tbuckley/cabot-search huggingface dataset:
83. Adenoviral Mediated Compartmentalized Liver Transduction Improves Safety and Yields Long-term Transgene Expression in a Porcine Model
Authors: Gustavo Cabrera, Blanca Segura, Martin Granados, Ana Luisa Esparza, Victor Manuel Oviedo, Andrés Catzín-Kuhlmann
Journal: Molecular Therapy (2015)

To stringently control the viremia associated with conventional routes of vector administration and significantly reduce the astronomical quantities of virus commonly infused in gene therapy, our group described compartmentalized liver transduction. Compartmentalized liver transduction is based on known adenoviral spatio-temporal kinetics and is achieved by the intra-parenchymal injection of a vector dose into a blood flow isolated portion of the liver; perfusion is reestablished after viral endocytosis has been completed (30 min). Given the encouraging results documented in rodents (rats), our group assessed compartmentalized liver transduction in a porcine model. To this end, a surgical device was conceptualized, prototyped and utilized to safely and securely transiently isolate a portion of the liver in 25- 30 kg Vietnamese pigs. Implementing compartmentalized liver transduction in pigs, no viremia was detected during the procedure and transgene expression and presence were confined to the site of vector injection. Neither inflammation, apoptosis or significant biochemical liver damage were observed. Using porcine alpha fetoprotein as a reporter gene, serum levels were documented with low quantities of vector dose (10^5) and prolonged transgene expression was achieved (10 months). Our results further support that compartmetalized liver transduction has profound paradoxic effects on the classic toxicological interactions between the liver and adenovirus. The lack of acute liver inflammation observed suggests that conventional immunolgical thresholds and relays were not triggered. We further postulate that compartmentalized liver transduction induces the local synthesis of tolerance inducing cytokines central to thwarting the acute, intermediate and late adenoviral induced immune responses and are critical in generating an immune priviledge liver compartment capable of long term protein synthesis and secretion. Our results further demonstrate that compartmentalized liver transduction is a safe and effective route of vector delivery with a promising future in the field of gene therapy.
High Risk Acute Lymphoblastic Leukemia with Rapid NOD/SCID Engraftment Is Characterized by High Protein Expression of CYCLIN B, Beta-CATENIN, ANNEXIN I and Decreased PKC Alpha Activation
Authors: Felix Seyfried, Benedetta Accordi, Manon Queudeville, Sarah Mirjam Eckhoff, Gloria Milani, Luisa Galla, Marco Giordan, Johann M Kraus, Giuseppe Basso, Hans Armin Kestler, Geertruy te Kronnie, Klaus-Michael Debatin, Lueder Hinrich Meyer
Journal: Blood (2011)
FLT3-Mediated MAPK Activation Participates in the Control of Megakaryopoiesis in Primary Myelofibrosis.
Authors: Christophe Desterke, Chrystele Bilhou-Nabera, Bernadette Guerton, Carole Tonetti, Denis Clay, Olivier Pierre-Louis, Alessandro M Vannucchi, Heinz Gisslinger, Dominique Bordessoule, Hans C Hasselbalch, Vladimir Lazar, William Vainchenker, Annelise Bennaceur-Griscelli, Stéphane Giraudier, Marie-Caroline Le Bousse-Kerdilès
Journal: Blood (2009)
Enhanced Potency of Glycoengineered Anti-CD52 Monoclonal Antibodies (MAbs).
Authors: Martin J.S. Dyer, Samuel Moser, Peter Brünker, Pru Bird, Neil Almond, Ursula Püentener, Luise M.W. Wheat, Emma Bolam, Eleanor Berrie, Roger Grau, Emma Buckby, Ben Kennedy, Richard Stebbings, Geoff Hale, Pablo Umana
Journal: Blood (2005)
The relationship of polymorphism Mad1 1673 G&gt;A on outcomes in patients with advanced ovarian cancer treated with carboplatine-paclitaxel.
Authors: M. Santibañez, D. Prada, C. Diaz, C. Castro, F. Morales-Vasquez, D. Gallardo Rincon, L. A. Herrera
Journal: Journal of Clinical Oncology (2011)

5050 Background: Genome integrity depends on the accurate segregation of chromosomes in mitosis. To maintain this condition, the spindle assembly checkpoint (SAC) activates a wait signal until all chromosomes are aligned in the metaphase plate. This arrest depends on the recruitment of a MAD1-MAD2 tetramer. The Mad1 1673 G>A polymorphism may disrupt the MAD1-MAD2 interaction. Results from our laboratory found a high frequency of this polymorphism in healthy individuals (HI). Here we analyzed the effect of this polymorphism in the mitotic arrest (MA) mediated by nocodazole (NDZ), and its influence in aneuploidy induction. Since a dysfunctional SAC could modify the clinical response to microtubule-disrupting drugs (i.e. paclitaxel, PTX), we also investigated the relationship of this polymorphism with disease progression, and survival in patients with advanced ovarian cancer (OCP) treated with carboplatine (CBP)-PTX. Methods: The polymorphism was evaluated by RFLP in lymphocytes from 144 HI. MA and aneuploidy induction were analyzed in cultured lymphocytes treated with 663 nM NDZ. The polymorphism was determined in blood and tumor samples from 73 OCP who received 3 cycles of 175 mg/m2 PTX and AUC6 CBP. Results: Allele distribution in HI was G: 50%, A: 50%, while in OCP was G: 38%, A: 62% (p<0.05). The percentage of cells in MA was 34% in AA and 71% in GG HI (p<0.05). Non-disjunction was increased in AA cells (p<0.05). Similarly, tumors from polymorphic OCP had a higher frequency of aneuploid cells (71% vs. 38% in GG OCP, p<0.05). There was a significant difference in progression free survival (PFS) between GG- and AA-OCP (HR 3.7; 95% CI, 1.1- 12.8; p= 0.026). Median PFS was 20 (GA) and 27 (AA) months shorter in polymorphic OCP compared to GG OCP. All GG OCP are alive at the present time compared with only 40% of polymorphic OCP (p=0.71). Conclusions: Our results show that the Mad1 1673 G>A polymorphism affects the functionality of the SAC, increasing the frequency of aneuploidy events in normal and tumor cells, and also modifies the response to microtubule-disrupting drugs hereby affecting the PFS and overall survival in OC patients.
510. Treating Epithelial and Metastatic Malignancies with Glycoform-Specific Chimeric Antigen Receptors
Authors: Avery D. Posey, Alina Boestaneau, Laura A. Johnson, Carl H. June
Journal: Molecular Therapy (2016)

Cancer-specific glycosylation deficiencies generating Tn or sTn O-linked glycans are found in >80% of the most lethal cancers (lung, prostate, breast, colon, ovary, pancreas). These hypoglycosylated cancer glycoantigens decrease cell-cell interactions and increase the mobility and metastatic potential of tumor cells. We developed a CAR specific to the Tn/sTn antigen of the oncogene Mucin-1 (MUC1), which is highly upregulated in many epithelial cancers and is heavily O- and N-glycosylated. Our CAR uses the scFv sequence derived from the 5E5 mAb and the endodomains of CD3zeta and 4-1BB that promote T cell activation and co-stimulation, respectively. We have shown that the 5E5 mAb and the 5E5 CAR are specific to the cancer-specific glycoform of MUC1 but not normal MUC1 through in vitro binding and cytokine assays and that the 5E5 CAR is non-reactive to normal human primary cells. We demonstrated that the 5E5 CAR T cells are responsive to ovarian, breast, lung, pancreatic, and leukemia cancers and developed NSG mouse xenograft models using Jurkat leukemia cell line and Hs766T metastatic pancreatic cell line that show rapid clearance of established tumors by 5E5 CAR T cells and prolonged survival of tumor-bearing mice. Restoring normal glycosylation in Jurkat leukemia cells abolishes the expression of the hypoglycosylated form of Muc1 and also prevents 5E5 CAR T cell cytotoxicity, further highlighting the specificity of the 5E5 CAR for the cancer-specific glycoform of MUC1. Infusion of human MUC1-transgenic mice with murine 5E5 CAR T cells showed an exquisite safety profile, while infusion of normal glycoform MUC1-specific murine CAR T cells (HMFG1 CAR, a previously described MUC1-specific CAR) demonstrate extreme safety concerns. These results demonstrate that targeting the cancer-specific glycoform of MUC1 provides a safe, yet potent cancer-specific immunotherapy for treating most epithelial malignancies and holds the potential to eradicate metastatic disease.
Abstract 1100: Functional genomics to investigate the genetic determinants of cell death induced by oxidative stresses
Authors: Chien-Kuang C. Ding, Xiaohu Tang, So Young Kim, Jen-Tsan A. Chi
Journal: Cancer Research (2015)

Abstract Increased oxidative stress in the tumor microenvironments is a prominent stress that many tumor cells need to cope with during oncogenesis. The stress depletes intracellular glutathione, increases reactive oxygen species, and finally triggers cell death in tumors. Despite its importance during oncogenesis, the genetic determinants and the cell death mechanisms under oxidative stress remain poorly defined. Here, we applied a genome-wide siRNA screen to oxidative-stress-induced cell death. Candidate genes were identified if the silencing could rescue cell death under oxidative stresses. The identified candidate genes are prioritized by the magnitude of rescue and the consistency among different siRNAs that target the same gene. Selected top hits were further functionally validated using independent siRNAs and chemicals in multiple cancer cell types. To further understand the functional aspects of these genes, we also analyzed the transcriptional and metabolomic response to oxidative stresses. By these functional genomics approach, we found that: 1) The Integrated Stress Response (ISR) is provoked by oxidative stresses to mediate cell death. Therefore, inhibition of IRE1-splicing activity, which is one of the major branches of ISR pathway, could abolish oxidative-stress-induced cell death. 2) Surprisingly, inhibition of multiple component of mTORC1 signaling, including mTOR itself, could rescue oxidative-stress-induced cell death. While further investigation is still in progress, these preliminary findings unravel a unique molecular process in which oxidative stress mediate cell death and the adaptive mechanism by which tumor cells survive these stresses. Citation Format: Chien-Kuang C. Ding, Xiaohu Tang, So Young Kim, Jen-Tsan A. Chi. Functional genomics to investigate the genetic determinants of cell death induced by oxidative stresses. [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 1100. doi:10.1158/1538-7445.AM2015-1100
Using Web 2.0 applications to promote health-related physical activity: findings from the WALK 2.0 randomised controlled trial
Authors: Gregory S Kolt, Richard R Rosenkranz, Corneel Vandelanotte, Cristina M Caperchione, Anthony J Maeder, Rhys Tague, Trevor N Savage, Itallie Anetta Van, W Kerry Mummery, Christopher Oldmeadow, Mitch J Duncan
Journal: British Journal of Sports Medicine (2017)

Web 2.0 internet technology has great potential in promoting physical activity. This trial investigated the effectiveness of a Web 2.0-based intervention on physical activity behaviour, and the impact on website usage and engagement.504 (328 women, 126 men) insufficiently active adult participants were randomly allocated to one of two web-based interventions or a paper-based Logbook group. The Web 1.0 group participated in the existing 10 000 Steps programme, while the Web 2.0 group participated in a Web 2.0-enabled physical activity intervention including user-to-user interaction through social networking capabilities. ActiGraph GT3X activity monitors were used to assess physical activity at four points across the intervention (0, 3, 12 and 18 months), and usage and engagement were assessed continuously through website usage statistics.Treatment groups differed significantly in trajectories of minutes/day of physical activity (p=0.0198), through a greater change at 3 months for Web 2.0 than Web 1.0 (7.3 min/day, 95% CI 2.4 to 12.3). In the Web 2.0 group, physical activity increased at 3 (mean change 6.8 min/day, 95% CI 3.9 to 9.6) and 12 months (3.8 min/day, 95% CI 0.5 to 7.0), but not 18 months. The Logbook group also increased physical activity at 3 (4.8 min/day, 95% CI 1.8 to 7.7) and 12 months (4.9 min/day, 95% CI 0.7 to 9.1), but not 18 months. The Web 1.0 group increased physical activity at 12 months only (4.9 min/day, 95% CI 0.5 to 9.3). The Web 2.0 group demonstrated higher levels of website engagement (p=0.3964).In comparison to a Web 1.0 intervention, a more interactive Web 2.0 intervention, as well as the paper-based Logbook intervention, improved physical activity in the short term, but that effect reduced over time, despite higher levels of engagement of the Web 2.0 group.ACTRN12611000157976.
Estrogen and vascular endothelial growth factor (VEGF): Their role in breast cancer (BC) carcinogenesis and disease progression in premenopause.
Authors: F. Recchia, G. Candeloro, G. Desideri, S. Necozione, S. Rea
Journal: Journal of Clinical Oncology (2011)

540 Background: Estrogen has a key role in BC development and there is evidence in vitro, that it modulates VEGF expression in BC cells through transcriptional activation. However few clinical studies investigated the association between VEGF and estrogens in humans. Objective of this study was to evaluate wether estrogen suppression with an LH-RH analogue was able to down regulate VEGF expression, and thus decrease its plasma concentration, in premenopausal patients with high-risk estrogen receptor positive (ER+) and negative (ER−) early BC. Methods: From 04-2003 to 10-2008, 100 premenopausal early BC patients were entered into the study. At baseline, after surgery, plasma VEGF and sex hormones were measured. Measurements were repeated every six months. Treatment: LH-RH analogue for 5 years, chemotherapy tailored to the biological characteristics of each patient, radiation therapy, and 5-year hormonal therapy in ER+ tumors. Primary end-point was the evaluation of VEGF. Secondary end points were progression-free survival (PFS) and overall survival (OS). Results: Median age was 43 years (range 26-45). Mean number of positive axillary nodes was 3.3. Eighty-three patients were ER+, 17 were ER − and progesterone receptor (PGR) -. Median KI-67 was 33% (range 15%−100%). Twenty patients were Herb−2 positive. A statistically significant decrease of VEGF was observed after 1 and 5 years, both in ER+ and ER− patients: In particular, VEGF decreased (p<0.001) in 94% of patients that were disease-free, while in 6% of patients with disease relapse, it increased with respect to baseline values. No unexpected toxicity of chemotherapy was observed, while hot flashes and G1 osteopenia occurred after LH-RH analogues administration. After a median follow-up of 50 months (range 24-90), 5-year disease free survival and overall survival rate were 94% and 100%, respectively. Conclusions: Estrogen deprivation with an LH-RH analogue is able to decrease plasma VEGF levels in premenopausal high risk ER+ and ER- BC patients. These data show how estrogens, through VEGF modulation, may be responsible for the worst prognosis that is observed in premenopausal BC patients.
PO22ELEVATED GLUTAMATE, USING MAGNETIC RESONANCE SPECTROSCOPY, IS ASSOCIATED WITH SEIZURES IN PATIENTS WITH GLIOBLASTOMAS
Authors: Sarah A. Leir, Timothy J. Larkin, Natalie R. Boonzaier, Victoria Lupson, Laila A. Mohsen, Adam Young, Stephen Price
Journal: Neuro-Oncology (2015)

INTRODUCTION: Seizures are common in patients with a Glioblastoma. Although the epileptogenic mechanism remains unclear, it is suggested to be dependent upon peritumoural changes. Histological analysis of human intratumoural and peritumoural glioma tissue demonstrated that glutamate concentrations in tissue from both sites were increased in patients with seizures when compared to those without. It would be advantageous to have a non-invasive method for predicting which patients are most likely to be affected by seizures. METHOD: 80 patients with a Glioblastoma were imaged pre-operatively at 3T with sequences including anatomical and multivoxel spectroscopy. Regions of interest (ROIs) were selected in a circumferential consecutive pattern from the border of the T1-weighted enhancing region to normal appearing brain. Glutamate parameters (Glu + Gln/Cr) were calculated per voxel and expressed as a ratio to normal brain. Clinical variables were analysed in relation to tumour progression and survival. RESULTS: The mean Glu + Gln/Cr concentration remained more than 1.5 times higher compared to normal brain at a 3 cm radial distance from the T1-weighted enhancing margin in the seizure group. At this distance, the mean Glu + Gln/Cr concentration ratio had returned to 1 in the non-seizure group (Seizures 1.56 ± 0.1 vs. non-seizures 0.92 ± 0.06, p < 0.001). The presence of seizures was associated with a shorter time to progression on multivariate analysis (HR = 7.55; p = 0.01). CONCLUSION: We demonstrate that the presence of seizures is associated with elevated tumour and peritumoural glutamate concentrations and a shortened time to tumour progression in Glioblastomas. Glutamate may play a role in the pathogenesis of seizures and represent a potential biomarker for tumour progression.
A Randomized Single−Blind Study of Extracorporeal Photopheresis with UVADEX® Plus Conventional Therapy (CT) Compared to CT Alone in Chronic GVHD.
Authors: Mary E.D. Flowers, Koen Van Besien, Jane Apperley, Andrea Bacigalupo, Ahmet Elmaagacli, Andrew Grigg, Hans-Jochem Kolb, Luis Fernando Bouzas, Mauricette Michallet, Vijay Reddy, Jim Wang, Paul Williamson, Robert Knobler, Hildegard Greinix
Journal: Blood (2006)
Acquired 1p Uniparental Disomy Is Associated with Biallelic MPL W515L Mutation in RARS-T.
Authors: Hadrian Szpurka, Lukasz P Gondek, Sanjay R Mohan, Eric D Hsi, Karl S Theil, Mikkael A Sekeres, Jaroslaw P Maciejewski
Journal: Blood (2008)
Validation of NF-kappaB p65 as a prostate cancer prognostic marker on a large European cohort.
Authors: P. O. Gannon, L. Lessard, V. Forest, L. R. Begin, T. Schlomm, S. Minner, M. Graefen, A. Mes-Masson, F. Saad
Journal: Journal of Clinical Oncology (2011)

4537 Background: Important advances in prostate cancer (PCa) diagnosis and treatment have resulted in increased patient survival. However, it remains difficult to identify accurately patients better suited for less-aggressive therapy (active surveillance) from those at higher risk of disease progression. Over the last decade, we and others have uncovered a robust association between the nuclear localization of NF-kB p65 and poor prognosis. In this study, we present validating results suggesting that NF-kB p65 can predict biochemical recurrence (BCR) in a large independent cohort. Methods: Primary tumors from radical prostatectomy were obtained from a large European PCa cohort and tumor specimens were spotted on tissue microarrays. NF-kB p65 expression was detected by immunohistochemistry on a final number of 1850 cores containing suitable malignant tissue. Results: We observed a significant correlation between an increase in the nuclear frequency of NF-kB p65 and overall BCR (p<0.001), metastasis (p=0.001) and mortality (p=0.008). In univariate COX regressions, the nuclear frequency and the nuclear intensity of NF-kB p65 were both associated with overall BCR (p<0.001, each). For the multivariate analyses, the clinical model included the following parameters: preoperative PSA, Gleason score, extra-capsular extension, lymph node (LN) invasion, seminal vesicle (SV) involvement and surgical margin status. We found that the nuclear frequency of NF-kB p65 was significantly associated with BCR (p<0.001) and improved the fitness of the clinical model when performing a Likelihood ratio and an Akaike Information Criterion (AIC) tests. Furthermore, we observed that the fitness of the clinical model was improved in sub-cohorts of patients at low-risk of BCR (negative margins; or negative LN; or negative SV) and in high-risk sub-cohorts (positive margins; or Gleason ≥ 4+3; or positive LN). Conclusions: Our study offers validating results linking the nuclear frequency of NF-kB p65 with disease progression using a large cohort of European men. These results, endorsed by a strong scientific literature, suggest that NF-kB p65 can be useful as a molecular biomarker in the clinical decision process for PCa patients.
363. Laser-Triggered Gold Nanoparticle-Assisted Cell Poration for Selective Gene Delivery
Authors: Weimeng Ding, Christos Boutopoulos, Eric Bergeron, Ariel Wilson, Santiago Costantino, Przemyslaw Sapieha, Michel Meunier
Journal: Molecular Therapy (2015)

We present an innovative approach using laser-triggered plasmonic gold nanoparticles to selectively transfect cells. This method emerged from the combination of the recent progress in photonics and nanotechnologies. To perform the laser-triggered delivery, spherical gold nanoparticles (d=100 nm) were first dispersed onto cells in vitro in a medium containing fluorescent molecules or exogenous genes, and then irradiated with a scanning picosecond laser beam at high repetition rate (f = 76 MHz, wavelength λ =1064 nm, pulse width τ = 7.5 ps). When irradiated under appropriate conditions, the gold nanoparticles locally amplify the laser energy (plasmonic effect) and create transient pores on the cell membranes, allowing the penetration of surrounding molecules or genes through the plasma membrane by fluid exchange. After the delivery, the cell membranes rapidly self-reseal and the cells continue to thrive. Our technique presents several advantages: First, the method is safe. Gold nanoparticles are biocompatible and are believed to be non-toxic both in vitro and in vivo at low concentration. The emitted laser energy in the near infrared is weak and harmless to the tissue, and is only amplified in the nearfield of gold nanoparticles within submicron distance. Second, the transfection is temporally and spatially controlled by the pattern of irradiation. Gold nanoparticles can be conjugated to selectively target and transfect desired cell populations. We performed experiments on different cell types including breast cancer cells, ocular epithelium cells and neurons. Cell poration efficiency increased with laser energy up to a certain threshold, and decreased as mortality became important at higher irradiation fluence. The optimal conditions for irradiation vary from one cell line to another. The general poration efficiency could reach 30-70% depending on the cell line, with mortality as low as < 3%. Ongoing in vitro and ex vivo experiments will be presented. Our studies suggest that the laser-triggered gold nanoparticle-assisted cell transfection is a promising physical delivery method enabling efficient, safe and selective gene delivery in a variety of cells. It is anticipated that it would be an increasingly useful tool for the development and improvement of new gene therapy for prevalent diseases such as cancers or neural degenerative diseases.