tbuckley/cabot-search huggingface dataset:
50. Efficacy of an Improved Cancer Stroma-Targeted Oncolytic Adenovirus on Human Derived Gynecologic Tumor Samples
Authors: Alejandro Nicola Candia, Ana L. Alfano, Cristian M. Malnero, Ismael R. Bermúdez, Nicasio A. Cuneo, Mariela A. Gangemi, Alejandro Soderini, Osvaldo L. Podhajcer, Veronica M. Lopez
Journal: Molecular Therapy (2015)

Gynecologic cancers originated in the female reproductive organs, including the cervix, ovaries, uterus, fallopian tubes, vagina and vulva. In 2013, it was estimated that 91,730 women would be diagnosed with a gynecologic cancer. Cervical cancer accounted for approximately 13%, ovarian cancer 24% and uterine cancer 54% of cases of cancer (American Cancer Society, Inc). We have recently developed a stroma-targeted CRAd also responsive to the tumor microenvironment, AdF512v4, that contain a chimeric promoter that combines a 0.5 Kb of the SPARC promoter, a Hypoxia-Response Element (HRE) and a NFkB-response element (NFkB). The chimeric promoter drives the expression of delta-RB E1A and the CRAd was pseudotyped with a chimeric fiber 5/3. We also constructed the non-replicative version of AdF512v4 (AdF512v4-luc). We have previously demonstrated the activity of the new promoter in ovarian cancer cell lines. First, we assessed the promoter activity following transduction of cervix cancer cell lines (HeLa, CaSki and SiHa) with the non-replicative adenovirus. We observed 10-35 fold induction of luciferase activity under hypoxic condition (0.1% O2) or/and TNF treatment (5 ng/ml). Next, we measured the efficacy of the CRAd in the 3 cervical cancer cell lines under normal oxygen levels (21% O2), hypoxic condition or TNF treatment. By using the MTS assay we observed that the larger lytic capacity was obtained in the presence of TNF treatment. In order to establish the potential clinical utility of AdF512v4 we assayed its replication capacity in a most rigorous preclinical setting by using slices obtained from fresh tissue explants of human tumors. AdF512v4 replicated in three out of six human cervix cancers, one tumor from uterus and three of four human ovarian carcinomas with no lytic effect on the paired normal tissues. It is of note that Ad-wt 5/3 could replicate in both malignant and normal ovarian samples. In conclusion, AdF512v4 demonstrated a strong killing effect on cervix and ovarian cancer cells in vitro, as well as a replication capacity in fresh human ovary, uterus and cervix cancer explants. AdF512v4 appears safe since no replication was observed in normal human ovary raising its potential use in the clinics. aaa
PO71METFORMIN, PHENFORMIN AND SORAFENIB AS POTENTIAL THERAPIES FOR HIGH GRADE BRAIN TUMOURS: INVESTIGATING SUPPRESSION OF TUMOUR CELL GROWTH
Authors: L. Eagles, F. Rowther, I. Tolaymat, J. Darling, T. Warr
Journal: Neuro-Oncology (2015)

INTRODUCTION: Current treatments for glioblastoma multiforme (GBM) do not yield large benefits to patients and hence the repurposing of existing medications is a potentially valuable treatment option. Metformin and phenformin have been used for >60 years for the treatment of type 2 diabetes and recent research indicates that metformin may be associated with reduced risk of developing cancer. Sorafenib is a multikinase inhibitor used in the treatment of kidney, liver and thyroid cancer. A synergistic effect of metformin and sorafenib has been identified in some tumour types. METHOD: The IC50 values for metformin and phenformin were evaluated using sulforhodamine B colorimetric assay for cytotoxicity in 13 GBM-derived short-term cell cultures and the established GBM cell line U251MG. The p53 mutation status had been determined in all cultures. In 4 cultures, the cytotoxic effects of sorafenib alone and in combination with metformin were determined using non-linear regression to fit a 4-parameter hill equation. Synergy was determined by calculating combination index (Chou-Talalay) method. RESULTS: For metformin the IC50 values ranged from 4.97(±1.36)mM to 72.23(± 3.16)mM compared to phenformin with an IC50 range of 0.41(±0.299951)mM to 7.32(±0.82)mM. For both drugs, response was associated with p53 mutation status (p = 0.0152, p = 0.0140). The IC50 range for Sorafenib was 5.5(±0.28)uM to 9.4(±0.69)uM. Combining metformin and sorafenib resulted in synergy in 3 cases and an additive effect in 1 culture. CONCLUSION: Metformin and phenformin have potential as treatment for GBM. The synergistic interaction between metformin and sorafenib indicates that these drugs in combination have a potential to be used for GBM therapy.
636. The Anti-Tumor Effects of Adipose Tissue Mesenchymal Stem Cell Transduced With HSV-1-TK Gene on U87-Driven Brain Tumor
Authors: Suely M. Melo, Simone Bittencourt, Enéas G. Ferrazoli, Clivandir S. Silva, Flavia F. Cunha, Roberta S. Stilhano, Priscila M. Denapoli, Bianca F. Zanetti, Pricila K. Martins, Leonardo M. Silva, Adara A. Santos, Leandra S. Baptista, Beatriz M. Longo, Sang W. Han
Journal: Molecular Therapy (2015)

Glioblastoma (GBM) is the most common and lethal primary intracranial tumor. Because GBM is highly invasive and diffusely infiltrates the brain, a complete resection of the tumor is unfeasible. The gene encoding thymidine kinase from herpes simplex virus-1 (HSV-Tk) is the most commonly used suicide gene in preclinical and clinical trials against GBM. Treating GBM with mesenchymal stem cells (MSCs) that have been modified with the HSV-Tk suicide gene has brought significant advances mainly because MSCs are chemoattracted to GBM and kill tumor cells via a bystander effect. Aiming at using this strategy in clinical trials, here we evaluated the abundantly present human adipose-tissue-derived mesenchymal stem cells (AT-MSC) to treat GBM in mouse model. AT-MSCs were prepared using a mechanical protocol to avoid contamination with animal proteins and transduced with HSV-Tk via a lentiviral vector. The U-87 glioblastoma cells cultured with AT-MSC-HSV-Tk died in the presence of 25 or 50 μM ganciclovir (GCV). U-87 glioblastoma cells injected into the brains of nude mice generated tumors larger than 3.5 mm2 after 4 weeks, but the injection of AT-MSC-HSV-Tk cells one week after the U-87 injection and treated with GCV drastically reduced tumors to smaller than 0.5 mm2. Immunohistochemical analysis of the tumors showed the presence of AT-MSC-HSV-Tk cells only within the tumor and its vicinity, but not in other areas of the brain, indicating specific migration of AT-MSC-HSV-Tk to and interaction with tumours. In conclusion, the AT-MSCs are good carriers of the suicide HSV-Tk gene for the treatment of GBM, and the abundance of AT-MSCs and the easier to obtain them mechanically are strong advantages when compared to using MSCs from other tissues.
Nanosized UCMSC-derived extracellular vesicles but not conditioned medium exclusively inhibit the inflammatory response of stimulated T cells: implications for nanomedicine
Authors: Marta Monguió-Tortajada, Santiago Roura, Carolina Gálvez-Montón, Josep Maria Pujal, Gemma Aran, Lucía Sanjurjo, Marcel·la Franquesa, Maria-Rosa Sarrias, Antoni Bayes-Genis, Francesc E. Borràs
Journal: Theranostics (2016)

Undesired immune responses have drastically hampered outcomes after allogeneic organ transplantation and cell therapy, and also lead to inflammatory diseases and autoimmunity. Umbilical cord mesenchymal stem cells (UCMSCs) have powerful regenerative and immunomodulatory potential, and their secreted extracellular vesicles (EVs) are envisaged as a promising natural source of nanoparticles to increase outcomes in organ transplantation and control inflammatory diseases. However, poor EV preparations containing highly-abundant soluble proteins may mask genuine vesicular-associated functions and provide misleading data. Here, we used Size-Exclusion Chromatography (SEC) to successfully isolate EVs from UCMSCs-conditioned medium. These vesicles were defined as positive for CD9, CD63, CD73 and CD90, and their size and morphology characterized by NTA and cryo-EM. Their immunomodulatory potential was determined in polyclonal T cell proliferation assays, analysis of cytokine profiles and in the skewing of monocyte polarization. In sharp contrast to the non-EV containing fractions, to the complete conditioned medium and to ultracentrifuged pellet, SEC-purified EVs from UCMSCs inhibited T cell proliferation, resembling the effect of parental UCMSCs. Moreover, while SEC-EVs did not induce cytokine response, the non-EV fractions, conditioned medium and ultracentrifuged pellet promoted the secretion of pro-inflammatory cytokines by polyclonally stimulated T cells and supported Th17 polarization. In contrast, EVs did not induce monocyte polarization, but the non-EV fraction induced CD163 and CD206 expression and TNF-α production in monocytes. These findings increase the growing evidence confirming that EVs are an active component of MSC's paracrine immunosuppressive function and affirm their potential for therapeutics in nanomedicine. In addition, our results highlight the importance of well-purified and defined preparations of MSC-derived EVs to achieve the immunosuppressive effect.
BMET-29ADDRESSING THE MOLECULAR MECHANISMS OF GBM CELL DISPERSAL
Authors: Fidan Seker, Tugba Bagci-Onder
Journal: Neuro-Oncology (2015)

Glioblastoma multiforme (GBM) is the most common and aggressive type of glioma with a mean survival of 1 year after diagnosis. A major obstacle in treating GBMs is extensive tumor cell infiltration into the surrounding brain. Despite tumor resection and combined therapy, recurrence occurs in the vicinity of the resection margin due to individual cells that dispersed out of the primary tumor. As this extreme dispersal ability of the tumor cells is a major cause for therapeutic failure, developing novel therapies that target tumor cell dispersal is of high priority. Therefore, there is an urgent need for understanding the molecular mechanisms that contribute to GBM cell motility. The overarching goal of this project is to identify genes that are differentially regulated during GBM cell dispersal and to validate their function in in vitro models of dispersal. While the basic mechanisms of cell migration operate in the context of GBM dispersal, the unique tumor-specific mechanisms that facilitate this extreme infiltrative ability of tumor cells are not well-defined. Therefore, profiling the changes in gene expression levels during cell movement might lead to the discovery of novel molecular players of GBM cell dispersal and provide new targets for GBM therapies. This project is based on a new in vitro model of cell motility developed in our laboratory, whereby the dynamics of GBM cell dispersal can be monitored in real-time and quantitated. Accordingly, motile/migratory/dispersive cells can be isolated from non-motile/core cells by a specific isolation method. Therefore, the genes that are differentially regulated in during different phases of cell movement can be profiled. Together, these studies have the potential to discover new players of GBM dispersal and open up new avenues for designing of new therapeutic strategies.
TNFα Mediated IL-6 Secretion Was Regulated by JAK/STAT Pathway but Not by MEK Phosphorylation and AKT Phopshorylaton In U266 Multiple Myeloma Cells
Authors: Jeong-In Oh, Juwon Park, Chansu Lee, Woojune Jung, Jiyeon Ryu, Byoung Kook Kim, Kwang-Sung Ahn, Sung-Soo Yoon
Journal: Blood (2010)
Incidence and Predictors of Early Treatment-Related Mortality In Pediatric Acute Lymphoblastic Leukemia In Baghdad (Iraq)
Authors: Anna Maria Testi, Robin Foa, Mazin Faisal Al-Jadiry, Maria Luisa Moleti, Salma Abbas Al-Hadad, Jawad Kadhum Al-Taee, Wisam Majeed Abed, Najiha Ahmed Ameen, Hasanein H. Ghali, Amir Fadhil Al-Darraji, Raghad Majid Al-Saeed, Valerio Cecinati, Annalisa De Vellis, Alfonso Piciocchi
Journal: Blood (2010)
Effect of CMX001 on Levels of DNA Virus In Patients After Allogeneic Stem Cell Transplantation.
Authors: Don A. Gabriel, Julia Whitley, Kamakshi Rao, Charles van der Horst, Jonathan Serody, James Coghill, Stefanie Sarantopoulos, Paul Armistead, William Wood, Thomas C. Shea
Journal: Blood (2010)
An Important Role for CD1d and NKT Cells in the Suppression of Hematopoiesis in Mice Induced by Infection with Cytomegalovirus.
Authors: Hal E. Broxmeyer, Alexander Dent, Scott Cooper, Giao Hangoc, Gourapura J. Renukaradhya, Venkataraman Sriram, Randy R. Brutkiewicz
Journal: Blood (2005)
Type 2 Diabetes Genetic Variants and Risk of Diabetic Retinopathy
Authors: Yong He Chong, Qiao Fan, Yih Chung Tham, Alfred Gan, Shu Pei Tan, Gavin Tan, Jie Jin Wang, Paul Mitchell, Tien Yin Wong, Ching-Yu Cheng
Journal: Ophthalmology (2016)
COX-2 Inhibition Suppresses the Interferon-γ-Induced Expression of Indoleamine 2,3-Dioxygenase (IDO) in Human Leukemia Cell Lines.
Authors: Maria Grazia Iachininoto, Eugenia Rosa Nuzzolo, Anna Di Maggio, Giuseppina Bonanno, Andrea Mariotti, Annabella Procoli, Maria Corallo, Giuseppe Leone, Raimondo De Cristofaro, Sergio Rutella
Journal: Blood (2008)
PTU-002 Analysis of factors predicting complete colonoscopy at a large teaching hospital: Abstract PTU-002
Authors: A J Ball, J S Leeds, J M Hebden, M T Donnelly
Journal: Gut (2010)

<h3>Introduction</h3> Caecal intubation rate (CIR) is an important quality assurance measure in colonoscopy. There are many factors known to affect this including; sex of patient, BMI, age, timing of list and volume of colonoscopies performed by endoscopist. We analysed the factors that predict colonoscopy completion in a high throughput UK Centre. <h3>Methods</h3> All patients that had colonoscopy over the course of a year were identified from the Sheffield Teaching Hospitals database (Infoflex). Potential determinants of CIR analysed include: patient factors (age, sex and indication for procedure); procedural factors (IV sedation used, endoscopist: gastroenterologist vs surgeon vs nurse). Individual factors were assessed using χ<sup>2</sup> test and subsequently multivariate analysis to identify independent risk factors for non-completion. <h3>Results</h3> 5227 colonoscopies were performed between September 2008 and August 2009 at Sheffield teaching hospitals. 50 of these were excluded from analysis due to incomplete information leaving a total of 5177 colonoscopies to analyse. The mean age of patients was 61.39 with an almost equal sex split (47.4% male). Seven nurse endoscopists performed 2380 procedures (mean 340/person), 28 gastroenterologists performed 1754 procedures (mean 63/person), 19 surgeons performed 858 procedures (mean 45/person). The overall CIR was 89.9%. Factors associated with non-completion on univariate analysis include; Female sex (352/2692 incomplete in females vs 168/2415 in males, OR 1.9 p=&lt;0.001) age &gt;64 (295/2573 incomplete in ≤64 vs 236/2737 in those &gt;64, OR 1.3 p =&lt;0.001). Procedural indications with a significantly different CIR included: abdominal pain (76/579 with vs 448/4598 without, OR 1.3 p=0.01) anaemia (125/1034 with vs 399/4143 without, OR 1.3 p=0.01) weight loss (39/198 with vs 485/4940 without, OR 1.7 p=0.009), non-surveillance (43/703 in surveillance patients vs 481/4474 in non-surveillance, OR 1.8 p=&lt;0.001). Use of iv sedation reduced CIR (243/2082 with vs 281/3095 without, OR 1.3 p=0.002). Endoscopist factors associated with non-completion include non-nurse endoscopist (218/2380 incomplete for nurses vs 306/2797 in non-nurses, OR 1.2 p=0.04) Multivariate analysis identified several independent factors for non-completion (Abstract 002). <h3>Conclusion</h3> Our study has identified new independent factors that predict CIR. These include; patient factors (Indication of weight loss) and endoscopist factors (nurse endoscopist). We feel nurse endoscopist is likely to be a surrogate marker for volume of colonoscopies performed. Perhaps this indicates fewer endoscopists should be performing more procedures.
Changes of ADAMTS13 Activity and VWF Level in the Plasma of Patients Undergoing Hematopoietic Stem-Cell Transplantation (HSCT)
Authors: Yue Han, Luping HU, Qian Zhu, Yang Xu, Xiaohui Hu, Jian Su, Zhenni Ma, Wei Zhang, Aining Sun, Huiying Qiu, Zhaoyue Wang, Changgeng Ruan, Wu Depei
Journal: Blood (2012)
Abstract 2600: Targeting cancer stem cell through blocking the Erk pathway with Kazinol-E from Broussonetia kazinoki
Authors: Yu-Chae Jung, Seula Han, Li Hua, Hui-Yuan Zhao, Cheol-Jung Lee, Yong-Yeon Cho, Raok Jeon, Jae-Ha Ryu, Woo-Young Kim
Journal: Cancer Research (2015)

Abstract Growing evidence suggests that a small population of cells, called cancer stem cells (CSCs) contribute to the heterogeneity, recurrence and resistance to chemotherapy in breast cancer. In this regard, CSC is considered to be a good target to cure breast cancers. The extracellular signal-regulated kinase (ERK) signaling pathway is one of the major determinants in the control of diverse cellular process including the maintenance of CSCs. Kazinol-E is an antioxidant flavan purified from the root bark of Broussonetia kazinoki (Moraceae, paper mulberry). In this study, we found the anti CSC effect of Kazinol-E through targeting ERK pathway. It decreased the population of a breast cancer cell (MCF-7) CSCs which are CD44+/CD24- or aldehyde dehydrogenase positive, at the concentration that does not influence the growth of general MCF-7 cells cultured with serum. It targeted and inhibited ERK kinase activities in vivo in both CSC and in regular cultured cells suggesting the CSCs depend more than the rest of cancer cells do on Erk signaling for the survival. In vitro kinase assay using purified Erk-1 and p90RSK2, as the substrate, and the molecular docking study suggest that the Kazinol-E suppress the Erk activity by direct binding to the ATP binding pocket of Erk-1. Interestingly, a Kazinol-C which is very similar with Kazinol-E in structure did not show the Erk-1 inhibition nor anti CSC activity. These results collectively suggest that Kazinol-E may be a specific anti CSC agent targeting Erk pathway. Citation Format: Yu-Chae Jung, Seula Han, Li Hua, Hui-Yuan Zhao, Cheol-Jung Lee, Yong-Yeon Cho, Raok Jeon, Jae-Ha Ryu, Woo-Young Kim. Targeting cancer stem cell through blocking the Erk pathway with Kazinol-E from Broussonetia kazinoki. [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 2600. doi:10.1158/1538-7445.AM2015-2600
710. Optimization of AAV Vector Design for Safe Expression of β-N-Acetylhexosaminidase in the Brain for Tay-Sachs Disease Gene Therapy
Authors: Diane Golebiowski, Keiko Petrosky, Kajo Van der Marel, Elizabeth Hutto, Elizabeth Curran, Elena Balkanska-Sinclair, Nina Bishop, Rosemary Santos, Sheila Cummings Macri, Douglas Martin, Matthew Gounis, Julie Pilitsis, Wael Asaad, Miguel Sena-Esteves
Journal: Molecular Therapy (2015)

The GM2 gangliosidoses are lysosomal storage disorders that encompass both Tay-Sachs and Sandhoff diseases. These diseases are associated with deficiencies in the lysosomal enzyme β-N-acetylhexosaminidase (HexA). These deficiencies result in accumulation of GM2 ganglioside (GM2) in the central nervous system leading to neuronal dysfunction and death. HexA is a heterodimer composed of α and β subunits encoded by HEXA and HEXB genes respectively. Gene therapy approaches using direct injection of AAV vectors into the brain of both small and large disease models (mice, cats, and sheep) have all been successful in treating CNS pathology as well as extending lifespan. These studies utilized two AAVrh8 vectors encoding species-specific alpha and beta subunits of HexA under a CBA promoter with a WPRE (CBA-HexA-WPRE). However, when preclinical safety studies were performed in cynomolgus macaques (cm) using the same strategy, severe neurotoxicity was observed for doses 0.1-3.2E12 vg, which are comparable to those tested in other species on a vg/kg brain weight basis. We hypothesized that the cause of unexpected toxicity was due to high expression of HexA. In order to reduce expression of HexA while maintaining our AAV dose (1.78E12-5.34E13 vg/kg brain weight), we generated a series of new vectors with different combinations of promoters and expression elements with a gradient of HexA expression levels. We tested 7 designs of AAVrh8 vectors encoding cm HexA subunits in athymic nude mice (3.3 E13 vg/kg brain weight). In mice injected with the original vector, AAVrh8-CBA-cmHexA-WPRE, we observed increased levels of reactive astrocytes (GFAP) and activated microglia (Iba1) at the injection site. We used this as a screen to test the other vectors for lower gliosis while expressing HexA activity above normal. Three vector designs emerged and were tested in cynomolgus macaques (n=2, 90 days) infused bilaterally into the thalamus and cerebral lateral ventricle at the intermediate dose (5.34 E12 vg/kg brain weight) as in the first study. The behavior of all monkeys remained normal throughout the study. An abnormal T2 weighted MRI signal was documented at day 90 post-injection in one injection site in a monkey in the cohort with the highest HexA activity (up to 88 fold over normal). This signal was absent in day 30 and 60 brain MRI. Neurohistopathological examination revealed considerable neurodegeneration at this site. The other two cohorts had minimal to no neurotoxicity associated with increased HexA expression (up to 9 fold). Two new AAV vectors have been identified for safe overexpression of HexA in the primate brain.
Novel In Vivo Model of Multiple Myeloma Bone Disease Using ß-Tricalcium Phosphate Artificial Bone Grafts
Authors: Miroslav Koulnis, Homare Eda, Loredana Santo, Ka Tat Siu, Janani Ramachandran, Cristina Panaroni, Takaaki Tanaka, Noopur S. Raje
Journal: Blood (2015)
Prognostic Importance of Soluble Form IL-2 Receptor á (sIL-2Rá) and Its Relationship with Surface Expression of IL-2Rá of Lymphoma Cell in Diffuse Large B-Cell Lymphoma Treated with Rituximab-Containing Chemotherapy: a Retrospective Analysis of 409 Cases.
Authors: Akihiko Yokohama, Yoko Hashimoto, Akio Saito, Hirotaka Nakahashi, Kohtaro Toyama, Hiromi Koiso, Takayuki Saito, Hiroshi Handa, Hideki Uchiumi, Takahiro Jimbo, Kayoko Murayama, Morio Sawamura, Morio Matsumoto, Masamitsu Karasawa, Hirokazu Murakami, Yoshihisa Nojima, Junko Hirato, Masaru Kojima, Norifumi Tsukamoto
Journal: Blood (2009)
Large Deletions Involving the Beta Globin Gene Complex: Genotype-Phenotype Correlation of 119 Cases
Authors: Molly Susan Hein, Jennifer L Oliveira, Kenneth C Swanson, Patrick A Lundquist, Joella A Yungerberg, Lea M Coon, Brian D Dawson, Ronald S. Go, Dragan Jevremovic, James D Hoyer
Journal: Blood (2015)
PO395 YEAR SURVIVAL WITH GLIOBLASTOMA: A NATIONAL PERSPECTIVE
Authors: A. Brodbelt, D. Greenberg, M. Williams, T. Karabatsou, S. Miller, VP Collins
Journal: Neuro-Oncology (2015)

INTRODUCTION: Median life expectancy of patients with Glioblastoma is 6 months in England for all therapies. Most studies of long term survivors of Glioblastoma include small numbers of patients from a single institution. METHOD: A Population based study using data linkage between the National Cancer Registration Service and Hospital Episode Statistics for England was performed to identify patients who have survived more than 5 years after a histological diagnosis of Glioblastoma from January 2000 to June 2009. RESULTS: 17,786 patients were identified with Glioblastoma in this 10 year period. Data quality was variable in the cohort but there appear to be at least 96 patients who have survived 5 years from diagnosis. 54% were women. The cohort are younger than the national profile, with 67% aged less than 50 years. 70% of patients overall had debulking surgery and chemoradiotherapy. Multiple operations were more common, 55% of patients were recorded as having more than one procedure, and one patient had 6 craniotomies during the course of their treatment. CONCLUSION: There is a cohort of patients that survive for more than 5 years. This cohort is younger, and has more aggressive treatment than is seen overall. Could some of these patients represent a cure? Further investigation into this group could lead to promising avenues for treatment. Aggressive treatment in a very selective cohort can lead to extended survival for patients with Glioblastoma.