers
Authors: Hidenori Mizugaki, Jun Sakakibara Konishi, Junko Kikuchi, Eiki Kikuchi, Jun Moriya, Kanako Kubota, Ichiro Kinoshita, Satoshi Oizumi, Hirotoshi Dosaka Akita, Yoshihiro Matsuno, Masaharu Nishimura
Journal: Cancer Research (2011)

Abstract [Background] CD133 is a membrance glycoprotein with five transmembrance loops. Previous reports have suggested that CD133-positive subpopulation of multipotent cells with extensive proliferative and self-renewal abilities has biological features as a cancer stem cell. In addition, it has been reported that the presence of CD133-positive cells was associated with a significantly poorer prognosis compared with the CD133-negative cells in some solid tumors, including colon cancer, hepatocellular carcinoma and glioma. However, little is known about the relationship between the expression of CD133 and clinical and clinicopathological characteristics in lung cancer. [Aim and Method] We conducted immunohistochemical assessment of 161 surgically resected non-small cell lung cancers (NSCLCs) at Hokkaido University Hospital between 1982 and 1994 to evaluate the correlation between CD133 expression and various features, including clinical and clinicopathological characteristics. [Results] Normal alveoli were used as negative controls and Bowman's capsule basement membrane as positive controls. CD133 expression was significantly correlated with advanced p-Stage (p=0.040). The Kaplan-Meier method demonstrated that NSCLC patients with CD133 expression in tumor cells showed poor prognosis compared to those without CD133 expression in p-Stage II, III and IV (p=0.0098). CD133 expression alone was an independent factor for unfavorable prognostic in those patients (Hazard Ratio=3.157, p=0.015). [Conclusion] CD133 expression was correlated with p-Stage and was an independent factor for unfavorable prognosis in patients with p-Stage II, III and IV NSCLCs. CD133 expression may be a novel prognostic marker for NSCLCs. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4118. doi:10.1158/1538-7445.AM2011-4118