tbuckley/cabot-search huggingface dataset:
472. Evaluation of Re-Administration of a Recombinant Adeno-Associated Vector Expressing Acid-Alpha-Glucosidase (rAAV9-DES-hGAA) in Pompe Disease: Preclinical to Clinical Planning
Authors: Manuela Corti, Brian Cleaver, Nathalie Clement, Thomas Conlon, Kaitlyn Faris, Gensheng Wang, Janet Benson, Alice Tarantal, Dave Fuller, Roland Herzog, Barry J. Byrne
Journal: Molecular Therapy (2016)

A recombinant serotype 9 adeno-associated virus (rAAV9) vector carrying a transgene that expresses codon optimized human acid alpha-glucosidase (hGAA, or GAA) driven by a human desmin (DES) promoter (i.e. rAAV9-DES-hGAA) has been generated as a clinical candidate vector for Pompe disease. The rAAV9-DES-hGAA vector is being developed as a treatment for both early and late onset Pompe disease, in which patients lack sufficient lysosomal alpha-glucosidase leading to glycogen accumulation. In young patients, the therapy may need to be re-administered after a period of time to maintain therapeutic levels of GAA. Administration of AAV-based gene therapies is commonly associated with the production of neutralizing antibodies (NAb) that may reduce the effectiveness of the vector, especially if re-administration is required. Previous studies have demonstrated the ability of rAAV9-DES-hGAA to correct cardiac and skeletal muscle pathology in Gaa−/− mice, an animal model of Pompe disease. We describe the IND-enabling pre-clinical studies supporting the program for a phase I/II clinical trial in adult patients with Pompe. These studies were designed to evaluate the toxicology, biodistribution, and potential for re-administration of rAAV9-DES-hGAA injected intramuscularly into the tibialis anterior (TA) muscle using an immune modulation strategy developed for this study. In the proposed clinical study, six adult participants with Late-Onset Pompe Disease (LOPD) will be enrolled. The goal of the immune modulation strategy is to ablate B-cells prior to the initial exposure of the study agent in one leg and the subsequent exposure of the same vector to the contralateral leg four months after initial dosing. The dosing of active agent is accompanied by a control injection of excipient dosing in the contralateral leg to allow for blinding and randomization of dosing, which may also strengthen the approach to gene therapy studies in the future. Patients will act as their own controls. Repeated measures, at baseline and during the 3 months following each injection, will assess the safety, biochemical, and functional impact of the vector.
47. Gene Transfer-Mediated Diversion Towards Non-Toxic Metabolites for Therapy of Primary Hyperoxaluria Type 1
Authors: Nicola Brunetti-Pierri, Raffaele Castello, Patrizia Annunziata, Roberta Borzone
Journal: Molecular Therapy (2016)

Primary hyperoxaluria type 1 (PH1) is an inborn error of liver metabolism due to mutations of the AGXT gene encoding the peroxisomal enzyme alanine: glyoxylate-aminotransferase (AGT) which catalyzes the conversion of glyoxylate to glycine. In PH1 patients, glyoxylate cannot be efficiently converted into glycine and is instead oxidized to oxalate resulting in systemic oxalosis with deposition of insoluble calcium oxalate in kidneys and in other tissues, leading to nephrolithiasis, nephrocalcinosis, kidney failure, and systemic tissue damage. Combined liver/kidney transplantation is the only therapeutic strategy available to prevent disease progression. We hypothesize that overexpression of specific genes encoding enzymes involved in glyoxalate metabolism will steer glyoxylate towards alternative pathways to diminish oxalate production. To test this hypothesis, we overexpressed murine glyoxylate reductase/hydroxypyruvate reductase (GRHPR), that converts glyoxylate into glycolate, by a helper-dependent adenoviral vector (HDAd-GRHPR) in livers of Agxt−/− mice. The intravenous injection of HDAd-GRHPR resulted in significant reduction of hyperoxaluria and concomitant increase of serum glycolate that was not associated with signs of toxicity. Glutamate-pyruvate transaminase (GPT) in the cytosol transaminate glyoxylate using glutamate and alanine as amino-group donors. We hypothesize that GPT overexpression will steer glyoxylate towards transamination to diminish oxalate production. The intravenous injection of a helper-dependent adenoviral vector expressing murine GPT (HDAd-GPT) in Agxt−/− mice also resulted in significant and sustained reduction of hyperoxaluria. Interestingly, co-administration of both HDAd-GRHPR and HDAd-GPT resulted in further reduction and normalization of hyperoxaluria. Glycolate is one of the substrates leading to glyoxylate production, via peroxisomal glycolate oxidase (GO). We also show that an HDAd expressing a short hairpin RNA against GO resulted in reduction of hyperoxaluria in Agxt−/− mice. In summary, the results of this study show that metabolic diversion towards non-toxic metabolites has potential for treatment of PH1 and potentially other forms of hyperoxalurias, both primary and secondary. The metabolic diversion could be also obtained by RNA-based molecules expressing GRHPR and/or GPT or inhibiting GO activity. In addition, this study shows that HDAd vectors can be used to functionally validate therapeutic enzyme targets in inherited metabolic diseases.
Abstract 4141: Hypoxia-induced transition from collective to amoeboid single cell dissemination in epithelial cancer cells
Authors: Steffi Lehmann, Veronika A M te Boekhorst, Julia Odenthal, Liying Jiang, Sjoerd van Helvert, Peter Friedl
Journal: Cancer Research (2015)

Abstract Tumor hypoxia, by elevating hypoxia-inducible factors (HIFs), is an established inducer of epithelial-to-mesenchymal transition (EMT) and subsequent cancer cell invasion and metastasis. Using epithelial carcinoma spheroids in 3D fibrillar collagen, we characterized the invasion patterns as well as cellular and molecular mechanisms of hypoxia-induced cancer cell migration modes. While epithelial cancer cells show collective invasion under normoxic conditions, hypoxia or pharmacological stabilization of HIF-1 using the prolyl hydroxylase inhibitor dimethyloxalylglycine (DMOG) induced EMT-like detachment and migration of single cells. Besides mesenchymal movement, most epithelial cells converted to amoeboid migration with characteristic actin-rich filopodal or distinctive blebby protrusions towards the direction of migration. Whereas mesenchymal migrating cells moved with low velocities in a directionally persistent manner, amoeboid migrating cells generated a broad spectrum of low to high velocities, but with less persistent invasion paths. Sub-cellular molecular analysis showed typical amoeboid features particularly in hypoxic blebby single cell migration, including low to lacking collagen degradation along the migration path and insensitivity to broad-spectrum matrix metalloproteinase (MMP)-inhibitor GM6001, non-focalized cortical actin cytoskeleton within blebs that interacted with collagen structures and low-beta1 integrin expression with lack of integrin focalization. Thus, tumor hypoxia induces a diversity of single-cancer cell invasion modes, including blebby amoeboid migration, thereby enhancing predominantly MMP- and integrin-independent amoeboid dissemination in parallel to EMT induction. Citation Format: Steffi Lehmann, Veronika A M te Boekhorst, Julia Odenthal, Liying Jiang, Sjoerd van Helvert, Peter Friedl. Hypoxia-induced transition from collective to amoeboid single cell dissemination in epithelial 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 4141. doi:10.1158/1538-7445.AM2015-4141
HIV-1 blocks the signaling adaptor MAVS to evade antiviral host defense after sensing of abortive HIV-1 RNA by the host helicase DDX3
Authors: Sonja I Gringhuis, Nina Hertoghs, Tanja M Kaptein, Esther M Zijlstra-Willems, Ramin Sarrami-Forooshani, Joris K Sprokholt, Nienke H van Teijlingen, Neeltje A Kootstra, Thijs Booiman, Karel A van Dort, Carla M S Ribeiro, Agata Drewniak, Teunis B H Geijtenbeek
Journal: Nature Immunology (2016)
Linker of Activation of T Cells – 2 (LAT2), a Lipid Raft-Associated Adaptor Protein, Is a Novel Target for Therapy in Acute Leukemia
Authors: Guilherme A dos Santos, Carolina H Thomé, Germano Aguiar Ferreira, Priscila S Scheucher, Antonio R Lucena-Araujo, Kleber T de Oliveira, Hamilton L. Gimenes-Teixeira, Pietro Ciancaglini, Roberto P. Falcao, Lewis J Greene, Faça M Vitor, Eduardo M. Rego
Journal: Blood (2011)
PWE-054 Treating hepatitis C in prisoners: is it worth it?: Abstract PWE-054
Authors: S Saksena, A Cook, M Hewett, D Jones, B Docherty
Journal: Gut (2010)

<h3>Introduction</h3> Due to a higher prevalence of intravenous drug use among offenders, prisons may have a higher prevalence of HCV than community, managing HCV and ensuring successful therapy may be more challenging in such settings.1 Durham has one of the largest prison populations in the UK. NICE endorsed therapy with pegylated interferon and ribavarin is recommended with reported rates of sustained viral response (SVR) of 75–85% with 6 months and 40–50% with 12 months therapy for genotypes 2/3 and 1, respectively.2 A new service was set up at University Hospital of North Durham in January 2008 to improve provision of HCV care within the NHS and the local prisons with a nurse led inreach service in prisons. <h3>Methods</h3> The aim of the study was to audit treatment outcomes of referrals to the HCV service in County Durham with current NICE guideline. Data were collected prospectively from January 08 using a computerised database. <h3>Results</h3> There were 120 referrals from January 3008 to September 2009; at time of abstract submission, follow-up data on SVR were available for those commenced on treatment between Jan to Dec 2008, data on these 59 HCV PCR positive patients including 47 prisoners are presented. 15 prisoners were unable to complete therapy as they were lost to follow-up following transfer/release from prisons in Durham. Reasons for not treating included patient refusal in 3 and DNAs of GP referrals and prisoners transferred elsewhere prior to start of therapy in 14 (Abstract 054). <h3>Conclusion</h3> Approximately three quarters of all HCV referrals were suitable for therapy; SVR of 100% and 86% were observed in those with genotype 2/3 and 1, respectively, who completed treatment, these outcomes are superior to those reported in NICE and were similar in prisoners and community referrals. There data suggest that while treatment outcomes for prisoners with HCV are similar to those treated in the community, the main obstacle in treating prisoners is ensuring therapy is completed as prisoners are lost to follow-up, in up to a quarter of cases due to transfers/ release. These findings indicate a need to improve the pathway for ensuring complete follow-up of this patient group.
Abstract 4360: Validation of phosphodiesterase 10A as a cancer target
Authors: Kevin Lee, Nan Li, Xi Chen, Bing Zhu, Larry Yet, Luciana Madeira da Silva, Suzanne Russo, Adam B. Keeton, Michael R. Boyd, Gary A. Piazza
Journal: Cancer Research (2015)

Abstract Phosphodiesterase 10A (PDE10) is a cAMP and cGMP degrading PDE isozyme that is highly expressed in the brain striatum where it plays an important role in cognition and psychomotor activity. PDE10 inhibitors are being developed for the treatment of schizophrenia and Huntington's disease and are generally well tolerated, likely because of low expression levels in peripheral tissues. We recently reported high levels of PDE10 in tumors and that genetic silencing by siRNA inhibits tumor cell growth with a high degree of selectivity over normal cells (Li et al., Oncogene 2014). These observations suggest that PDE10 may have an unrecognized role in tumorigenesis and represents a novel cancer target. To further test this possibility, we studied the effects of a highly specific PDE10 inhibitor, Pf-2545920 (MP-10) on colon tumor cell growth. Here we show that Pf-2545920 selectively inhibits tumor cell growth, causes G1 cell cycle arrest, and induces apoptosis. The concentration range by which Pf-2545920 inhibits tumor cell growth parallels the concentration range required to increase intracellular cyclic nucleotide levels and activate PKA and PKG. Moreover, PDE10 knockdown by siRNA reduces the sensitivity of tumor cells to the growth inhibitory activity of Pf-2545920. Using the crystal structure of PDE10 to design novel inhibitors, a series of compounds were synthesized and screened for tumor cell growth inhibitory activity and PDE10 isozyme specificity. A lead compound, ADT-030 was found to inhibit tumor cell growth and PDE10 enzymatic activity with IC50 values in the nanomolar range, but did not significantly affect the growth of normal cells. Unlike Pf-2545920, ADT-030 exhibits high selectivity for activating PKG signaling without affecting PKA signaling. Inhibitors of PKA and PKG were used to confirm that the tumor cell growth inhibitory activity associated with PDE10 inhibition involves PKG activation, while PKA activation appears to be ancillary. These findings serve to validate PDE10 as a cancer target, whereby novel inhibitors can be designed to specifically activate cGMP/PKG signaling with a high degree of tumor cell selectivity. Supported by NIH grants 1R01CA155638 and 1R01CA131378 (Piazza). Citation Format: Kevin Lee, Nan Li, Xi Chen, Bing Zhu, Larry Yet, Luciana Madeira da Silva, Suzanne Russo, Adam B. Keeton, Michael R. Boyd, Gary A. Piazza. Validation of phosphodiesterase 10A as a cancer target. [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 4360. doi:10.1158/1538-7445.AM2015-4360
Abstract 2225: c-Myc and Frizzled 8 play a major role in the regulation of cancer stem cells and drug resistance in triple-negative breast cancer
Authors: Shuping Yin, Vino T. Cheriyan, Arun K. Rishi, Kaladhar B. Reddy
Journal: Cancer Research (2015)

Abstract Triple-negative breast cancer (TNBC) studies have shown that neoadjuvant chemotherapy before surgery was effective in the minority of women, whereas the majority that had a residual tumor had a relatively poor outcome. We have previously shown that cisplatin plus TRAIL treatment was most effective compared to PARP -inhibitors, pacliotaxol, dacelotaxol or cisplatin alone in TNBC cells. To identify the mechanism by which residual cancer cells survive chemotherapy, we initially performed gene expression profiling using the CRL2335 and MDA-MB-468 TNBC cells before and after treatment with cisplatin plus TRAIL. Gene expression prolife revealed that cisplatin plus TRAIL significantly inhibited major signaling pathways related with cancer stem cells (CSCs) such as Notch, Hedgehog, TGFβ and most of the Wnt/β-catenin signaling when compared with untreated control group. However, residual cells after cisplatin plus TRAIL treatment showed a significant increase in the expression of Frizzled 8 (FZD8 -one of the Wnt receptors) and c-Myc. In vivo, animal studies indicate that cisplatin plus TRAIL treatments predominantly eliminated non-cancer stem cells (non-CSCs), as demonstrated by whole-body fluorescent imaging of mice injected with mammosphere-forming CRL2335 cells that were stably transfected with dsRed. This led to CSCs enrichment in residual tumors, as confirmed by immunostaining for CSC markers. Increase in FZD8 and c-Myc expression was also observed in residual tumors following treatment with cisplatin and TRAIL. In this study, we have found that c-Myc overexpression increased FZD8 expression, and its downstream signaling and together protect the cells from drug mediated cell death compared to vector transfected cells. c-Myc over-expressing cells do not show increased mammosphere formation; the numbers of CSCs per mammosphere are much higher compared to vector transfected controls. CDK inhibitor (dinaciclib) enhanced the cell death in c-Myc over expressing non-CSCs with minimal effect on CSCs. Inhibition of c-Myc using siRNA reduced c-Myc, FZD-8 and CSCs and enhanced sensitivity of cells to cisplatin plus TRAIL. Taken together, our findings suggest that c-Myc may play a major role in mediating CSC survival and resistance to chemotherapy, making it a potential target to enhance chemotherapeutic efficacy in patients with TNBC. Citation Format: Shuping Yin, Vino T. Cheriyan, Arun K. Rishi, Kaladhar B. Reddy. c-Myc and Frizzled 8 play a major role in the regulation of cancer stem cells and drug resistance in triple-negative breast 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 2225. doi:10.1158/1538-7445.AM2015-2225
Improved Tumor Uptake by Optimizing Liposome Based RES Blockade Strategy
Authors: Xiaolian Sun, Xuefeng Yan, Orit Jacobson, Wenjing Sun, Zhantong Wang, Xiao Tong, Yuqiong Xia, Daishun Ling, Xiaoyuan Chen
Journal: Theranostics (2016)

Minimizing the sequestration of nanomaterials (NMs) by the reticuloendothelial system (RES) can enhance the circulation time of NMs, and thus increase their tumor-specific accumulation. Liposomes are generally regarded as safe (GRAS) agents that can block the RES reversibly and temporarily. With the help of positron emission tomography (PET), we monitored the in vivo tissue distribution of 64Cu-labeled 40 × 10 nm gold nanorods (Au NRs) after pretreatment with liposomes. We systematically studied the effectiveness of liposome administration by comparing (1) differently charged liposomes; (2) different liposome doses; and (3) varying time intervals between liposome dose and NR dose. By pre-injecting 400 μmol/kg positively charged liposomes into mice 5 h before the Au NRs, the liver and spleen uptakes of Au NRs decreased by 30% and 53%, respectively. Significantly, U87MG tumor uptake of Au NRs increased from 11.5 ± 1.1 %ID/g to 16.1 ± 1.3 %ID/g at 27 h post-injection. Quantitative PET imaging is a valuable tool to understand the fate of NMs in vivo and cationic liposomal pretreatment is a viable approach to reduce RES clearance, prolong circulation, and improve tumor uptake.
The GATA-1 Cofactor FOG-1 Recruits NuRD to Promote Normal Erythroid and Megakaryocyte Development and Maintain Lineage Fidelity by Restricting Mast Cell Gene Expression.
Authors: Gregory D Gregory, Yuhuan Wang, Wei Hong, Annarita Miccio, Alexey Bersenev, Xiang Yu, Hongxin Wang, John Choi, Suresh Shelat, Wei Tong, Mortimer Poncz, Gerd Blobel
Journal: Blood (2008)
Abstract 5552: Medicinal plants show anticancer splicing activity of apoptotic genes
Authors: Zodwa Dlamini, David Bates
Journal: Cancer Research (2015)

Abstract Oncogenesis is associated with splicing switches and a disruption of splicing regulation being specific for cancer formation and tumour progression. An association between differential expression of splicing isoforms and tumour progression has been shown for several proteins, such as MDM2 and survivin. Currently the analysis of cancer-specific alternative splicing is a promising step forward in basic and translational molecular biology. Traditional medicine has a long history and is still the major source of medicine in developing countries. Approximately 70% of the South African population consults traditional healers, perpetuating the need for scientific appraisal of traditional medicine as a means to establish its efficiency and safety Also, pharmacological and phytochemical insights into several plants have led to the discovery of novel chemicals and therefore novel drugs. Alternatively, such novel chemical structures can serve as lead compounds/templates for the design of new drugs. The aim was to ascertain if the South African medicinal plants have anticancer splicing activity. 10c cells were treated with Tulbhaghia violacea and Cotyledon orbiculata, followed by mRNA extraction and RT-PCR. The results showed that Tulbhaghia violacea and Cotyledon orbiculata extracts have anti-cancer splicing activity on the BCLX and the AXL apoptosis genes. Additionally Cotyledon orbiculata extract has an anticancer splicing activity of the angiogenesis gene VEGF165. VEGF Elisa also confirmed the VEGF165 VEGF165b splicing switch. We have shown that South African medicinal plants have anti-cancer splicing activity. The anti-cancer splicing activity of the VEGF gene by Cotyledon orbiculata could mean that this extract has both angiostatic and apoptotic anti-cancer activities. We are continuing to screen more medicinal plants and will select those extracts with anti-cancer splicing activity for further studies. These further studies should identify numerous splicing pathways and completely elucidate the splicing target compounds that may serve as novel anti-cancer drugs or lead compounds. Note: This abstract was not presented at the meeting. Citation Format: Zodwa Dlamini, David Bates. Medicinal plants show anticancer splicing activity of apoptotic genes. [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 5552. doi:10.1158/1538-7445.AM2015-5552
619. AAV9 Transduction Is Similar in Adult and Aged Mouse Brains Following Intraparenchymal Injection
Authors: Sara E. Gombash, Julie A. Fitzgerald, Christopher J. Cowley, Mitchell G. Neides, Emily Armstrong, Diana M. Norden, Jonathan P. Godbout, Kevin D. Foust
Journal: Molecular Therapy (2016)

We previously reported that systemic injection of AAV9 in aged mice (P550) results in significantly fewer transduced CNS cells compared to adult mice (P49). This was not due to the presence of neutralizing antibodies in the aged mice. To determine whether aging in the brain and/or the periphery is responsible for this reduction, we quantified CNS transduction following stereotaxic brain injection in aged or adult mice. Aged male Balb/c mice (n = 6, P550) and adult mice (n = 7, P50) received direct injections into the striatum and ipsilateral hippocampus with scAAV9-CB expressing green fluorescent protein or scAAV9-CB expressing glial cell line derived neurotrophic factor (GFP or GDNF). All mice were euthanized three weeks post-injection. Brains of aged and adult mice injected with scAAV9-CB-GFP were sliced and processed for near-infrared imaging to quantify vector spread and GFP intensity. GFP expression was similar in directly injected aged and adult brains. Vector spread along the rostrocaudal axis was approximately 2 mm from either the striatal or hippocampal injection site and did not vary with age. Brains of mice directly injected with scAAV9-CB-GDNF were hemisected and processed for ELISA to quantify GDNF protein levels. GDNF levels in the striatum and hippocampus reached 2x those of uninjected controls and no differences in GDNF expression were detected between aged and adult injected mice. Together, we found that AAV9 CNS transduction is similar in aged and adult mouse brains following direct injection. These results suggest that reduced CNS transduction in aged mice following AAV9 systemic injection is due to alterations in the periphery. Future studies include investigation of altered viral blood brain barrier penetration and viral retention within peripheral tissues of aged mice.