tbuckley/cabot-search huggingface dataset:
Abstract 4945: A novel role for drebrin in regulating progranulin bioactivity in bladder cancer
Authors: Shi-Qiong Xu, Simone Buraschi, Alaide Morcavallo, Marco Genua, Tomoaki Shirao, Stephen C. Peiper, Leonard G. Gomella, Antonino Belfiore, Renato V. Iozzo, Andrea Morrione
Journal: Cancer Research (2015)

Abstract Bladder cancer (BC) is one of the most common cancers in the United States with 56,390 estimated new cases and 11,170 estimated deaths in 2014. The majority of deaths is due to metastatic spread. Understanding the molecular mechanisms regulating bladder tumor cell invasion and progression toward metastases is essential for developing better therapies to treat bladder cancer patients. The growth factor progranulin plays an important role in cell proliferation, wound healing and transformation. We have recently established a critical role for progranulin in bladder cancer insofar as progranulin promotes urothelial cancer cell motility and contributes, as an autocrine growth factor, to the transformed phenotype by modulating invasion and anchorage-independent growth. In addition, progranulin expression is upregulated in invasive bladder cancer tissues compared to normal controls. However, the molecular mechanisms of progranulin action in bladder cancer have not been fully elucidated. In this study, we searched for novel progranulin-interacting proteins using pull-down assays with recombinant progranulin and proteomics. We discovered that drebrin, an F-actin binding protein, bound progranulin in urothelial cancer cells. We characterized drebrin function in various urothelial cancer cell lines and showed that drebrin is critical for progranulin-dependent activation of the Akt and MAPK pathways and modulates F-actin remodeling, motility, invasion and anchorage-independent growth. In addition, drebrin regulates tumor formation in vivo and its expression is upregulated in bladder cancer tissues compared to normal tissue controls. Our data are translationally relevant as indicate that drebrin exerts an essential functional role in the regulation of progranulin action and may constitute a novel target for therapeutic intervention in bladder tumors. In addition, drebrin may serve as novel biomarker for bladder cancer. This work was supported by the Benjamin Perkins Bladder Cancer Fund, National Institutes of Health Grants RO1 CA164462 (A.M., R.V.I.), and RO1 CA39481 and RO1 CA47282 (R.V.I.), Associazione Italiana per la Ricerca sul Cancro (AIRC) (grant n. 10625/12), AIRC project Calabria 2014 and Fondazione Cassa di Risparmio di Calabria e Lucania PON01_01078 (A.B.). Alaide Morcavallo was supported in part by Fondazione Diabete Ricerca. Citation Format: Shi-Qiong Xu, Simone Buraschi, Alaide Morcavallo, Marco Genua, Tomoaki Shirao, Stephen C. Peiper, Leonard G. Gomella, Antonino Belfiore, Renato V. Iozzo, Andrea Morrione. A novel role for drebrin in regulating progranulin bioactivity in bladder cancer. [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 4945. doi:10.1158/1538-7445.AM2015-4945
Overexpression of EVI1 in Translocation t(3;8)(q26;q24) in a Patient with Trilineage AML.
Authors: Martin Wernli, Paula C. Fernandez, Benno Roethlisberger, Ingmar Heijnen, Johanna Burger, Dominique Muehlematter, Martine Jotterand, Andreas R. Huber, Mario J. Bargetzi
Journal: Blood (2004)
Use of a prognostic pathway signature for colorectal cancer comprised of EGFR/COX2 and imatinib drug target activation to predict occult metastasis in M0 CRC
Authors: M. Pierobon, A. Silvestri, V. Calvert, J. Deng, C. Belluco, D. Nitti, A. Colombatti, E. Mammano, L. Liotta, E. Petricoin
Journal: Journal of Clinical Oncology (2009)

4042 Background: Development of distant metastasis is the main cause of death among CRC patients. Approximately 30% of CRC patients initially staged M0-N0 die from tumor recurrence. Previously, we determined that members of EGFR/PDGFR/cAbl/cKit pathways were hyperactivated in hepatic synchronous CRC metastasis compared to primary tumor. In order to determine if this signature was a distinguished repertoire of the early stage primary tumor, we analyzed 58 CRC M0 at the moment of the diagnosis that upon 5 yr follow-up had differing disease progressions. Methods: All tissues were immediately snap frozen after surgery. Reverse phase protein microarray (RPMA) was performed using microdissected material to generate multiplexed pathway profiling. For each sample 75 different endpoints were analyzed. Results: Statistical comparison of the 75 endpoints in 8 M0 patients who progressed to M1 and 50 patients who remained M0 regardless of initial staging, revealed a number of signaling proteins whose activation/phosphorylation were elevated and subsumed in a linked pathway. Specifically COX2 and c-Kit/PDGFR/Notch were highly activated in the 8 patients with occult metastasis. A prognostic pathway signature comprised of 13 interlinked molecules was developed. Univariate, ROC and Kaplan-Meier analysis of this signature revealed a statistically significant prognostic signature with an AUC of 0.87 and a 95% confidence interval. Conclusions: A signaling portrait of 13 interlinked proteins provided a strong prognostic indicator for metastasis regardless of stage. This signature was comprised of the phosphorylation/activation of growth factor receptors, including the entire suite of Gleevec targets. A large number of these prognostic signature components were previously found activated in the metastatic lesions themselves which indicates a potential functional role of this linked protein network in metastatic progression and maintenance. If validated in larger study sets, clinical trials to test Gleevec therapy combined with Cox2 /EGFR inhibitors to prevent/delay development of distant metastasis in patients with M0 should be considered. [Table: see text]
Prognostic burden of heart failure recorded in primary care, acute hospital admissions, or both: a population‐based linked electronic health record cohort study in 2.1 million people
Authors: Stefan Koudstaal, Mar Pujades‐Rodriguez, Spiros Denaxas, Johannes M.I.H. Gho, Anoop D. Shah, Ning Yu, Riyaz S. Patel, Chris P. Gale, Arno W. Hoes, John G. Cleland, Folkert W. Asselbergs, Harry Hemingway
Journal: European Journal of Heart Failure (2016)

Abstract Aims The prognosis of patients hospitalized for worsening heart failure ( HF ) is well described, but not that of patients managed solely in non‐acute settings such as primary care or secondary outpatient care. We assessed the distribution of HF across levels of healthcare, and assessed the prognostic differences for patients with HF either recorded in primary care (including secondary outpatient care) ( PC ), hospital admissions alone, or known in both contexts. Methods and results This study was part of the CALIBER programme, which comprises linked data from primary care, hospital admissions, and death certificates for 2.1 million inhabitants of England. We identified 89 554 patients with newly recorded HF , of whom 23 547 (26%) were recorded in PC but never hospitalized, 30 629 (34%) in hospital admissions but not known in PC , 23 681 (27%) in both, and 11 697 (13%) in death certificates only. The highest prescription rates of ACE inhibitors, beta‐blockers, and mineralocorticoid receptor antagonists was found in patients known in both contexts. The respective 5‐year survival in the first three groups was 43.9% [95% confidence interval ( CI ) 43.2–44.6%], 21.7% (95% CI 21.1–22.2%), and 39.8% (95% CI 39.2–40.5%), compared with 88.1% (95% CI 87.9–88.3%) in the age‐ and sex‐matched general population. Conclusion In the general population, one in four patients with HF will not be hospitalized for worsening HF within a median follow‐up of 1.7 years, yet they still have a poor 5‐year prognosis. Patients admitted to hospital with worsening HF but not known with HF in primary care have the worst prognosis and management. Mitigating the prognostic burden of HF requires greater consistency across primary and secondary care in the identification, profiling, and treatment of patients. Trial registration : NCT02551016
Defects in E2F1/2 Expression Are Associated with Abnormalities in Cell Cycle and Differentiation in EKLF-Deficient Erythroid Cells.
Authors: Andre M. Pilon, Murat O. Arcasoy, Serena E. Vayda, Holly K. Dressman, James J. Bieker, David M. Bodine, Patrick G. Gallagher
Journal: Blood (2006)
Gastrin-releasing peptide receptor expression in Brazilian and Japanese patients with lung cancer and normal lung tissue samples from healthy individuals.
Authors: J. Mattei, Y. Kato, M. W. Wynes, C. H. Cano, R. D. Achcar, B. Reyna Asuncion, B. R. de Macedo, L. Meurer, J. Kulczynski, R. Roesler, K. Yoshida, J. Matsubayashi, T. Ohira, T. Nagao, K. Furukawa, N. Ikeda, A. Brunetto, G. Schwartsmann
Journal: Journal of Clinical Oncology (2011)

10588 Background: Gastrin-releasing peptide receptors (GRPR) are over-expressed in several neoplasms and can play a critical role in tumor cell survival in preclinical models. A Phase I trial of RC-3095, a synthetic GRPR antagonist, conducted by our group, showed antitumor activity but no significant dose-limiting toxicities. For the development of Phase II clinical trials program of RC-3095, candidate tumor types are being selected on basis of GRPR expression. Data on GRPR expression in lung cancer is limited. Methods: We analyzed the expression of GRPR receptors in tumor samples obtained from patients (pts) with lung cancer from a Brazilian (n=238) and a Japanese cohort (n=96), as well as from a control group of individuals with normal lung tissue (n=23). Standard immunohistochemistry (IHC) technique was used. Our aim was: (1) to determine GRPR expression in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC); (2) to correlate its expression with clinical stages and demographic variables; (3) to compare GRPR expression in Asian and non-Asian population. Results: In a control group of normal lung tissue samples, GRPR expression was absent or very low as compared to tumor samples (p=0.049). GRPR expression was higher in NSCLC as compared to SCLC (48% weak; 16% moderate; 7.5% strong IHC intensity versus 34% weak; 16% moderate; 3% strong ICH intensity, respectively; p=0.3). Strong GRPR expression was more pronounced in patients at advanced stages (III and IV) vs. samples from patients presenting at earlier clinical stages (p=0.01). GRPR expression was more prevalent in Japanese pts. vs. the Brazilian pts. (93% vs. 62%, respectively; p= 0.001). Conclusions: This is the first study to demonstrate that significant levels of GRPR expression can be found in both NSCLC and SCLC. As it was previously shown for EGFR expression, GRPR expression also differs among Asian and non-Asian lung cancer pts. On the basis of these results, pts. with advanced lung cancer, whose tumors exhibit a moderate/high GRPR expression, will be considered candidates for our Phase II trials, regardless of the histological classification.
123. Gene Editing as a Therapeutic Approach to Treat IPEX Syndrome
Authors: Marianne Goodwin, Francesca Santoni de Sio, Daniel Dever, Matthew Porteus, Maria Grazia Roncarolo, Rosa Bacchetta
Journal: Molecular Therapy (2016)

Site-specific gene editing combined with autologous stem cell transplantation holds tremendous potential to treat both inherited and acquired diseases. However, the translational applications of gene editing are limited by the challenge of achieving sufficient levels of gene targeting in human primary cells. Recent advances in gene editing, including use of the CRISPR-Cas9 system, nuclease-resistant chemically modified small guide RNAs (sgRNAs), and serotype-optimized AAV delivery of donor repair DNA templates, are enabling clinically relevant levels of gene editing in human primary cells. Here, we build upon these advances to develop a gene editing strategy to treat the immune-dysregulation polyendocrinopathy-enteropathy-X-linked (IPEX) syndrome, a severe primary immune deficiency manifesting with life-threatening multi-organ autoimmunity in children. IPEX is caused by mutations in the forkhead box protein 3 gene (FOXP3), resulting in dysfunction of T regulatory cells (Tregs) and T effector cell lymphoproliferation. Due to the presence of disease causative mutations throughout the entire FOXP3 gene and the complex nature of FOXP3 regulatory elements, we designed a strategy to functionally correct the gene in IPEX patient cells using on-target, homology directed repair (HDR)-mediated insertion of the FOXP3 coding sequence into the gene locus. By targeting the FOXP3 gene using a CRISPR system comprised of Cas9 mRNA and chemically modified sgRNAs, we were able to attain high targeting frequencies, reaching 70-80% in human primary CD4+ T cells. We use this CRISPR system in combination with a repair donor DNA template delivered with AAV to demonstrate FOXP3 gene correction in human CD34+ hematopoietic stem and progenitor cells (HSPCs). In addition to gene correction of FOXP3, we use a similar strategy in parallel to knockout FOXP3 in wild-type human CD34+ HSPCs. We use the knockout HSPCs to generate a humanized mouse model of FOXP3 dysfunction, which enables us to study the pathophysiology of IPEX and to ultimately test the efficacy of gene-corrected Treg cell-based therapies. These results will help demonstrate the feasibility of FOXP3 gene editing, which we propose for the translational application of autologous transplant of Tregs and HSPCs as a therapy for IPEX syndrome.
A Clinical Pharmacology and Exploratory Study of Azacitidine Administered Subcutaneously or Intravenously In Japanese Patients with Myelodysplastic Syndrome
Authors: Yukio Kobayashi, Michinori Ogura, Kiyoshi Ando, Kensei Tobinai, Toshiki Uchida, Yoshiaki Ogawa, Takayuki Ishikawa, Haruhiko Ohashi, Tomoko Hata, Noriko Usui, Masafumi Taniwaki, Kazunori Ohnishi, Hideki Akiyama, Keiya Ozawa, Kazuma Ohyashiki, Shinichiro Okamoto, Akihiro Tomita, Shinji Nakao, Tomomitsu Hotta
Journal: Blood (2010)
Abstract 3221: Development of patient-derived xenograft (PDX) models for gastrointestinal stromal tumors (GIST) as a pre-clinical platform for drug development
Authors: Jill Ricono, Chelsea Mullins, Praveen Nair, Cyrus Mirsaidi, Thomas Broudy
Journal: Cancer Research (2015)

Abstract Patients with gastrointestinal stromal tumors (GIST) continue to face a poor prognosis. GISTs are a type of soft tissue sarcoma primarily affecting adults over the age of 50. They are the most common mesenchymal tumor within the GI tract. Survival rates vary greatly depending on the location when it is first diagnosed and there has been minimal progress in improving the survival rates of metastatic GISTs. It has been difficult to accurately evaluate the effectiveness of targeted drugs to develop treatment strategies due to the rarity and complexity of GISTs. In an effort to overcome this challenge, we have established PDX models to recapitulate the original patient tumor. In this work, we selected four primary GIST samples based on mutational and clinical profile. PDX models were developed in immunocompromised mice and were further characterized by immunohistochemistry, sequencing and pharmacological efficacy. We then evaluated the efficacy of chemotherapeutic agents in these models. Our data demonstrates that these preclinical PDX models could be used in evaluation and development of novel drug candidates for GIST. Citation Format: Jill Ricono, Chelsea Mullins, Praveen Nair, Cyrus Mirsaidi, Thomas Broudy. Development of patient-derived xenograft (PDX) models for gastrointestinal stromal tumors (GIST) as a pre-clinical platform for drug development. [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 3221. doi:10.1158/1538-7445.AM2015-3221
A retrospective analysis about Stenotrophomas maltophiria sepsis in patients with hematological malignancy
Authors: Tatsuo Oyake, Maki Asahi, Norifumi Sugawara, Yuzo Suzuki, Yoshiaki Okano, Yukiteru Fujishima, Yusei Aoki, Shugo Kowata, Shigeki Ito, Yoji Ishida
Journal: Annals of Oncology (2015)
PWE-071 The natural history of Barrett's oesophagus: the view from a UK district general hospital: Abstract PWE-071
Authors: K D Bardhan, C Royston, B Hoeroldt, P J Willemse, M Lambertz, M Srinivas, P Basumani
Journal: Gut (2010)

<h3>Introduction</h3> All patients diagnosed with gastro-oesophageal reflux disease (GERD) in our DGH over the last 3 decades have been systematically followed up. We present the outcome of BE cohort diagnosed 1977–2006 and followed until 31.10.2009, set against the numbers of newly diagnosed GERD. <h3>Methods</h3> BE was diagnosed visually and confirmed by histology in about 90%. Follow-up (FU) was by surveillance endoscopy+biopsy in the fit or clinically (clinic visit/telephone survey) with endoscopy reserved for alarm symptoms in the others. The GI database closed for non-BE GERD 31.12.2001 but continues for BE. <h3>Results</h3> BE and GERD 1977-2001 Comparison 1. Incidence (Abstract 071): Both GERD and BE rose in successive 5-year periods. 2. Demography: BE patients were a decade older than reflux patients (mean age at presentation 62 vs 52 years); both had a slight male preponderance (BE 62%, GERD 55%). 3. Complications: Presentation with complications was more common in BE patients (haemorrhage and/or anaemia 10% vs 5%, stricture 10% vs 2%). 4. Mortality. BE 316/752 (42%), GERD 2799/11 622 (24%), mean FU 6 years, range 0–31. BE 1977-2009 Natural history. 1. Numbers continued to rise, 364 diagnosed in the final 5 years (2002-06), totalling 1116. 2. Oesophageal adenocarcinoma (EAC). 53 who presented with or developed EAC within 1 year are excluded as prevalent cancers. Outcome: The remaining 1063 BE had total FU of 6885 patient-years (mean 6.5 years range 0–31) during which 42 (4%) developed EAC, that is, 1 tumour per 164 patient-years of FU. The mean time from diagnosis of BE to EAC was 9 years (range 13 months–24.4 years) occurring at a mean age of 71 years (range 50–86). 3. Mortality: 320/1063 (30%) died during follow-up, 27 (2.5%) from EAC, 54 (5%) from other tumours, the remaining 239 (22%) mainly from cardio-vascular and respiratory causes. 4. Surveillance group, development of EAC, potentially curative resection and outcome. Endoscopic FU: EAC n=26; resection 12; 6/12 died from tumour. Clinical FU: EAC n=11; resection 4; all 4 died from tumour. No FU: EAC n=5; resection 1, still alive. <h3>Conclusions</h3> (1). During BE follow-up 4% developed EAC. (2) 8% of BE deaths were from EAC but the vast majority from other causes, perhaps reflecting their older age. (3) Surveillance. The rising prevalence of BE and increasing use of endoscopic therapy for early cancer in those unfit for resection has nevertheless strengthened the case for surveillance.
Unrelated Donor Stem Cell Transplantation for 36 Patients(pts) with Fanconi Anemia(FA): A Single Center Experience.
Authors: Carmem M.S. Bonfim, Marco A. Bitencourt, Daniela C. Setubal, Vaneuza A. Funke, Carlos R. deMedeiros, Jefferson Ruiz, Mary E. Flowers, Jose Zanis-Neto, Ricardo Pasquini
Journal: Blood (2004)
706. Consistent Viral Vector Manufacturing for Phase III Using iCELLis 500 Fixed-Bed Technology
Authors: Minna Karhinen, Elisa M. Nurminen, Piia Valonen, Outi Rautsi, Vesa Huusko, Kati Heikkilä, Janne Weisell, Achim Muller, Hanna P. Lesch, Outi Närvänen, Minna M. Hassinen, Minna Pollen, Steve Parrish, Robert Shaw, Nigel R. Parker, Seppo Ylä-Herttuala
Journal: Molecular Therapy (2016)

Single use disposable technology faces further challenges in producing viral vectors in sufficient large quantities especially where adherent cells are needed. Scaling up the adherent system has proven to be troublesome. The PALL iCELLis® disposable fixed-bed bioreactors offer a novel option for viral vector manufacturing in large quantities in an adherent environment. We have made process development in iCELLis Nano, where the cultivation area varies between 0.53 - 4 m2, after which we went forward to iCELLis 500, where the cultivation volume can be upgraded to 500 m2 (66 - 500 m2). iCELLis 500 has proven to be ideal to satisfy upstream demand and large-scale downstream purification process was developed to supply high quality recombinant adenovirus based gene products in our fully-licensed GMP manufacturing facility for pre-clinical and clinical trials The process is initiated by HEK293 cell mass expansion in suspension mode using Biostat® CultiBag RM (Sartorius Stedim Biotech S.A.) bioreactor. The expanded suspension cell mass is inoculated into iCELLis 500 for further expansion in adherent mode. This is infected by Working Viral Seed Stock and subsequent virus is released from the infected cells by chemical lysis. Downstream process contains Benzonase digestion, clarification, concentration and conditioning by crossflow ultrafiltration, capture and polishing by anion exchange chromatography, and final concentration and formulation is achieved using crossflow filtration. All product contact parts are fully disposable. Several batches have been produced with consistent results. Further validation of the process for commercial manufacturing is currently ongoing. We established a scalable, large-scale manufacturing process to supply high quality recombinant adenovirus based gene products in our fully-licensed GMP manufacturing facility for clinical trials. Alongside this we have validated assays which are providing a relevant quantitative measure of biologic function of the vector and demonstrating the quality and comparability of drug product batches in Phase 3 and commercial use.
Abstract 2064: GSK3 regulation of Mcl1 and beta catenin involves I kappa B alpha
Authors: Vineshkumar Thidil Puliyappadamba, Nanda Kumar Thudi, Markus Bredel
Journal: Cancer Research (2015)

Abstract Recently we demonstrated that the gene NFKBIA is deleted in most of the nonclassic sub types of Glioma. We have also shown that the over-expression of NFKBIA causes sensitization of the cancer cells towards various chemotherapeutic agents. We further extended our study to investigate the mechanism behind this chemo-sensitization by using temazolamide and and BAY 11-7082. We used two glioma cell lines U251, LN229 and one breast cancer cell line MDAMB231. Very interestingly we found that over expression of NFKBIA itself results in the down regulation of two major anti apoptotic proteins Mcl1 and Bcl-XL respectively. Next we treated the cells with Temozolamide and BAY 11-7082 separately and analysed the protein profile by western blotting. We have seen a strong down regulation of Mcl1 in all the cell lines and BCL-xl in two cell lines. But we didn't see any difference in the abundance of another related anti apoptotic protein Bcl2. We have seen enhanced apoptotic signal corresponding with the Mcl1 degradation. So it is clear from the study that the down regulation of Mcl1 by NFKBIA makes cells more susceptible towards the chemotherapeutic drugs. Interestingly we also found that the protein beta-catetnine, a major component of a Wnt signaling pathway, is up regulated with the IκBα over expression and remain unchanged with the chemotherapeutic drugs in all the cell lines. Mcl1 degradation was mediated by the phosphorylation of GSK3 and the phosphorylated GSK3 prevent the usual proteasomal degradation of the beta-catetnine leading to it's accumulation in the cell. Thus we can conclude that NFKBIA paly an important role in the phosphorylation of GSK3 and results in the regulation of Mcl-1 and beta catenine. Citation Format: Vineshkumar Thidil Puliyappadamba, Nanda Kumar Thudi, Markus Bredel. GSK3 regulation of Mcl1 and beta catenin involves I kappa B alpha. [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 2064. doi:10.1158/1538-7445.AM2015-2064