tbuckley/cabot-search huggingface dataset:
Abstract 3208: Stromal up-regulation of gene expression in prostate cancer cells: Role of microenvironment
Authors: Shingo Ashida, Chiaki Kawada, Keiji Inoue, Taro Shuin
Journal: Cancer Research (2015)

Abstract Recently, tumor microenvironment has been reported to be important in carcinogenesis and tumor progression. Especially in prostate cancer (PC), it has been suggested that tumor microenvironment plays an important role in progression, acquisition of androgen independence, and distant metastasis. However, little is known about the genetic basis of human PC microenvironment. To clarify the mechanism of PC progression and metastasis, we previously reported the analysis of genome-wide gene expression profiles using human PC cells (LNCaP), normal human prostate epithelial cells (PrEC), and normal human prostate stromal cells (PrSC). In that study, we identified genes that were up-regulated in LNCaP when co-cultured with PrSC, which included alpha-methylacyl-CoA racemase (AMACR), homeobox B13 (HOXB13), and UDP glucuronosyltransferase 2 family, polypeptide B17 (UGT2B17). We often confront the discrepancy in the difference of gene expression between cancer cells and tissues. Our data reveals that stromal cells could affect on PC cells to increase their gene expression, which might contribute to aggressiveness of PC cells. We then focused on secreted proteins that can mutually affect in this experimental design and identified genes that were overexpressed only in stromal cells. They included chemokine (C-C motif) ligand 2 (CCL2), hepatocyte growth factor (HGF), insulin-like growth factor binding protein 5 (IGFBP5), wingless-type MMTV integration site family, member 5A (WNT5A), and collagens (COL1A1, COL1A2, COL3A1, COL6A3, COL15A1). We further investigated the influence of these genes on the expression of AMACR, HOXB13, and UGT2B17 in PC cells to identify crucial signaling pathways in this process. This study provides potential candidate genes the products of which might serve as microenvironmental targets for the treatment of PC. Citation Format: Shingo Ashida, Chiaki Kawada, Keiji Inoue, Taro Shuin. Stromal up-regulation of gene expression in prostate cancer cells: Role of microenvironment. [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 3208. doi:10.1158/1538-7445.AM2015-3208
Abstract 3671: Loading and molecular labeling of cell-specific exosomes by HDL-like AuNPs
Authors: Nicholas L. Angeloni, Kaylin M. McMahon, C. Shad Thaxton
Journal: Cancer Research (2015)

Abstract Exosomes are 30-100 nm diameter lipid vesicles produced by most cells. Exosomes carry diverse cargo, such as RNA and proteins. Cancer cells produce an abundant amount of exosomes, which are released from cells of the primary tumor into the tumor microenvironment and the circulation. Data show that exosomes can promote cancer progression and metastasis by delivering, for instance, pro-metastatic factors to pre-metastatic sites. It is not currently possible to specifically separate tumor-derived exosomes from complex matrices. This ability would provide a better understanding of their contribution to tumorigenesis and cancer progression. Furthermore, the targeting properties of exosomes make them appealing vehicles for encapsulating and delivering therapeutic cargo. However, it is challenging to isolate and then load exosomes with specific drugs. Uniquely, our data reveal that synthetic high-density lipoprotein nanoparticles (HDL NPs) can be tailored to achieve cell-specific exosome labeling and loading of therapeutic cargo. HDL NPs are synthesized using a 5 nm diameter spherical gold nanoparticle. The gold NP serves as a template to control size and shape. Apolipoprotein A-I and phospholipids are conjugated to the gold surface, yielding a synthetic HDL NP similar in size, shape, surface chemistry, and function to some natural HDLs. Our data demonstrate that, upon addition of HDL NPs to cultured CWR 22Rv1 prostate cancer cells, they are packaged into exosomes that are secreted from these cells. Furthermore, HDL NPs made using phospholipids functionalized with either biotin or fluorophore molecules leads to the incorporation of the phospholipids into the exosomes. Thus, the specific cell-derived exosomes are labeled with gold, a molecular fluorophore label, and/or biotin. In each case, the specific exosomes are easy to isolate using methods such as fluorescent isolation or by the robust streptavidin-biotin interaction. Isolated exosomes retain the same size and molecular markers as exosomes from untreated cells. Overall, this unique method may provide control over exosomes for a myriad of diagnostic and therapeutic uses. Citation Format: Nicholas L. Angeloni, Kaylin M. McMahon, C. Shad Thaxton. Loading and molecular labeling of cell-specific exosomes by HDL-like AuNPs. [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 3671. doi:10.1158/1538-7445.AM2015-3671
Phase II Study of High Dose Lenalidomide as Initial Treatment for Older Acute Myeloid Leukemia Patients: Early Results Show a Significant Reduction of Bone Marrow Blasts after 14 Days of Therapy.
Authors: Todd A. Fehniger, Alissa Nelson, Kathryn Trinkaus, Camille N. Abboud, Amanda F. Cashen, John F. DiPersio, Timothy A. Graubert, Timothy J. Ley, Michael H. Tomasson, Geoffrey L. Uy, Matthew J. Walter, Peter Westervelt, Ravi Vij
Journal: Blood (2007)
519. Unique Role of the TLR9-MyD88 Signaling Pathway in Dendritic Cells in AAV Capsid-Specific CD8+ T Cell Activation
Authors: Geoffrey L. Rogers, Irene Zolotukhin, Roland W. Herzog
Journal: Molecular Therapy (2015)

Clinical trials of adeno-associated virus (AAV)-mediated gene therapy for hemophilia B have revealed a deleterious role for memory CD8+ T cell responses to the AAV capsid, which can eliminate transduced hepatocytes and transgene expression. However, the mechanisms underlying this response remain unclear, and have been difficult to study because the functional anti-capsid CTL response is not observed in murine models. To better identify capsid-specific T cells, we have created a modified AAV2 vector with a series of substitution mutations that contains the peptide sequence SIINFEKL, which is the CD8+ immunodominant epitope of the model antigen ovalbumin in C57BL/6 mice. With this vector, capsid-specific CD8+ T cells can be identified using an H2-Kb-SIINFEKL tetramer. We have used this vector to study the innate immune mechanisms underlying the formation of AAV capsid-specific CTLs—which pattern recognition receptors and which antigen-presenting cell types are required. Using knockout mice, we determined that sensing of the viral genome by toll-like receptor 9 (TLR9) and its downstream signaling through MyD88 are required for the formation of tetramer-positive (capsid-specific) CD8+ T cells after i.m. injection of AAV2-SIINFEKL. Similarly, OT-1 CD8+ T cells (TCR transgenic specific for SIINFEKL) adoptively transferred to wild-type (WT) mice proliferated following administration of AAV2-SIINFEKL but not with unmodified AAV2 lacking the SIINFEKL motif. In contrast, there was a lack of proliferation in TLR9−/- mice. TLR2 (which has been reported to sense the AAV capsid), AP3 (required for type I interferon signaling downstream of TLR9), and STING (a downstream signaling adaptor of several cytoplasmic sensors of DNA) were dispensable for the anti-capsid CTL response. In terms of the antigen presenting cell requirements, we found that transient depletion of dendritic cells (DCs) in CD11c-DTR mice delayed the development of tetramer-positive CD8+ T cells relative to WT mice. The response in mice that received gadolinium chloride to inactivate macrophages or in B cell-deficient μMT mice was comparable to WT mice. To test the hypothesis that TLR9-MyD88 signaling in DCs is required for capsid-specific CTL responses, we have crossed mice expressing Cre recombinase under the control of the CD11c promoter with mice in which the MyD88 gene is flanked by LoxP sites, creating DC-MyD88−/- mice which specifically lack MyD88 expression—and thus TLR9 signaling—in DCs. Moreover, we have acquired inhibitors of TLR9 and MyD88 to determine if pharmacological inhibition of these pathways is a viable strategy to prevent the formation of capsid-specific CD8+ T cells. In conclusion, TLR9-MyD88 signaling, most likely in DCs, is required for the formation of de novo anti-capsid CD8+ T cell responses.
Abstract 4340: Nuclear expression of antizyme inhibitor is associated with poor prostate cancer prognosis
Authors: Liangzhe Wang, Yingjie Xu, Shulin Wu, Mary Fergus, Chin-Lee Wu, Bruce Zetter
Journal: Cancer Research (2015)

Abstract Novel molecular markers that are associated with prostate cancer progression are needed to provide more useful information for the diagnosis and treatment of this disease. The antizyme inhibitor (AZI), a non-enzymatic homologue of ornithine decarboxylase (ODC), is upregulated in many cancer types, including: prostate cancer, breast cancer, hepatocellular carcinoma and non-small cell lung cancer. In this study, we examined the distribution of AZI in benign prostate tissues and in prostate cancers at differing stages. We were interested specifically in the possible correlation between AZI expression and patient survival. We found that AZI can reside in the cytoplasm and/or nuclear space in prostate cancer tissue. Nuclear AZI was observed in nearly all of the prostate cancer specimens but not in benign prostate tissue. Cytoplasmic AZI was found both in tumor cells and in adjacent benign prostate tissue. Nuclear AZI was associated significantly with prostate-specific antigen recurrence-free survival but not with overall survival. Further, we found that the presence of nuclear AZI could distinguish poor survival in lower grade patients (Gleason score ≤ 7), especially in samples with non-cribriform tumors. Our results demonstrate a potential role for nuclear AZI as an independent marker of patient outcome in prostate cancer patients. Citation Format: Liangzhe Wang, Yingjie Xu, Shulin Wu, Mary Fergus, Chin-Lee Wu, Bruce Zetter. Nuclear expression of antizyme inhibitor is associated with poor prostate cancer prognosis. [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 4340. doi:10.1158/1538-7445.AM2015-4340
eNOS polymorphisms in relation to outcome in advanced HCC patients receiving sorafenib. Final results of ePHAS study
Authors: A. Casadei Gardini, G. Marisi, M. Scartozzi, L. Faloppi, F. Foschi, J. Corbelli, E. Scarpi, M. Iavarone, G. Lauletta, P. Ulivi, S. Tamberi, O. Nanni, S. Cascinu, E. Tenti, G.L. Frassineti
Journal: Annals of Oncology (2015)
Abstract 10246: Hydroxychloroquine Pretreatment Reduces Myocardial Ischemia-Reperfusion Injury: Role of Cardiac Extracellular-Signal-Regulated Kinase 5 and Autophagy
Authors: Feiyan Yang, Chang Yin, Lei Xi, Rakesh C Kukreja
Journal: Circulation (2015)

Background: Hydroxychloroquine (HCQ) is an antimalarial drug, which is also widely used to treat chronic rheumatologic diseases. Since HCQ was reported to inhibit cell autophagy and to activate extracellular-signal-regulated kinase 5 (ERK5) in vascular endothelial cells, we designed the current study to determine the effects of HCQ on cardiac ischemia-reperfusion (I-R) injury and post-I-R expression of ERK5 and autophagy marker proteins. Methods: Adult C57BL/6J mice of both genders were pretreated with HCQ (50 mg/kg, i.p.) 1 hour prior to isolation of the hearts, which were subjected to 30 min of no-flow global ischemia followed by 60 min of reperfusion in Langendorff mode. Ventricular function was continuously assessed and myocardial infarct size was determined at the end of I-R. Heart samples were collected following normoxic perfusion (no-ischemic controls), I-R, or I-R with HCQ for assessing ERK5 and autophagy-related proteins with Western blots. Results: HCQ pretreatment reduced infarct size significantly in the female hearts (P&lt;0.05) as compared with the male hearts (Fig. A). Post-I-R cardiac function was better in HCQ-treated males (Fig. B). I-R resulted in a robust increase in total ERK5 (Fig. C) and phosphorylated ERK5 (Thr218/Tyr220) in both genders, which was abolished in HCQ-treated groups. Conversely, either I-R or HCQ did not affect the post-I-R cardiac expression of autophagy-related proteins (e.g., Atg5, Beclin-1, LC3II/LC3I ratio), except Beclin-1 phosphorylation was inhibited in HCQ-treated male hearts, but not females (Fig. D). Conclusions: Acute HCQ pretreatment affords cardioprotection against I-R injury in both genders. Interestingly, cardioprotective effects of HCQ are associated with a strong inhibitory effect on the induction of ERK5 following I-R in the heart, indicating a novel molecular mechanism underlying the HCQ-induced cardioprotection. However, the cardioprotective dose of HCQ has no major impact on cardiac autophagy.
323. Adenoviral Compartmentalized Liver Transduction Improves Safety and Yields Longerm Transgene Expression
Authors: Gustavo Cabrera, Blanca Segura, Martin Granados, Ana Luisa Esparza
Journal: Molecular Therapy (2015)

Still unresolved complications associated with adenoviral mediated hepatic-based gene therapy are a strong immunological response with damage to the organ and short-term gene expression. Our group hypothesized that the two components at the core of these drawbacks are: 1) the astronomically high quantities of vector infused and 2) the viremia associated with the conventional routes of vector administration. To stringently manipulate these two variables and assess their effect on adenoviral mediated liver transduction our group implemented compartmentalized liver transduction. Compartmentalized liver transduction is based on known adenoviral spatio-temporal kinetics and is achieved by the direct intra-parenchymal injection of adenovirus into a blood-flow isolated portion of the liver; blood flow is reestablished after viral endocytosis has been completed. Implementing compartmentalized liver transduction in a rat model, gene expression and transgene presence was confined to the site of injection, no inflammation nor liver damage was observed, reporter protein expression with low quantities of vector (10^2) as well as linear dose response curves were documented and prolonged transgene expression was achieved. Our results conclude that compartmentalized liver transduction is a safe and effective mode of vector delivery with a promising future in the field of gene therapy.
Thymic-Derived Tolerizing Dendritic Cells Are up-Regulated upon Treatment with Intravenous Immunoglobulin or Splenectomy in a Murine Model of Immune Thrombocytopenia
Authors: Rick Kapur, Rukhsana Aslam, Edwin R. Speck, Michael Kim, Anne Zufferey, Li Guo, George B. Segel, Heyu Ni, John W. Semple
Journal: Blood (2015)
Outpatient Administration of High Dose BEAM Chemotherapy As Conditioning for Autologous Stem Cell Transplantation for Lymphoma Results in Fewer Infectious Complications and Improved Survival
Authors: Robin M. Reid, Andrea Baran, Paul M. Barr, Michael W. Becker, Steven H. Bernstein, Jonathan W. Friedberg, Jane L. Liesveld, Gordon L. Phillips, Lucy Wedow, Laurie A. Milner
Journal: Blood (2014)
The Impact of Relative Dose Intensity (RDI) of CHOP on Outcome of Diffuse Large B-Cell Lymphoma: Results of a Single Center Study.
Authors: Yoshiki Terada, Hirohisa Nakamae, Takahiko Nakane, Hideo Koh, Yasunobu Takeoka, Ran Moriguchi, Mizuki Aimoto, Yuki Akazawa, Eri Wada, Hiroshi Kanashima, Erina Sakamoto, Ki-Ryang Koh, Takahisa Yamane, Kensuke Ohta, Yoshitaka Nakao, Hirofumi Teshima, Masayuki Hino
Journal: Blood (2007)
Molecular Markers Beyond Microsatellite Instability for Assessing Prognosis in Early-Stage Colorectal Cancer
Authors: Andrea Sartore-Bianchi
Journal: JAMA Oncology (2016)

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Blastic Plasmacytoid Dendritic Cell Neoplasm Is Dependent on BCL2 and Sensitive to Venetoclax
Authors: Joan Montero, Jason Stephansky, Tianyu Cai, Gabriel K. Griffin, Lucia Cabal-Hierro, Katsuhiro Togami, Leah J. Hogdal, Ilene Galinsky, Elizabeth A. Morgan, Jon C. Aster, Matthew S. Davids, Nicole R. LeBoeuf, Richard M. Stone, Marina Konopleva, Naveen Pemmaraju, Anthony Letai, Andrew A. Lane
Journal: Cancer Discovery (2016)

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive hematologic malignancy with dismal outcomes for which no standard therapy exists. We found that primary BPDCN cells were dependent on the antiapoptotic protein BCL2 and were uniformly sensitive to the BCL2 inhibitor venetoclax, as measured by direct cytotoxicity, apoptosis assays, and dynamic BH3 profiling. Animals bearing BPDCN patient-derived xenografts had disease responses and improved survival after venetoclax treatment in vivo Finally, we report on 2 patients with relapsed/refractory BPDCN who received venetoclax off-label and experienced significant disease responses. We propose that venetoclax or other BCL2 inhibitors undergo expedited clinical evaluation in BPDCN, alone or in combination with other therapies. In addition, these data illustrate an example of precision medicine to predict treatment response using ex vivo functional assessment of primary tumor tissue, without requiring a genetic biomarker.Therapy for BPDCN is inadequate, and survival in patients with the disease is poor. We used primary tumor cell functional profiling to predict BCL2 antagonist sensitivity as a common feature of BPDCN, and demonstrated in vivo clinical activity of venetoclax in patient-derived xenografts and in 2 patients with relapsed chemotherapy-refractory disease. Cancer Discov; 7(2); 156-64. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 115.
160. Additive Nanocomplexes of Cationic Lipopolymers for Improved Non-Viral Gene Delivery to Mesenchymal Stem Cells
Authors: K.C.B. Remant, Cezary Kucharskia, Hasan Uludag
Journal: Molecular Therapy (2015)

It has been a challenging task to transform MSC into therapeutically useful cells. Most studies were conducted with viral vectors, despite serious concerns on immunogenicity of the viral approach [1]. Cationic polymers display greater chemical diversity than lipids and accommodate versatile chemical schemes to incorporate functional moieties for better transfection[2]. Herein, we have developed a ternary nano-formulation for gene delivery to umbilical cord blood MSC and bone marrow MSC by using lipid-modified small (1.2 kDa) molecular weight polyethylenimine (PEI1.2) (Figure 1). Linoleic acid (LA) was end-capped with carboxyl functionality by coupling with mercaptopropionic acid through thio-ester linkage, and then grafted onto PEI1.2 via N-acylation. Structural functionalities of modified LA (tLA) and thio-ester LA grafted PEI1.2 (PEI-tLA) were analyzed through 1H-NMR spectroscopy and TNBS assay. To create polymer/pDNA complexes that more conducive for dissociation, polyanionic additive (hyaluronic acid, HA) was incorporated along with pDNA to PEI-tLA complexes. The binding capacity of the polymers and unpacking of resultant complexes was elucidated by an agarose gel retardation assay. PEI-tLA displayed a significantly lower (up to 6-fold) pDNA binding capability and a higher dissociation propensity. The dissociation ability of PEI-tLA/pDNA complexes was further enhanced by HA incorporation. The effect of HA was negligible in hydrodynamic size of the complexes but it significantly decreased surface charge which is essential to minimize cellular toxicity of cationic polymers [3]. PEI-tLAs displayed better compatibility to MSC compared to commercial targeting agents and conventional PEI-LA polymers. In vitro transfection efficiency of PEI-tLAs in MSC was substantially higher than positive control. The higher gene expression was the consequence of better cellular uptake, observed through confocal microscopy and flowcytometric study. Transfection efficiency of PEI-tLA was further increased using ternary complexes with HA, which was comparable to or higher than Lipofectamine™ 2000 and PEI25. The synergism between polyanionic additive (e.g. HA) and electronegative functionality (e.g. thio-ester, -S-CO-) of aliphatic lipids can generates a supersensitive nano-formulation which could be a potential carrier for the modification of primary cells.