tbuckley/cabot-search huggingface dataset:
Abstract 2052: The transcriptional co-regulator and emerging cancer drug target C-terminal binding protein (CtBP) is a transforming oncogene
Authors: Evan T. Sumner, Steven R. Grossman
Journal: Cancer Research (2015)

Abstract The paralogous C-terminal binding proteins (collectively CtBP) 1 and 2 are evolutionarily conserved transcriptional co-regulators which demonstrate oncogene-like properties such as allowing for the progression of EMT and cellular invasion/migration, and supporting cellular survival through suppression of tumor suppressors (PTEN, p16, E-cadherin, BRCA-1) and pro-apoptotic genes (Bik, Puma, Noxa). Overexpression of CtBP is found in colon, ovarian, breast, and prostate cancers, and often correlates with loss of the tumor suppressors ARF and APC and with poorer prognosis for the patient. CtBP is also an emerging cancer drug target, encoding a dehydrogenase domain that can be targeted with small molecule inhibitors to kill cancer cells. CtBP appears to fit the criteria for a driver oncogene, though has never been fully characterized as such. To investigate the hypothesis that CtBP is a transforming oncogene, we subjected CtBP2 to multiple assays for cellular oncogenic activity including loss of contact inhibition, invasion, and anchorage independent growth. Previously immortalized NIH 3T3 mouse fibroblasts expressing CtBP2 or mutant H-Ras as a positive control were analyzed for focus formation, Matrigel-invasion, and soft agar colony formation. Consistent with the hypothesis that CtBP exhibits properties of an oncogene, CtBP2 potently induced focus formation, Matrigel-invasion, and soft agar colony formation with similar potency to oncogenic mutant H-Ras. Moreover, CtBP2 cooperated with the adenovirus E1A oncoprotein but not H-Ras to transform primary mouse embryonic fibroblasts (MEFs). Taken together, the 3T3 and MEF transformation data suggest CtBP2 acts as a “Ras-like” oncogene in rodent cell transformation assays. Previous research from our lab has shown that CtBP's ability to induce migration in HCT116 cells depends in part on its activation of T-cell lymphoma invasion and metastasis 1 (Tiam1). Work is ongoing to characterize critical downstream targets for CtBP's transforming activity. Targeting CtBP and its dehydrogenase domain in cancers where the protein is found to be overexpressed, or where its regulators, ARF and APC are found to be inactive, could lead to a therapeutic approach specific for an emerging driver oncogene. Citation Format: Evan T. Sumner, Steven R. Grossman. The transcriptional co-regulator and emerging cancer drug target C-terminal binding protein (CtBP) is a transforming oncogene. [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 2052. doi:10.1158/1538-7445.AM2015-2052
Human asthma is characterized by more IRF5+ M1 and CD206+ M2 macrophages and less IL-10+ M2-like macrophages around airways compared with healthy airways
Authors: Christina Draijer, Carian E. Boorsma, Patricia Robbe, Wim Timens, Machteld N. Hylkema, Nick H. Ten Hacken, Maarten van den Berge, Dirkje S. Postma, Barbro N. Melgert
Journal: Journal of Allergy and Clinical Immunology (2016)
Abstract 1487: Rotating 3D projections of prostate lesions imaged by Cu-64-VPAC1 ligand PET and CT
Authors: Matthew E. Wampole, Bishnuhari Paudyal, Edouard J. Trabulsi, Mathew L. Thakur, Eric Wickstrom
Journal: Cancer Research (2015)

Abstract Surgeons are obliged to examine multiple planar images of fine needle biopsies, CT, and PET images for diagnosis and evaluation of prostate cancer. We hypothesize that optimal comprehension of prostate lesions in the prostate, as they present in the surrounding tissue, will be achieved by 3D registration and presentation of all available images. In particular, PET imaging of a cancer cell surface marker maximizes specificity, relative to imaging of F-18-deoxyglucose uptake. We have demonstrated specific PET imaging in patients of vasoactive intestinal peptide and pituitary adenylate cyclase activating peptide receptor 1 (VPAC1), which is overexpressed on breast cancer and prostate cancer cells. Our PET agent is Cu-64-TP3805, a peptide derived from vasoactive intestinal peptide. From our ongoing prostate cancer patient imaging study, we segmented and co-registered CT image slices and TP3805 PET image slices, then created moving 3D images. Viewing the rotating 3D images from all sides revealed clear delineation of prostate lesions from the adjoining bladder. The lesion images colocalized in space with intraprostatic tumor foci identified from H&amp;E staining of whole mount slices after prostatectomy. Thus, rapid 3D presentation of anatomical, histological, and molecular images could be a useful preparative tool to minimize complications during prostate cancer surgery. This result supports proceeding to 3D analysis of a larger prostate cancer cohort. Citation Format: Matthew E. Wampole, Bishnuhari Paudyal, Edouard J. Trabulsi, Mathew L. Thakur, Eric Wickstrom. Rotating 3D projections of prostate lesions imaged by Cu-64-VPAC1 ligand PET and CT. [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 1487. doi:10.1158/1538-7445.AM2015-1487
The histone demethylase UTX regulates the lineage-specific epigenetic program of invariant natural killer T cells
Authors: Semir Beyaz, Ji Hyung Kim, Luca Pinello, Michael E Xifaras, Yu Hu, Jialiang Huang, Marc A Kerenyi, Partha P Das, R Anthony Barnitz, Aurelie Herault, Rizkullah Dogum, W Nicholas Haining, Ömer H Yilmaz, Emmanuelle Passegue, Guo-Cheng Yuan, Stuart H Orkin, Florian Winau
Journal: Nature Immunology (2016)
The Impact of Immunosuppressive Therapy on an Early Quantitative Reconstitution of NK Cells after Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Sebastian Giebel, Joanna Dziaczkowska, Iwona Wylezol, Jerzy Wojnar, Malgorzata Krawczyk-Kulis, Krystyna Jagoda, Aleksandra Holowiecka-Goral, Jerzy Holowiecki
Journal: Blood (2004)
Abstract 4884: Highly sensitive fusion transcript detection and quantification in cancer
Authors: Lisa C. Watson, Stephen M. Gross, Irina Khrevtukova, Smita Pathak, Claire Attwooll, Jason Goode, Anthony Mai, Gary P. Schroth
Journal: Cancer Research (2015)

Abstract Gene fusion detection in cancer samples can provide tumor-specific information for cancer research, clinical diagnosis and targeted treatment. Common fusion detection methods such as qPCR and FISH are restricted to known fusion junctions and limited in the number of genes that can be detected in parallel. In contrast, RNA sequencing is a powerful approach for simultaneous discovery of all possible fusion junctions in a single reaction. But, the sequencing depth required for sensitive detection of fusions from whole-transcriptome libraries can be cost-prohibitive. Here we describe a cancer-specific capture-based approach for fusion detection by RNA sequencing that requires only a fraction of the sequencing depth of whole-transcriptome methods. We designed oligo probes that densely target coding regions of over 200 clinically relevant gene fusions and cancer-associated genes. This oligo panel was used to capture cancer-specific fusions from total RNA-Seq libraries. We used commonly studied cancer cell lines including MCF-7, K562, PC-3, LnCAP, A431 and Universal Human Reference RNA (UHRR) to compare the sensitivity of fusion detection across three RNA-Seq library prep methods: (1) cancer panel library capture (2) whole-transcriptome library capture and (3) PolyA selection. We show that probes targeting individual exons can robustly capture well-characterized cancer gene fusions such as BCR-ABL and BCAS4-BCAS3, as well as translocations where fusion junctions are unknown. Furthermore, these comparisons demonstrate the enhanced sequencing efficiency of the targeted cancer panel, while maintaining highly accurate quantitation of gene expression. We show that selective enrichment of RNA-Seq libraries with cancer-specific capture probes enables high-resolution mapping of genomic rearrangements in patient cancer samples, even those derived from FFPE, facilitating sequencing studies that were not previously possible. Citation Format: Lisa C. Watson, Stephen M. Gross, Irina Khrevtukova, Smita Pathak, Claire Attwooll, Jason Goode, Anthony Mai, Gary P. Schroth. Highly sensitive fusion transcript detection and quantification in 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 4884. doi:10.1158/1538-7445.AM2015-4884
Understanding the Role of TRKA Receptor in Acute Myeloid Leukemias: From Proliferation and Pro-Survival Signals to a Novel Therapeutic Approach
Authors: Maurizio L Ghisoli, Wendy Fang, Timothy C Graham, Alejandro G Levy, Lizhi Zeng, Sankaranarayanan Kannan, Riitta M Nolo, Christine Pien, Jeffrey L Brown, Patrick A Zweidler-McKay
Journal: Blood (2008)
PWE-056 A compensatory anti-inflammatory response syndrome triggered by neutrophil-induced oxidative stress is associated with chronic low grade hepatic encephalopathy in patients with advanced cirrhosis
Authors: N J Taylor, R Abeles, Y Ma, J A Wendon, D L Shawcross
Journal: Gut (2010)

<h3>Introduction</h3> The systemic inflammatory response syndrome (SIRS) exacerbates hepatic encephalopathy (HE) in patients with cirrhosis. SIRS is a proinflammatory response tasked with killing infectious organisms through activation of the immune system, whereas CARS is a global deactivation of the immune system aimed at restoring homeostasis. The timing and magnitude of CARS may impact on patient outcomes. This study aimed to characterise the relationship between neutrophil oxidative stress, plasma cytokine profile and ammonia in a cohort of patients with advanced cirrhosis undergoing assessment for liver transplantation (LT). Patients specifically referred for LT with chronic HE (n=7) were compared to those who had no history of overt HE (n=17) and healthy controls (HC) (n=8). <h3>Methods</h3> Neutrophils were isolated at the time of LT assessment and 72 h following LT (n=6/24). Quantification of spontaneous oxidative burst (OB) was determined by measuring the percentage of neutrophils producing reactive oxidants at rest. Formation of oxidative reactants was monitored by oxidation of dihydrorhodamine (DHR 123) to rhodamine. To identify neutrophils, cells were stained with anti- CD16-PE IgG1 and analysed by flow cytometry. Clinical data, blood biochemistry, arterial ammonia and a full set of microbial cultures were collected. Cytokine analysis for TNF-α, IL-1ß, IL-6, IL-8, IL-10 and IL-17 were performed by ELISA. <h3>Results</h3> There were no differences in MELD score, neutrophil count, ammonia (p=0.85) or empirical antibiotic use between those with chronic HE and those without. Neutrophil spontaneous OB was elevated in those with HE (30% (9–77) vs 13% (9–41), p=0.04) compared to those without. Patients with chronic HE had markedly decreased proinflammatory cytokines (TNF-α, p=0.02; IL-6, p=0.009 and IL-17, p=0.01) compared to those without HE but not the neutrophil-specific cytokine IL-8, upregulated in response to oxidative stress. The anti-inflammatory cytokine IL-10 was low in patients with HE compared to those without HE (6 (5–65) vs 207 (34–369) pg/ml, p=0.02) and HCs. Cirrhotic cytokine profiles and elevated spontaneous OB returned to HC levels post-LT. <h3>Conclusion</h3> These data suggest that patients with advanced cirrhosis and chronic HE have neutrophil-induced oxidative stress which triggers CARS rather than SIRS with time. IL-10 may protect against chronic HE and oxidative stress.
Effects of fosaprepitan (Fosa) on ifosfamide (Ifex) metabolism in sarcoma patients (pts) receiving multi-day chemotherapy (CT) regimen on doxorubicin (Dox) and Ifex (AI): Randomized, cross-over study.
Authors: Saroj Vadhan-Raj, Vinod Ravi, Xiao Zhou, Dejka M. Araujo, Neeta Somaiah, Anthony Paul Conley, Mary Daniel, Robert S. Benjamin, Shreyaskumar Patel, Ivan Spasojevic
Journal: Journal of Clinical Oncology (2015)

e20714 Background: AI is highly emetogenic regimen. Single dose Fosa with 5HT3RA and dexamethasone has improved the CINV control. However, delayed N/V is problematic. This study aimed to examine the effects of Fosa single dose vs 2 doses on safety, efficacy, and effects on Ifex/metabolites, due to potential drug interactions via CYP450. Methods: 47 pts planned to receive AI, were randomized 1:1 to Arm A (single dose Fosa on day 1) or Arm B (2 doses, on days 1 and 4). Blood samples were drawn for pharmacokinetics (PK) before and 4, 6, 8, and 24 hr after Ifex infusion, on days 1 and 4 in first 2 cycles. The absence of PK drug interaction was determined if the 95% CI of the geometric mean (GoM) AUC ratio of Fosa/control was within 80-125%. Results: The complete response to N/V was significantly higher (p = 0.013) with the two dose than single dose or control (Vadhan-Raj ASCO 2014). As shown below, in the control, there was decrease in the AUC (and ratios day4/day1) of Ifex from days 1 to 4, due to autoinduction of Ifex metabolism via Cyp3A4. During treatment, the GoM AUC ratios of Fosa/control were largely within pre-defined range for single dose, and were marginally increased (Ifex) and decreased (4-OHIF) with 2 doses, compensating for Ifex autoinduction. The treatment was well tolerated with no enhanced neurologic/urinary toxicity. Conclusions: Two doses of Fosa better controls multi-day CINV with marginal effect on Ifex metabolism. However, autoinduction of Ifex activation compensates for any Fosa-related decrease in activation. Clinical trial information: NCT01490060. GoM AUC (uM h) GoM AUC Ratio Fosa/control (95% CI) Fosa Control Arm A Day 1 Ifex 2269.5 2098.3 1.08 (1.02-1.15) 4-OHIF 10.1 11.5 0.87 (0.80-0.95) Day 4 Ifex 1367.5 1483.6 0.92 (0.83-1.02) 4-OHIF 20.3 18.2 1.12 (0.92-1.36) Day 4/Day 1 ratio (95% CI) Ifex 0.60 (0.54-0.66) 0.69 (0.61-0.77) 4-OHIF 2.06 (1.66-2.47) 1.64 (1.43-1.84) Arm B Day 1 Ifex 2473.8 2056.3 1.20 (1.13-1.28) 4-OHIF 9.6 12.4 0.77 (0.65-0.92) Day 4 Ifex 1744.4 1455.6 1.20 (1.09-1.32) 4-OHIF 17.4 19.2 0.91 (0.75-1.10) Day 4/Day 1 ratio (95% CI) Ifex 0.71 (0.67-0.75) 0.71 (0.67-0.75) 4-OHIF 1.98 (1.64-2.33) 1.69 (1.42-1.96) 4-OHIF: 4-hydroxyifosfamide
41. U2 snRNP Spliceosome Proteins Block Recombinant AAV Vector Transduction
Authors: Claire Schreiber, Toshie Sakuma, Yoshihiro Izumiya, Sara Holditch, Raymond Hickey, Robert Bressin, Upamanyu Basu, Kazunori Koide, Aravind Asokan, Yasuhiro Ikeda
Journal: Molecular Therapy (2015)

The recent approval, continued success and safety of recombinant adeno-associated viral (AAV) vectors in gene therapy clinical trials have paved the way for therapeutic modalities for a range of genetic disorders. However, efficient therapeutic gene expression by AAV vectors can often require high vector doses, presenting potential challenges related to production and dose-related toxicity. In this regard, a particularly well known barrier to AAV transduction is the host proteasomal machinery. To identify specific host restriction factors, we screened an siRNA library that revealed several candidate genes including the PHD finger-like domain protein 5A (PHF5A), a U2 snRNP-associated protein. Disruption of PHF5A expression selectively increased transduction by multiple AAV serotypes. Notably, genetic disruption of U2 snRNP and associated proteins, such as SF3B1 and U2AF1, also increased AAV vector transduction, suggesting the critical role of U2 snRNP spliceosome complex in this host-mediated restriction. Moreover, pharmacological inhibition of U2 snRNP by meayamycin B, a potent SF3B1 inhibitor, substantially enhanced AAV vector transduction of clinically relevant cell types. Further study indicated that U2 snRNP proteins suppress AAV vector transgene expression through recognition of incoming AAV capsid and enhanced histone recruitment to the vector genome, independently of the cellular splicing machinery. In summary, we postulate a novel cellular mechanism involving spliceosome U2 snRNP proteins in regulating AAV vector epigenetic modification and its manipulation to enhance transgene expression for human gene therapy.
Treatment of AML in First Remission (CR1) with Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) Using Unrelated Donors (UD).
Authors: Leandro de Padua Silva, Borje S. Andersson, Uday Popat, Lori Griffin, Michele Alvarez, Poliana Patah, Simrit Parmar, Sergio Giralt, Gabriela Rondon, Marcelo Fernandez-Vina, Pedro Cano, Richard E. Champlin, Marcos De Lima
Journal: Blood (2008)
Abstract 5326: Intracellular bacterial delivery of a NIPP1-peptide kills tumor cells
Authors: Nele Van Dessel, Neil S. Forbes
Journal: Cancer Research (2015)

Abstract Protein phosphatase-1 (PP1) is a cancer target because it is involved in many cell signaling pathways. Its activity is tightly regulated by its interaction partners, mainly via the RVxF-binding motif. RVxF-containing peptides deregulate PP1 and have therapeutic potential as antagonists of increased cancer kinase signaling. Because PP1 is responsible for more than half of the dephosphorylations on Ser/Thr sites, it is essential in all eukaryotic cells and it is difficult to target systemically. Moreover, delivering peptides to cells extracellularly is inefficient because of poor cell permeability and proteolytic instability. To specifically transport therapeutic peptides into cancer cells, we engineered bacteria to be intracellular delivery vectors. A bacterial delivery system (BDS) was designed by creating a strain that lyses after cell invasion and releases its contents into the cytoplasm of cancer cells. A BDS strain was then manipulated to express a peptide containing the RVxF motif of Nuclear Inhibitor of PP1 (NIPP1; AA 142-224). The therapeutic potential of this strain was tested on MCF-7 cell monolayers and on 3D tumor tissue. The BDS was cloned by inserting the bacterial phage lysis gene E under the control of the sseJ promoter, a Salmonella promoter that is activated after cell invasion. The specificity of the sseJ promoter was tested by inserting GFP under its control and infecting MCF-7 cancer cells with Salmonella containing the plasmid. All intracellular bacteria expressed GPF after 4 hours of infection, while no fluorescence was measured in the bacteria outside the mammalian cells. After infection, the created BDS lysed in 78% of invaded cells. BDS delivery of the NIPP1-peptide to MCF-7 cancer cells killed 41% of infected cells while infection with control, empty BDS did not result in any death. When treating tumor tissue with BDS expressing NIPP1-peptide, 39% of tumor tissue was killed after 9.5 hours, compared to 8% when treated with BDS alone. These results indicate that targeting phosphatases with intracellular peptide delivery by bacteria is feasible and reduces tumor tissue viability. Citation Format: Nele Van Dessel, Neil S. Forbes. Intracellular bacterial delivery of a NIPP1-peptide kills tumor cells. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5326. doi:10.1158/1538-7445.AM2015-5326
Differential Expression Genes of CLL Subgroups Defined by Ki67 Expression Level Which Correlated with Clinical Outcome
Authors: Xiao-Jie Yan, Daniel Kalenscher, Erin Boyle, Arrti Damle, Sophie Yancopoulos, Rajendra N Damle, Houman Khalili, Annette Lee, Wentian Li, Igor Dozmorov, Matthew Kaufman, Peter Gregersen, Steven L. Allen, Kanti R. Rai, Nicholas Chiorazzi
Journal: Blood (2010)
549. Fine Tuning of Transduction Efficiency of rAAV Vectors via Modulation of Capsid Composition
Authors: Oleksandr Kondratov, Damien Marsic, Mario Mietzsch, Regine Heilbronn, Sergei Zolotukhin
Journal: Molecular Therapy (2016)

Recombinant Adeno-associated virus (rAAV) vectors have emerged as one of the most versatile and successful gene therapy delivery vehicles. Even though the industry is poised for the expansion into several application areas represented by orphan diseases, a simple and scalable rAAV production technology is still lacking. We have recently developed the OneBac system to allow scalable, high-titer production of the full range of rAAV serotypes by infection of stable insect Sf9 cell lines with a single baculovirus. Some of the serotypes produced in this system, however, were characterized by a low transduction efficiencies compared to HEK 293-derived vectors. Here we describe an approach for resolving this drawback by modulating the ratios of VP1:VP2:VP3 capsid composition to derive particles with a higher VP1 content. This is accomplished by modifying a canonical Kozak sequence preceding VP1 ATG start codon. A range of Kozak sequences has been tested and the most favorable have been identified for AAV5 and AAV9 serotypes. These newly designed capsid genes were incorporated into Sf9 stable cell lines mediating packaging of AAV5 and AAV9 vectors which exceeded transduction efficiencies of HEK 293-derived counterparts by 2-3 folds. Curiously, the optimal ratios of VP1:VP2:VP3 were serotype-specific requiring fine-tuning to achieve a compromise between higher VP1 content mediating higher transduction potencies vs. lower packaging efficiencies impeding production yield. In summary, we have developed a novel approach of significantly enhancing biological potencies of AAV vectors derived from baculovirus system thus facilitating translational applications.