tbuckley/cabot-search huggingface dataset:
Abstract 3653: Structure-based study to overcome cross-reactivity of novel androgen receptor inhibitors
Authors: Huifang Li, Nada Lallous, Kush Dalal, Eric Leblanc, Fuqiang Ban, Fabrice Ciesielski, Paul S. Rennie, Artem Cherkasov
Journal: Cancer Research (2015)

Abstract The mutation-driven transformation of clinically used anti-androgens into agonists of human androgen receptor (AR) represents a major challenge in the current treatment of prostate cancer (PCa). To address this problem, we have developed a novel class of AR inhibitors targeting the DNA-binding domain (DBD) of the receptor, which is distanced from the mutations-prone androgen binding site (ABS) in the ligand-binding domain (LBD) of the AR, targeted by all conventional antiandrogens. While many members of the developed phenyl-thiazol-2-yl-morpholine series demonstrated potent sub-micromolar inhibition of the wild-type AR, some compounds also exhibited an undesired partial agonistic effect toward the T877A mutated form of the receptor, implying their cross-interaction with the AR ABS. To study the molecular basis of the cross-reactivity, we have solved the T877A mutated form of the AR LBD in complex with one developed compound exhibiting such unwanted partial agonism. Based on the resolved crystal structure, we have identified critical protein-ligand interactions and conformational changes in wild-type and T877A forms of AR that drive observed agonistic effects. The identified structural basis has further been used to modify the scaffold of developed AR DBD binders to eliminate their cross-reactivity toward T877A mutated AR LBD. In particular, the replacement of the phenyl ring with less hydrophobic heterocycles resulted in a series of inhibitors that did not demonstrate affinity toward ABS or exhibit an undesired agonistic effect on AR. This study provides insights into the development of AR inhibitors with high specificity, which may help overcome the mutation-driven resistance of anti-AR drugs in the treatment of PCa. Citation Format: Huifang Li, Nada Lallous, Kush Dalal, Eric Leblanc, Fuqiang Ban, Fabrice Ciesielski, Paul S. Rennie, Artem Cherkasov. Structure-based study to overcome cross-reactivity of novel androgen receptor inhibitors. [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 3653. doi:10.1158/1538-7445.AM2015-3653
Fetal Hemoglobin Induction in Baboons (P. Anubis) Following Admistration of a Novel Decitabine Dinucleotide (S110) Compound.
Authors: Donald Lavelle, Kestis Vaitkus, Virryan Banzon, Maria Hankewych, Pasit Phiasivongsva, Sanjeev Redkar, Sarath Kanekal, David Bearss, Chongtie Shi, Roger Inloes, Joseph DeSimone
Journal: Blood (2007)
XGR software for enhanced interpretation of genomic summary data, illustrated by application to immunological traits
Authors: Hai Fang, Bogdan Knezevic, Katie L. Burnham, Julian C. Knight
Journal: Genome Medicine (2016)

Biological interpretation of genomic summary data such as those resulting from genome-wide association studies (GWAS) and expression quantitative trait loci (eQTL) studies is one of the major bottlenecks in medical genomics research, calling for efficient and integrative tools to resolve this problem. We introduce eXploring Genomic Relations (XGR), an open source tool designed for enhanced interpretation of genomic summary data enabling downstream knowledge discovery. Targeting users of varying computational skills, XGR utilises prior biological knowledge and relationships in a highly integrated but easily accessible way to make user-input genomic summary datasets more interpretable. We show how by incorporating ontology, annotation, and systems biology network-driven approaches, XGR generates more informative results than conventional analyses. We apply XGR to GWAS and eQTL summary data to explore the genomic landscape of the activated innate immune response and common immunological diseases. We provide genomic evidence for a disease taxonomy supporting the concept of a disease spectrum from autoimmune to autoinflammatory disorders. We also show how XGR can define SNP-modulated gene networks and pathways that are shared and distinct between diseases, how it achieves functional, phenotypic and epigenomic annotations of genes and variants, and how it enables exploring annotation-based relationships between genetic variants. XGR provides a single integrated solution to enhance interpretation of genomic summary data for downstream biological discovery. XGR is released as both an R package and a web-app, freely available at http://galahad.well.ox.ac.uk/XGR .
Wound Healing: Production of Hollow Bacterial Cellulose Microspheres Using Microfluidics to Form an Injectable Porous Scaffold for Wound Healing (Adv. Healthcare Mater. 23/2016)
Authors: Jiaqing Yu, Tzu‐Rung Huang, Zhen Han Lim, Rongcong Luo, Rupali Reddy Pasula, Lun‐De Liao, Sierin Lim, Chia‐Hung Chen
Journal: Advanced Healthcare Materials (2016)

Well-defined hollow microspheres consisting of bacterial cellulose are fabricated using a microfluidic process by Chia-Hung Chen and co-workers on page 2983. The cellulose-producing bacteria Gluconacetobacter xylinus is encapsulated in the core-shell structured hydrogel template to form desired hollow cellulose microspheres, which can be used as ideal building blocks forming a scaffold with high porosity for 3-D cell proliferation, tissue regeneration and wound healing.
A 41-Gene Signature Predicts Complete Response (CR) to Bortezomib-Thalidomide-Dexamethasone (VTD) As Induction Therapy Prior to Autologous Stem-Cell Transplantation (ASCT) in Multiple Myeloma (MM)
Authors: Carolina Terragna, Daniel Remondini, Sandra Durante, Marina Martello, Francesca Patriarca, Anna Levi, Lucia Pantani, Daniela Donnarumma, Claudia Crippa, Sara Bringhen, Alessandro Rambaldi, Massimo Offidani, Paolo Corradini, Franco Narni, Giuseppe Fioritoni, Alfonso Zaccaria, Luca Baldini, Tommaso Caravita, Giorgio La Nasa, Sergio Cortelazzo, Giovanni Martinelli, Michele Baccarani, Michele Cavo
Journal: Blood (2011)
Forodesine (FodosineTM), a PNP Inhibitor Active in Relapsed or Refractory T-Cell Leukemia Patients (Phase II Study).
Authors: Richard R. Furman, Genadi Iosava, Luis Isola, Farhad Ravandi, Mamia Zodelava, J. Claude Bennett, J. Michael Kilpatrick, Shanta Bantia
Journal: Blood (2005)
106. A Sleeping Beauty Transposase System in the Context of HD-Ad5/35++ Vectors Achieves Stable In Vivo Transduction of Hematopoietic Stem Cells in Mouse Models
Authors: Maximilian Richter, Jing Liu, Zsuzsanna Izsvák, Roberto Cattaneo, Wolfgang Uckert, Philip Ng, Anja Ehrhardt, Thalia Papayannopoulou, André Lieber
Journal: Molecular Therapy (2016)

Hematopoietic stem cells (HSCs) are important targets for the gene therapy of infectious diseases, genetic disorders, and cancer. Our aim is to transduce HSCs in vivo after mobilization from the bone marrow and intravenous injection of a gene transfer vector. We employed helper-dependent adenovirus vector containing Ad35 fiber mutants with enhanced affinity to CD46 (HD-Ad5/35++) for gene transfer into HSCs. HD-Ad5/35++ vectors efficiently transduced human HSCs and human CD46-transgenic mouse HSCs in vitro. To trigger chromosomal transgene integration we utilized the hyperactive Sleeping Beauty transposase system (SB100x). The system consists of two vectors; the transposon vector carrying a GFP gene and the SB100x vector that mediates integration of the GFP cassette into a TA dinucleotide of the genomic DNA. As a limitation, this system requires the co-infection of the same target cell with two vectors to achieve stable transduction. This is exemplified in a study with two Ad5/35++ reporter vectors, expressing either GFP or mCherry. Human CD46tg mice were mobilized with GSCF/AMD3100 and intravenously injected with either vector alone or the vector combination. Reporter gene expression in bone marrow localized HSCs was analyzed 3 days later. While 2% of lineage depleted cells expressed either GFP or mCherry only 0.25% expressed both. In spite of these limitations, we tested whether the co-injection of a HD-Ad5/35++ -GFP transposon vector and a HD-Ad5/35++ SB100x vector, supplying a Sleeping Beauty transposase in trans into mobilized mice would lead to stable HSC transduction. Twelve weeks post-injection, we detected stable GFP expression in bone marrow HSCs in the range of 1 to 2%. GFP integration through SB100X was confirmed by genome-wide sequencing of integration sites. Our data indicate that HD-Ad5/35++ vectors preferentially target primitive HSCs and that this increases the chance of co-infection with both vectors. This is supported by a comparison of GFP marking in HSCs and more differentiated marrow and blood cells four weeks after in vivo transduction. While in the HSC-containing LSK fraction of the bone marrow the marking rate was on average 7.7%, marking rates for total mononuclear cells of the bone marrow and peripheral blood were only 2.5% and 0.3%, respectively. The preferential HSC targeting in hCD46tg and humanized mice can be explained by higher CD46 levels on primitive HSCs compared to more differentiated cells in the bone marrow and the dependence of Ad5/35 infection efficiency (at low MOIs) on CD46 density on the cell surface.
Abstract 2143: A 3D system to elucidate a direct role for epiregulin mistrafficking in epithelial transformation
Authors: Bhuminder Singh, Galina Bogatcheva, Robert J. Coffey
Journal: Cancer Research (2015)

Abstract The EGF receptor (EGFR) ligand epiregulin (EREG) is delivered preferentially to the basolateral cell surface of polarized MDCK cells. Previously, we showed that EREG basolateral trafficking is regulated by a conserved tyrosine residue within a YXXΦ motif (Y156ERV) in its cytoplasmic domain. Interestingly, a Y156A substitution led to apical mistrafficking of EREG and transformation of polarized MDCK cells (PNAS 110: 8960-5, 2013). We have identified an EREG mutation (R147stop) in human tumors that we now report mistrafficks to the apical surface. To test the hypothesis that apical mistrafficking of EREG can be a driver event, we have generated MDCK cells stably expressing inducible (Tet-ON) wild-type and Y156A mutant EREG. In 3D Matrigel cultures, we show that uninduced clones form normal-appearing cysts, regardless of EREG status. Induction of WT or mutant EREG leads to increased cyst diameter. However, only (Y156A)EREG-expressing cells form abnormal cysts with ectopic lumens and inward growth, features of in vivo transformation. Furthermore, we show that ligand processing and EGFR activity is required for EREG mistrafficking-induced ectopic lumen formation as preincubation with a broad-spectrum metalloprotease inhibitor, BB-94, abrogates ectopic lumen formation. We have extended these studies to polarizing human colon cancer cells, HCA-7, which preserve the trafficking fidelity of WT and mutant EREG. Furthermore, using EREG cytoplasmic domain as a bait in a yeast-2-hybrid screen, we have identified APOBEC3C as an interacting protein. APOBECs are a family of cytidine deaminases that have been identified as a major contributor to human cancer mutations. We have subsequently confirmed EREG-APOBEC3C interaction by co-immunoprecipitation. Results from MDCK cells stably expressing differentially inducible EREG (Tet-ON) and APOBEC3C (Cumate-ON) will be presented. Note: This abstract was not presented at the meeting. Citation Format: Bhuminder Singh, Galina Bogatcheva, Robert J. Coffey. A 3D system to elucidate a direct role for epiregulin mistrafficking in epithelial transformation. [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 2143. doi:10.1158/1538-7445.AM2015-2143
Abstract 2345: The collagen-dense tumor microenvironment increases neutrophil recruitment in mouse mammary carcinoma
Authors: Maria Gracia Garcia Mendoza, David Inman, Suzanne M. Ponik, Patricia J. Keely
Journal: Cancer Research (2015)

Abstract The breast tumor microenvironment (TME) is a diverse area where complex interactions between the extra-cellular matrix (ECM) and multiple cell types (tumor epithelial, endothelial, and inflammatory cells, fibroblasts, and adipocytes) occur resulting in tumor promotion, invasion and metastasis. Changes in breast tissue density have been correlated with a 4-6-fold increased risk for developing breast cancer, and are associated with increased stromal deposition of the ECM protein, collagen I. In a transgenic mouse model of increased collagen (Col1A1Tm1Jae), there is a 3-fold increase in MMTV-PyMT tumor formation and lung metastases compared to control mice. Of the non-malignant cells in the TME, tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs) have been shown by several investigators to alter the TME and ECM, enhance tumor cell migration and invasion, stimulate angiogenesis, and suppress antitumor immunity. The direct interaction of both increased collagen and immune (myeloid) cell recruitment leading to increased cancer progression and metastasis has not been characterized. We hypothesized that a collagen-dense tumor microenvironment recruits an abnormal population of myeloid cells, which promotes tumor progression and metastasis. Flow cytometry analysis of cells from collagen-dense mouse tumors showed an increase in Ly6G+ TAN recruitment compared to wild type tumors, while TAM recruitment did not seem to be affected. The increased Ly6G+ neutrophil recruitment is a global immune response also observed in the spleens and circulating blood. Using a cytokine/chemokine ELISA plate array, we found that the collagen-dense TME cytokine cross talk supports neutrophil and monocyte recruitment and maturation. In addition, many classic inflammatory signals that support lymphocyte recruitment and activation, B and T-cell proliferation, and natural killer cell and monocyte activation are downregulated in the collagen-dense TME. Further experiments will determine the time point where neutrophil recruitment is critical for tumor progression. Experiments are underway to study the possible suppression of natural killer cell activity in the collagen-dense TME. This work is being supported by NIH grants (NIH-CA-114462 and NIH-U54-CA163131) to P.J.K. and NSF Graduate Research Fellowship (2011129283) to M.G.G.M. Citation Format: Maria Gracia Garcia Mendoza, David Inman, Suzanne M. Ponik, Patricia J. Keely. The collagen-dense tumor microenvironment increases neutrophil recruitment in mouse mammary carcinoma. [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 2345. doi:10.1158/1538-7445.AM2015-2345
Abstract LB-040: mTOR inhibitors induce apoptosis in colon cancer cells via CHOP-dependent DR5 induction upon 4E-BP1 dephosphorylation
Authors: Kan He, Xingnan Zheng, Mei Li, Lin Zhang, Jian Yu
Journal: Cancer Research (2015)

Abstract The mammalian target of rapamycin (mTOR) is commonly activated in colon cancer. mTOR complex 1 (mTORC1) is a major downstream target of the PI3K/ATK pathway and activates protein synthesis by phosphorylating key regulators of mRNA translation and ribosome synthesis. Rapamycin analogs Everolimus and Temsirolimus are non-ATP-competitive mTORC1 inhibitors, and suppress proliferation and tumor angiogenesis and invasion. We now show that apoptosis plays a key role in their anti-tumor activities in colon cancer cells and xenografts through the DR5, FADD and caspase-8 axis, and is strongly enhanced by TRAIL and 5-fluorouracil. The induction of DR5 by rapalogs is mediated by the ER stress regulator and transcription factor CHOP, but not the tumor suppressor p53, upon rapid and sustained inhibition of 4E-BP1 phosphorylation, and attenuated by eIF4E expression. ATP-competitive mTOR/PI3K inhibitors also promote DR5 induction and FADD-dependent apoptosis in colon cancer cells. These results establish activation of ER stress and the death receptor pathway as a novel anticancer mechanism of mTOR inhibitors. Citation Format: Kan He, Xingnan Zheng, Mei Li, Lin Zhang, Jian Yu. mTOR inhibitors induce apoptosis in colon cancer cells via CHOP-dependent DR5 induction upon 4E-BP1 dephosphorylation. [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 LB-040. doi:10.1158/1538-7445.AM2015-LB-040
Abstract 4988: A7 nicotinic acetylcholine receptor mediated the chemosensitivity of gastric cancer cells
Authors: Chien-Yu Huang, Yu-Jia Chang
Journal: Cancer Research (2015)

Abstract Background: Gastric cancer is important healthy issue in the worldwide. A7-nAChR has become a potential therapeutic target for cancer. Highly expression of A7-nAChR caused the benefit of cell survival in gastric cancers. However, it is unclear for the role of A7-nAChR in chemotherapy therapy on gastric cancer. Methods: In this study, we generated A7-nAChR knockdown (A7-nAChR-KD) AGS cells by a short interfering RNA (siRNA) technique in gastric cancer cells. The anti-proliferation effects of chemotherapy drugs were determined by biosensor system, MTT assay, TUNEL assay, and cell cycle determination. Results: We determined the IC50 of 5-FU, taxane, epirubicin, cisplastin, gemcitabine, labtinibine, sunitinib in both A7-nAChR-Kd cells and scrambled control cells by MTT assay. We found that there is no difference between A7-nAChR-KD cells and scrambled control cells for epirubicin, cisplastin, labtinibine, sunitinib treatments. Interestingly, A7-nAChR-KD cells were less resistant to taxane treatment compared with the scrambled control cells. The apoptosis cell population was increased less in scrambled control cells treated with taxane than A7-nAChR-KD cells in cell cycle distribution and TUNEL assays. Conclusions: We conclude that A7-nAChR may be a key biomarker in mediating the chemotherapy efficacy on gastric cells. Citation Format: Chien-Yu Huang, Yu-Jia Chang. A7 nicotinic acetylcholine receptor mediated the chemosensitivity of gastric cancer 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 4988. doi:10.1158/1538-7445.AM2015-4988
596. AAV Gene Delivery of the Anti-Tau Antibody PHF1 Reduces Brain Tau Pathology in P301L Mice
Authors: Wencheng Liu, Lingzhi Zhao, Maria J. Chiuchiolo, Fangmin Yu, Thomas Woo, Man-Ying Wong, Brittany Black, Peter Davies, Clarisse Jose, Jonathan Rosenberg, Stephen M. Kaminsky, Dolan Sondhi, Ronald G. Crystal, Steven M. Paul
Journal: Molecular Therapy (2015)

Anti-tau immunotherapy has been proposed as a promising therapy for various tauopathies including Alzheimer's disease (AD), frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). However, there are limitations to passive immunization including the need for repeated administration and the very low levels of antibody that get into brain from the circulation. To circumvent the disadvantages of passive immunization, we have used serotype rh. 10 adeno-associated virus vectors to deliver an anti-tau monoclonal antibody PHF1, known to reduce tau pathology following passive immunization in several tauopathy mouse models directly to the CNS. To accomplish this, we stereotactically administered 1010 viral genomes (vg) of AAVrh. 10-PHF1 or AAVrh. 10-mCherry as a control, bilaterally into the hippocampus of young (3.5-month old) homozygous P301L mice, a model that develops robust tau pathology in an age- and brain region-dependent manner. Six months after injection, mice were sacrificed to measure the presence of anti-tau antibody as well as the effects of treatment on tau pathology in several brain regions using specific ELISAs and immunohistochemistry (IHC) for quantifying pathological and normal tau. In pilot experiments using wild-type C57BL/6 and P301L mice, we observed much higher levels of PHF1 antibody in the hippocampus when delivered via the AAVrh. 10 vector compared to passive immunization (3100-fold higher). We observed that treatment with AAVrh. 10-PHF1 resulted in a marked antibody-dependent reduction in tau pathology in P301L mice, including a highly significant reduction in tau pathology in the hippocampus (≥80-90% p=0.001) compared to the control vector. There was also no reduction in total tau measured by ELISA in any brain region examined. Based on these observations, AAVrh. 10 gene delivery of anti-tau monoclonal antibodies to the CNS may represent a novel therapeutic strategy for treating various tauopathies including FTD, PSP and AD.
Abstract 5565: Antitumor activities of psammaplin A analogues in human lung cancer cells
Authors: Yoonho Shin, Suckchang Hong, Jongheon Shin, Hyeung-geun Park, Sang Kook Lee
Journal: Cancer Research (2015)

Abstract Histone deacetylase inhibitors (HDACi) are considered to be potential candicates for cancer therapeutic agents. HDACi suppresses the progression of tumorigenesis through epigenetic regulation of target protein acetylation. Psammaplin A (PsA), originated from a marine product Pseudoceratina purpurea, also showed a potential HDAC inhibition. Based on the potential anticancer activity of PsA, various PsA analogs were designed and synthesized to explore novel candidates in the development of anticancer agents. Among compounds tested, a β-napthyl-derivertive of PsA (compound 30) exhibited a strong growth-inhibitory activity against human lung cancer cells and the activity was comparable to PsA. Compound 30 also effectively inhibited HDAC and up-regulated the level of ac-Histone3, p-AKT, p-ERK in human A549 lung cancer cells. In in vivo xenograft animal model implanted A549 cells, the administration of compound 30 intraperitoneally for 35 days exhibited a potential growth inhibitory activity of the tumor (47.6% inhibition at 30 mg/kg). The immunohistochemical analysis of tumor tissues also revealed the inhibition of the cell proliferation biomarker Ki-67 expression by compound 30. Taken together, these data suggest that a β-napthyl analog of PsA has the potential antitumor activity and thus to be prioritized in the development of cancer chemotherapeutic agents. Citation Format: Yoonho Shin, Suckchang Hong, Jongheon Shin, Hyeung-geun Park, Sang Kook Lee. Antitumor activities of psammaplin A analogues in human lung cancer 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 5565. doi:10.1158/1538-7445.AM2015-5565