tbuckley/cabot-search huggingface dataset:
696. Pre-Clinical Evaluation of Allele-Specific Mutant Huntingtin Gene Silencing Antisense Oligonucleotides
Authors: Amber L. Southwell, Niels H. Skotte, Nicholas Caron, Holly Kordasiewicz, Michael Oestergaard, Crystal N. Doty, Erika B. Villanueva, Yuanyun Xie, Boguslaw Felczak, Susan M. Freier, Eric E. Swayze, Punit P. Seth, C. Frank Bennet, Michael R. Hayden
Journal: Molecular Therapy (2015)

Huntington disease (HD) is a dominant, genetic neurodegenerative disease characterized by progressive loss of voluntary motor control, psychiatric disturbance, and cognitive decline, for which there is currently no disease-modifying therapy. HD is caused by the expansion of a CAG tract in the huntingtin (HTT) gene. The mutant HTT protein (muHTT) acquires toxic functions, and there is significant evidence that muHTT lowering would be therapeutically efficacious. However, the wild-type HTT protein (wtHTT) serves vital functions, making allele-specific muHTT lowering strategies potentially safer than non-selective strategies. CAG tract expansion is associated with single nucleotide polymorphisms (SNPs) that can be targeted by gene silencing reagents such as antisense oligonucleotides (ASOs) to accomplish allele-specific muHTT lowering. We have evaluated ASOs targeted to HD-associated SNPs in acute in vivo studies including screening, distribution, duration of action and dosing, using a humanized mouse model of HD, Hu97/18, that is heterozygous for the targeted SNPs. We have identified four well-tolerated lead ASOs that potently and selectively silence muHTT at a broad range of doses throughout the central nervous system for 36 weeks or more after a single intracerebroventricular injection. We next conducted a pre-clinical therapeutic efficacy trial of lead ASOs and evaluated them for effect on the HD-like phenotypes of Hu97/18 mice. Treated mice underwent longitudinal behavioral and biochemical assessment followed by terminal neuropathology. Thus far we have determined that pre-symptomatic allele-specific muHTT silencing prevents onset of behavioral HD-like phenotypes. Evaluation of neuropathology and post-symptomatic intervention is ongoing. Contingent on findings from these studies and using delivery and dosing information gained from ongoing CNS ASO clinical trials, a primary SNP-targeted ASO drug could be fairly rapidly translated for human applications.
Incidental Detection of Thyroid Metastases From Renal Cell Carcinoma Using 68Ga-PSMA PET/CT to Assess Prostate Cancer Recurrence
Authors: Helle D. Zacho, Julie B. Nielsen, Katja Dettmann, Uwe Haberkorn, Lars J. Petersen
Journal: Clinical Nuclear Medicine (2016)

Ga-PSMA PET/CT is increasingly used to assess prostate cancer. Avid Ga-PSMA uptake by thyroid cancer and renal cell carcinoma (RCC) has been reported in few cases. A 75-year-old man who received a diagnosis of RCC in 2006 and prostate cancer in 2009 presented with elevated prostate-specific antigen levels (0.7 ng/mL) following prostatectomy. Ga-PSMA PET/CT showed avid Ga-PSMA uptake in 1 pelvic and 1 retroperitoneal lymph node and focal Ga-PSMA accumulation in the thyroid. Excised retroperitoneal lymph node and thyroid tissues showed metastases from RCC, whereas the pelvic lymph node exhibited metastasis from prostate cancer.
Abstract A49: Pharmacological inhibition of PIM kinases in combination with chemotherapeutic drugs decreases cell viability of pancreatic cancer cells
Authors: Brittany K. Nixon, Qingping He, Vandana Singh, Sarah A. Compton, Steve Warner, David Bearss, Jonathan Z. Sexton, Antonio T. Baines
Journal: Cancer Research (2016)

Abstract Current drug treatments have proven ineffective in pancreatic ductal adenocarcinoma (PDAC) as chemoresistance is a common occurrence in this disease. In order to improve survival rates, a combination treatment regimen of anti-cancer drugs will most likely be needed. The oncogenic serine/threonine PIM kinase family has been shown to regulate drug resistance in various cancers, including pancreatic cancer. Several PIM kinase inhibitors have been developed over the years and tested against a number of cancers, including solid tumors. Previous studies in our laboratory have shown a potential synergistic effect on cell viability of PDAC cells when treated with the PIM kinase inhibitor SGI-1776 and gemcitabine. Unfortunately, due to medical problems occurring during Phase I clinical trials , clinical studies using SGI-1776 were terminated. This led to the development by Tolero Pharmaceuticals of a more selective second generation PIM kinase inhibitor, TP-3654. However, to our knowledge no research has been conducted on the interaction of TP-3654 with gemcitabine or other FDA-approved chemotherapeutics. To address this concern, a 384-well high-content cell viability assay was designed to assess synergism between TP-3654 and the National Cancer Institute (NCI) catalog of 88 FDA-approved chemotherapeutics. Using high-content automated microscopy and image analysis, we acquired total cell counts and other important cellular data, such as nuclear and cell morphology. While some drug combinations with TP-3654 proved ineffective, decreased cell viability was observed in several drug classes, including hormonal agents, mTOR inhibitors, and alkylating agents. Compounds causing significant cytotoxicity in combination with TP-3654 were further evaluated to not only confirm synergism, but to potentially understand the cellular mechanisms and signaling pathways involved. Additional studies will include testing TP-3654 with non-chemotherapeutic compounds and purified natural products. The results of these studies could be used to help develop better drug combination strategies to treat pancreatic cancer and increase the survival rate of patients. Citation Format: Brittany K. Nixon, Qingping He, Vandana Singh, Sarah A. Compton, Steve Warner, David Bearss, Jonathan Z. Sexton, Antonio T. Baines.{Authors}. Pharmacological inhibition of PIM kinases in combination with chemotherapeutic drugs decreases cell viability of pancreatic cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr A49.
PEOT/PBT Guides Enhance Nerve Regeneration in Long Gap Defects
Authors: Daniel Santos, Paul Wieringa, Lorenzo Moroni, Xavier Navarro, Jaume Del Valle
Journal: Advanced Healthcare Materials (2016)

Development of new nerve guides is required for replacing autologous nerve grafts for the repair of long gap defects after nerve injury. A nerve guide comprised only of electrospun fibers able to bridge a critical (15 mm) nerve gap in a rat animal model is reported for the first time. The nerve conduits are made of poly(ethylene oxide terephthalate) and poly(butylene terephthalate) (PEOT/PBT), a biocompatible copolymer composed of alternating amorphous, hydrophilic poly(ethylene oxide terephthalate), and crystalline, hydrophobic poly(butylene terephthalate) segments. These guides show suitable mechanical properties, high porosity, and fibers aligned in the longitudinal axis of the guide. In vitro studies show that both neurites and Schwann cells exhibit growth alignment with PA fibers. In vivo studies reveal that, after rat sciatic nerve transection and repair with PEOT/PBT guides, axons grow occupying a larger area compared to silicone tubes. Moreover, after repair of limiting (10 mm) and critical (15 mm) nerve gaps, PEOT/PBT guides significantly increase the percentage of regenerated nerves, the number of regenerated myelinated axons, and improve motor, sensory, and autonomic reinnervation in both gaps. This nerve conduit design combines the properties of PEOT/PBT with electrospun structure, demonstrating that nerve regeneration through long gaps can be achieved through the design of instructive biomaterial constructs.
Abstract 3174: Retinoblastoma protein 1 implication in the monocytic - granulocytic transition
Authors: Jerome Mastio, Thomas Condamine, Dmitry Gabrilovich
Journal: Cancer Research (2015)

Abstract Alterations in the myeloipoiesis during cancer lead to production of myeloid-derived suppressor cells (MDSC). MDSC are comprised of two subsets: monocytic MDSC (M-MDSC) and polymorphonuclear MDSC (PMN-MDSC). Both subsets contribute to the immunosuppressive tumor microenvironment. Therefore elimination of MDSC could potentially improve the clinical success of cancer immune therapy. Direct targeting of MDSC progenitors is an attractive possibility. Our laboratory has recently discovered that M-MDSC from the bone-marrow can give rise to PMN-MDSC and that this phenomenon is mediated by the loss of retinoblastoma protein 1 (Rb1) expression. However, a full phenotypic and molecular characterization of these MDSC progenitors has not been established. To identify the subpopulation able to give rise to PMN-MDSC within the M-MDSC population, we used Rb1-GFP reporter mice to track Rb1 expression in vivo. We found that Rb1 low M-MDSC express the stem cell marker c-Kit and low levels of CD115. These Rb1 low c-Kit + M-MDSC are substantially expanded in tumor-bearing mice. Interestingly, this population is also present in naive mice, albeit at very low frequency. Rb1 low c-Kit + monocytic cells from naïve and tumor bearing mice can give rise to granulocytic cells in vitro. These preliminary results indicate that these cells are indeed granulocytic progenitor and are expanded during tumor development. Although this monocyte-granulocyte conversion is associated with a decrease in Rb1 expression, it seems that a minimal Rb1 level is required to ensure this process, at least in naïve mice. Further characterization of the phenotype and molecular profiles of this new MDSC progenitor could lead to the development of new ways to target MDSC. Citation Format: Jerome Mastio, Thomas Condamine, Dmitry Gabrilovich. Retinoblastoma protein 1 implication in the monocytic - granulocytic transition. [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 3174. doi:10.1158/1538-7445.AM2015-3174
Abstract 2038: A novel role for the NLRP3 inflammasome in lung cancer
Authors: Virginie Petrilli, Mélanie Bodnar, Baptiste Guey, Sabine Hacot, Sylvie Lantuejoul
Journal: Cancer Research (2015)

Abstract Although significant advances have been made in the diagnosis and treatment of lung cancer, it remains the most fatal cancer worldwide. This poor outcome is mainly due to the limited curative options available especially for advanced cancer stages. About 80% of lung cancers are Non Small Cell Lung Cancers (NSCLC). Although several mutations in oncogenes and tumor genes have been identified in NSCLC, the oncogene K-ras and the Receptor Tyrosine Kinases (RTK) being the most frequently mutated, about 40% of cancers are driven by unidentified mutations. Many cancer cells activate a proinflammatory program to manipulate the host immune system to support their growth. Inflammasomes are crucial effectors of the innate immunity. Upon activation, inflammasomes assemble into multiprotein complexes controlling the activation of the inflammatory caspase-1 and the maturation of the pro-Interleukin-1beta (pro-IL-1b) and the pro-IL-18 into active cytokines. The NLRP3 inflammasome detects pathogens, airborne pollutants but also self-danger signals released by dying cells. In the lung, hyperactivation of this complex upon bleomycin or asbestos exposure drives an inflammatory response resulting in lung fibrosis. Published large-scale genomic analyses of NSCLC identified somatic mutations in the NLRP3 gene and scored NLRP3 as a putative oncogene. Little is known about the role of the NLRP3 inflammasome in lung cancer. We speculated that the NLRP3 inflammasome could play a prominent role in NSCLC and studied the function of NLRP3 inflammasome in human non-transformed and transformed lung epithelial cells. Our data unravel new functions for the NLRP3 inflammasome in DNA damage sensing and unexpectedly suggest that NLRP3 could act as a tumor suppressor gene in lung cancer. Citation Format: Virginie Petrilli, Mélanie Bodnar, Baptiste Guey, Sabine Hacot, Sylvie Lantuejoul. A novel role for the NLRP3 inflammasome in lung 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 2038. doi:10.1158/1538-7445.AM2015-2038
ATPS-31POLYMERIC BIO-SCAFFOLDS INCREASE THE EFFICACY OF STEM CELL-MEDIATED THERAPY FOR GLIOBLASTOMA
Authors: Juli Bago, Guillaume Pegna, Onyi Okolie, Mahsa Mohiti-Asli, Elizabeth Loboa, Shawn Hingtgen
Journal: Neuro-Oncology (2015)

Engineered stem cell (SC)-based therapy holds enormous promise for treating the incurable brain cancer glioblastoma (GBM). Retention of the cytotoxic SCs within the GBM resection is one of the greatest challenges to this approach. Here, we describe a biocompatible polymeric bio-scaffold (bPBS) transplant strategy that is capable of delivering and retaining tumor-homing cytotoxic SCs to prevent recurrence of surgically resected GBM. As a new approach to GBM therapy, we created bPBS bearing drug-releasing human mesenchymal stem cells (hMSCs). Using unique models of GBM resection/recurrence in mice, we discovered that bPBS-based transplant stabilizes cytotoxic hMSCs in the surgical cavity, increasing SC retention 5-fold and prolonging persistence 3-fold compared to standard direct injection. Time-lapse kinetic imaging and analysis showed the pPBS still allowed hMSCs to rapidly migrate off the matrix as they homed to GBMs but not normal cells of the brain. 3-dimension co-culture assays showed cytotoxic hMSC/bPBS treatment reduced the viability of multiple human GBM cells 50-90%. In vivo, bPBS loaded with cytotoxic hMSCs releasing the anti-tumor protein TRAIL (bPBSsTR) transplanted over established human GBM xenografts reduced tumor volumes 3-fold. Mimicking clinical GBM patient therapy, lining the post-operative GBM surgical cavity with bPBSsTR implants reduced post-surgical GBM volumes 2.3-fold and prolonged post-surgical median survival from 13.5 to 31 days compared to control-treated mice. These results suggest that polymeric bio-scaffold SC therapies could be an innovative new approach to improve the outcomes of patients suffering from terminal brain cancer.
Pentostatin Combined with Cyclophosphamide, and Rituximab Induces High Response Rates in Patients with Untreated Indolent B-Cell Lymphoma.
Authors: Felipe Samaniego, Luis E. Fayad, Barbara Pro, Peter McLaughlin, Maria Alma Rodriguez, F.B. Hagemeister, Michelle Fanale, Sattva Neelapu, Anas Younes, Larry W. Kwak
Journal: Blood (2006)
129. Vector and Cell Mediated BMPR2 Therapy Ameliorates PAH
Authors: Rebecca L. Harper, Feng Feng, Paul N. Reynolds
Journal: Molecular Therapy (2015)

Inherited pulmonary arterial hypertension is a fatal disease caused by mutations in, and reduced expression of, the bone morphogenetic type 2 receptor (BMPR2), leading to abnormal proliferation of pulmonary vascular cells and obliteration of small pulmonary vessels. BMPR2 expression is also reduced in secondary forms of PAH. We previously showed that upregulation of BMPR2 expression in the pulmonary vascular endothelium achieved by an endothelialtargeted adenoviral vector ameliorated PAH in rat models. In the current work, we evaluated a similar vector approach in a transgenic, BMPR2-mutation related PAH model, further characterised signaling mechanisms involved in the rat model, and extended the approach to the use of ex vivo transduced endothelial progenitor cells (EPCs) as a cell therapy approach to BMPR2 upregulation.Methods: SM22-tet / R899x mice were fed doxycycline-containing chow to induce expression of BMPR2 dominant negative protein. Mice were then injected via the tail vein with a pulmonary vascular targeted AdBMPR2-conjugate complex (or control vector), and right ventricular pressure measured (RVSP) by transthoracic puncture. For the EPC approach, rat bone marrow-derived EPCs were cultured in endothelial selective media then transduced ex-vivo with AdBMPR2 for 48 hours. The transduced cells (or untransduced controls) were then injected via tail vein into rats that had induced PAH via subcutaneous monocrotaline injection (60mg/kg) 10 days previously.Results: In the murine experiment, BMPR2 delivery led to a 24% reduction of RVSP compared to disease and vector control animals. Analysis of whole lung lysate using RT-PCR revealed an increase in eNOS expression in the AdBMPR2 treated group. This effect was confirmed in vitro by transduction of cultured endothelial cells, and further confirmed by demonstration of increased NO production. The Ad vector approach in the rat MCT model ameliorated PAH as previously described, an effect associated with an increase in Smad1/5/8 phosphorylation and decreased Smad3 phosphorylation. In the EPC approach, PAH was also ameliorated following EPC+AdBMPR2 treatment, demonstrated by significant reduction compared to MCT only and EPC only for Fulton Index (26% and 16% respectively), RVSP (34% and 36%) and mPAP (25% and 16%), while analysis of downstream signaling is ongoing.Conclusion: These findings indicate that gene delivery strategies via direct vector approaches or cell therapy to upregulate in BMPR2 in the pulmonary vasculature have therapeutic potential in PAH.
Intrinsic transcriptional heterogeneity in B cells controls early class switching to IgE
Authors: Yee Ling Wu, Michael J.T. Stubbington, Maria Daly, Sarah A. Teichmann, Cristina Rada
Journal: The Journal of Experimental Medicine (2016)

Noncoding transcripts originating upstream of the immunoglobulin constant region (I transcripts) are required to direct activation-induced deaminase to initiate class switching in B cells. Differential regulation of Iε and Iγ1 transcription in response to interleukin 4 (IL-4), hence class switching to IgE and IgG1, is not fully understood. In this study, we combine novel mouse reporters and single-cell RNA sequencing to reveal the heterogeneity in IL-4–induced I transcription. We identify an early population of cells expressing Iε but not Iγ1 and demonstrate that early Iε transcription leads to switching to IgE and occurs at lower activation levels than Iγ1. Our results reveal how probabilistic transcription with a lower activation threshold for Iε directs the early choice of IgE versus IgG1, a key physiological response against parasitic infestations and a mediator of allergy and asthma.
Hydrogel Functionalized Janus Membrane for Skin Regeneration
Authors: Young‐Hyeon An, Seung Jung Yu, In Seon Kim, Su‐Hwan Kim, Jeong‐Mi Moon, Seunghyun L. Kim, Young Hwan Choi, Joon Sig Choi, Sung Gap Im, Kyung Eun Lee, Nathaniel S. Hwang
Journal: Advanced Healthcare Materials (2016)

In this study, a hydrogel functionalized Janus membrane is developed and its capacity is examined as a wound dressing biomaterial. A hydrophobic fluoropolymer, poly(3,3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10‐heptadecafluorodecyl methacrylate) (PHFDMA), is uniformly coated onto macroporous polyester membrane through initiated chemical vapor deposition process on both sides. PHFDMA‐coated macroporous membrane exhibits antibacterial property, allows air permeation, and inhibits water penetration. Janus membrane property is obtained by exposing one side of PHFDMA coated membrane with 1 m KOH solution, which allows PHFDMA cleavage resulting in carboxylic acid residue. This carboxylic acid residue is then further functionalized with gelatin methacrylate‐based photocrosslinkable hydrogel for moisture retention and growth factor release. When applied to full thickness dorsal skin defect model, functionalized hydrogel allows moisture retention and hydrophobic surface prevents exudate leaks via water repellence. Furthermore, hydrogel functionalized Janus membrane enhances the wound healing rate and induces thick epidermal layer formation. In conclusion, the multifunctional Janus membrane with hydrophobic outer surface and immobilized hydrogel on the other surface is fabricated for an innovative strategy for wound healing.
TROPICS 1: A Phase III, Randomized, Double-Blind, Placebo-Controlled Study of Tenecteplase for Restoration of Function in Central Venous Catheters.
Authors: Nashat Gabrail, Eric Sandler, Veena Charu, Nick Anas, Eduardo Lim, Martha Blaney, Mark Ashby, Barbara S Gillespie, Susan M Begelman
Journal: Blood (2009)
193. Establishment of an Optimization Procedure for Large-Scale Production of Patient-Specific Cardiomyocytes from hiPSCs
Authors: Jian-Chang Liu, Chang-Yi Chen, Jingjing Ye, Giau Hua, Jing Chai, David Hsu, Larry A. Couture
Journal: Molecular Therapy (2015)

Cardiovascular diseases are a leading cause of morbidity and mortality worldwide. Human embryonic stem cells (hESCs) and induced pluripotent stem cells (hiPSCs), with their ability of indefinite self-renewal and capability to differentiate into all three germ layers, provide a powerful tool in developmental biology, for drug screening, disease modeling, and potentially cell replacement therapy for diseases, such as myocardial infarction and heart failure. Unlike hESCs, hiPSCs are generated from reprogrammed somatic cells without using of human embryos and thus hold a great promise for cell-based therapy as they avoid ethical and immune rejection issues. However, due to scalability limitation of current hiPSC adherent culture platform and potential variation of culture and differentiation conditions among hiPSC lines, production of hiPSC-derived cells to a scale sufficient for therapeutic application in a timely manner has been challenging. Previously we have developed a scalable, defined, and cGMP-compliant suspension culture system for hPSC expansion and cardiac differentiation using spinner flasks by optimizing critical culture parameters we identified. In the present study, we tested the feasibility of applying our suspension culture platform and optimization strategy to establish a process for scale-up production of cardiomyocytes (CM) from individual hiPSC lines in a timely manner. We optimized cell seeding density, agitation rate, concentration of differentiation inducer, and timing for differentiation induction to determine an optimal condition for large-scale CM production. The process from suspension adaptation, differentiation optimization to CM production was accomplished in 3 months. With optimized culture and differentiation conditions, we showed that the hiPSC suspension culture can be serially passaged and expanded, and maintained normal karyotype. At a scale of 500mL suspension culture, 4-5×108 cells with 70-90% CM purity were manufactured. In summary, we demonstrated the feasibility of applying the suspension culture platform and optimization strategy we developed to establish a production process for individual hiPSC line to manufacture CM in a large scale in a timely manner.