tbuckley/cabot-search huggingface dataset:
616. Disc Gene Therapy: Development of a Novel Inducible System To Regulate Expression of the Therapeutic Transgene TIMP1
Authors: Zhihua Ouyang, Yingchao Han, Adam H. Richman, Qing Dong, Wan Huang, Ying Tang, Bing Wang, Nam Vo, Gwendolyn Sowa, James D. Kamg
Journal: Molecular Therapy (2015)

Introduction: Gene therapy using the anti-catabolic factor Tissue Inhibitor of Metalloproteinase-1 (hTIMP1) has shown promising efficacy in treating disc degeneration. However, a major limitation of the current gene therapy technique is the use of a constitutive promoter to drive transgene expression that results in uncontrolled and excessive expression of therapeutic gene product which could result in undesirable side effects. To overcome this important limitation, we successfully developed a new gene therapy recombinant adeno-associated viral (rAAV)vector, rAAV-NFkB-hTIMP1, in which the therapeutic recombinant human TIMP1 gene is placed under the control of a promoter containing the NF-kB element. The rAAV-NFkB-hTIMP1 construct is designed to produce the therapeutic gene product TIMP1 only when the cells experience stress which activates the NF-kB pathway. Hence we expect using this strategy that hTIMP1 will be selectively expressed in cells under inflammatory conditions typically found in active degenerating discs and not under normal conditions, in which the therapeutic gene was not needed. In this study we tested our hypothesis that rabbit annulus fibrosus cells transfected with aserotype 2 of rAAV vector carrying a hTIMP1 gene will not express high level of hTIMP1 unless stimulated with the IL-1b. Methods: Cultured rabbit annulus fibrosus (rAF) cells were divided into six groups; "Control" (cell only); "rAAV-CMV-hTIMP1(cells transfected with AAV-CMV-hTIMP1 plasmid DNA)" and "rAAV-NFkB-hTIMP1(cells transfected with AAV-NFkB-hTIMP1 plasmid DNA)" treated with and without IL-1b (n=4 for each group). Production of hTIMP1 was determined by RT-PCR. To determine if MMP activity was inhibited by the produced TIMP1, MMP activity assay was measured by following cleavage of a fluorogenic substrate. Results: RT-PCR analysis demonstrated that the level of hTIMP1 transcription from cells and culture media transfected with rAAV-NFkB-hTIMP1 construct was greater than in the IL-1b stimulated condition compared to unstimulated control. The result shows that the level of MMP activity was decreased compared to baseline levels or cells exposed to IL-1. Discussion: The RT-PCR result showed cells transfected with AAV-NFkB-hTIMP1 plasmid DNA had significant increase in the hTIMP-1 mRNA expression after stimulation with IL-1b. These results demonstrate the novelty of this strategy in which the NF-kB element containing promoter ensures that the transgene hTIMP1 is expressed highly only under conditions of inflammation typically found in injured and degenerating discs which would act to block MMP-mediated matrix proteolytic destruction. Low levels of hTIMP1 were also observed under unstimulated conditions and the bioenergetic consequences of the cell are unclear.
Antisense Long Non-Coding RNA in the LEF1 Locus Regulates Sense LEF1 Expression in Leukemic Cell Line KG1
Authors: Ada Congrains, João Agostinho Machado-Neto, Flávia Adolfo Corrocher, Renata Giardini Rosa, Fernanda Soares Niemann, Sara Teresinha Olalla Saad
Journal: Blood (2015)
The human thymus perivascular space is a functional niche for viral-specific plasma cells
Authors: Sarah Nuñez, Carolina Moore, Baoshan Gao, Kortney Rogers, Yessia Hidalgo, Pedro J. del Nido, Susan Restaino, Yoshifumi Naka, Govind Bhagat, Joren C. Madsen, María Rosa Bono, Emmanuel Zorn
Journal: Science Immunology (2016)

The human thymus is susceptible to viral infections that can severely alter thymopoiesis and compromise the mechanisms of acquired tolerance to self-antigens. In humans, plasma cells residing primarily in the bone marrow confer long-lasting protection to common viruses by secreting antigen-specific antibodies. Since the thymus also houses B cells, we examined the phenotypic complexity of these thymic resident cells and their possible protective role against viral infections. Using tissue specimens collected from subjects ranging in age from 5 days to 71 years, we found that starting during the first year of life, CD138+ plasma cells (PC) begin accumulating in the thymic perivascular space (PVS) where they constitutively produce IgG without the need for additional stimulation. These, thymic PC secrete almost exclusively IgG1 and IgG3, the two main complement-fixing effector IgG subclasses. Moreover, using antigen-specific ELISpot assays, we demonstrated that thymic PC include a high frequency of cells reactive to common viral proteins. Our study reveals an unrecognized role of the PVS as a functional niche for viral-specific PCs. The PVS is located between the thymic epithelial areas and the circulation. PCs located in this compartment may therefore provide internal protection against pathogen infections and preserve the integrity and function of the organ.
Abstract 4389: Liposomes containing piperazine compounds inhibit tumor growth in a patient-derived xenograft model of glioblastoma multiforme
Authors: Elden P. Swindell, Andrey Ugolkov, Christian Freguia, Oleksii Dubrovskyi, Patrick L. Hankins, Jeong Yang, Jeffrey J. Raizer, James P. Chandler, Charles David James, Andrew P. Mazar, Thomas V. O'Halloran
Journal: Cancer Research (2015)

Abstract Glioblastoma multiforme (GBM) is fatal in nearly all instances, and responds poorly to current standards of care. GBMs exhibit resistance to chemotherapy which leads to tumor recurrence following initial surgical debulking. We have recently developed an 80 nm liposome containing a novel hydrophobic microtubule disrupting piperazine. This novel nanostructure, called IM-1 nanobin, contains 500-1000 piperazine drug molecules encapsulated in the hydrophobic inner leaflet of the lipid bilayer in each liposome. This nanoparticle inhibited the proliferation of GBM cells in vitro, although its cytotoxicity was reduced (3-5 fold) compared to free drug dissolved in DMSO. Results from FACS analysis showed that sub-micromolar concentrations of IM-1 caused G2/M phase cell cycle arrest and apoptosis of U87 GBM cells, as well as early passage GBM cells derived from a patient-derived xenograft (PDX). In collaboration with the Northwestern Brain Tumor Institute, we have established a panel of PDX. Since these tumors are not propagated in culture, they preserve the mixture of tumor cells and stroma critical for conducting meaningful therapy response experiments. IM-1 was evaluated in GBM PDX propagated in subcutaneous and intracranial compartments. In mice bearing subcutaneous PDX tumors, IM-1 treatment delayed the growth of the tumors compared to free drug alone; orthotopic GBM PDX studies are ongoing. Our results show that a novel liposome encapsulated piperazine, IM-1, is a promising new nanostructure for development as a therapeutic for treating patients with GBM. Citation Format: Elden P. Swindell, Andrey Ugolkov, Christian Freguia, Oleksii Dubrovskyi, Patrick L. Hankins, Jeong Yang, Jeffrey J. Raizer, James P. Chandler, Charles David James, Andrew P. Mazar, Thomas V. O'Halloran. Liposomes containing piperazine compounds inhibit tumor growth in a patient-derived xenograft model of glioblastoma multiforme. [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 4389. doi:10.1158/1538-7445.AM2015-4389
Abstract 4993: β-arrestin-2 regulates CXCR7-mediated EGFR transactivation and tumor cell proliferation in prostate cancer cells
Authors: Georgios Kallifatidis, Daniel Munoz, Rajendra K. Singh, Bal L. Lokeshwar
Journal: Cancer Research (2015)

Abstract We have previously shown that the chemokine receptor CXCR7 trans-activates the epidermal growth factor receptor (EGFR) and is implicated in prostate tumor growth. However, the molecular mechanisms of CXCR7 mediated EGFR-trans-activation are not known. In the present work we show that CXCR7 induced EGFR transactivation is independent of EGF-like ligands such as amphiregulin and heparin-bound EGF. Importantly, treatment with pertussis toxin, a known G-protein inhibitor, had no effect on EGFR phosphorylation, indicating that G-protein signaling was not involved in CXCR7 mediated EGFR transactivation. Since CXCR7 is known to signal through β-arrestin-2 in its ligand dependent manner, we evaluated the role of β-arrestin-2 in CXCR7 induced EGFR trans-activation in prostate cancer cells. We used shRNA to stably down regulate β-arrestin-2 in LNCaP cells to evaluate the role of β-arrestin-2 in CXCR7 mediated induction of EGFR and downstream mitogenic signaling such as ERK1/2 and the phosphoinositide 3-kinase/Akt pathway. Interestingly, down regulation of β-arrestin-2 significantly induced phosphorylation of EGFR at Y1110 and Y1068 along with the phosphorylation/activation of ERK and AKT and an induction of proliferation/colony formation in prostate tumor cells. Moreover, shRNA mediated down regulation of β-arrestin-2 resulted in a decrease of p21 which is in accordance with the observed increased proliferation rate. The results of our study suggest that β-arrestin-2 is crucial negative regulator of CXCR7/EGFR signaling and underscore the importance of β-arrestin-2 in regulation of CXCR7/EGFR mediated tumor cell proliferation. Citation Format: Georgios Kallifatidis, Daniel Munoz, Rajendra K. Singh, Bal L. Lokeshwar. β-arrestin-2 regulates CXCR7-mediated EGFR transactivation and tumor cell proliferation in prostate 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 4993. doi:10.1158/1538-7445.AM2015-4993
Myocardial Injury, Obesity, and the Obesity Paradox
Authors: Yashashwi Pokharel, Wensheng Sun, Salim S. Virani, Vijay Nambi, Ron C. Hoogeveen, Patricia P. Chang, Chiadi E. Ndumele, Scott D. Solomon, Biykem Bozkurt, Elizabeth Selvin, Christie M. Ballantyne, Anita Deswal
Journal: JACC Heart Failure (2016)
230. Designing High-Titer Lentiviral Vectors for Gene Therapy of Sickle-Cell Disease
Authors: Fabrizia Urbinati, Valentina Poletti, Beatriz Campo Fernandez, Roger P. Hollis, Colin Koziol, Michael L. Kaufman, Devin Brown, Annarita Miccio, Michael Antoniou, Donald B. Kohn, Fulvio Mavilio
Journal: Molecular Therapy (2016)

Sickle cell disease (SCD, OMIM 603903) is one the most common inherited blood disorders worldwide, caused by a single amino acid substitution (E6V) in the β-globin chain. SCD is associated with abnormal red cell morphology, hemolytic anemia, vascular occlusion, severe pain, progressive organ damage and reduced life expectancy. Gene therapy by transplantation of autologous, genetically corrected hematopoietic stem cells could be a therapeutic alternative, particularly in patients lacking an allogeneic bone marrow donor. Recent attempts to treat β-thalassemia and SCD with gene therapy showed encouraging results as well as potential limits of a technology based on complex lentiviral vectors for stem cell transduction due to the vector size and complexity, and limited globin synthesis. Designing an efficient vector that combines high-level globin expression with high titer and infectivity remains a formidable challenge. The GLOBE vector carries a β-globin gene under the control of its promoter and a reduced version of the β-globin locus control region (LCR); it was designed to reduce the size and complexity of the LCR while maintaining its enhancer and chromatin opening activity (Miccio et al., PNAS 2008). Based on the GLOBE design, we developed novel LVs for SCD gene therapy, carrying a modified transgene encoding an anti-sickling β-globin gene with 3 amino acid substitutions (AS3), alternative β-globin promoters and a short sequence (FB) with insulating and enhancer-blocking activity in the LTR. The vectors are produced at high titer and reproducibly transduce 60-70% of human BM CD34+ cell-derived clonogenic progenitors at an average VCN of 3. The GLOBE vectors were compared to the Lenti/βAS3-FB vector (Romero, Urbinati et al. JCI 2013), previously developed for a gene therapy clinical trial of SCD. We will present data comparing the different vectors for transduction efficiency in BM CD34+ cells from healthy donors and SCD patients, βAS3-globin transgene expression and anti-sickling activity, in vivo repopulation activity in NSG mice and vector integration profiles in repopulating cells before and after transplantation. This study provides a comprehensive analysis of different LV vectors, useful to determine the optimal candidate for gene therapy of SCD that can provide high transduction of Hematopoietic Stem and Progenitor Cells (HSPCs) as well as maintaining an adequate expression of the anti-sickling globin gene.
Donor lymphocyte infusion for relapsed chronic myelogenous leukemia : The first dose decides outcome.
Authors: C Guglielmi, W Arcese, F Dazzi, D Bunjes, LF Verdonck, A Schattenberg, HJ Kolb, P Ljungman, A Devergie, A Bacigalupo, M Gomez, M Michallet, A Elmaagacli, A Gratwohl, J Apperley, D Niederwieser
Journal: Blood (2001)
Abstract 4992: Nicotinic acetylcholine receptor α5 mediates low-dose nicotine-dependent regulation of tumorigenesis in lung adenocarcinoma cells
Authors: Mong-Lien Lotus Wang, Yi-Fan Hsu, Chih-Hsuan Liu, Cheng-Wen Wu
Journal: Cancer Research (2015)

Abstract The concept that lung adenocarcinoma is less related to smoking behavior than lung squamous cell carcinoma may be due to the fact that a considerable number of LAC patients do not have smoking habit. However, this argument may mislead the effect of tobacco smoke on LAC because it ignores the potential effects of environmental smoking that cause second hand smoking in non-smokers. In Taiwan, 70% of female LAC patients would encounter heavy smokers either at home or in working place, suggesting that environmental smoke may have substantial effects than we thought. Transcriptional deregulation at the chromosome 15q25 locus revealed an association between the gene encoding CHRNA5 with lung adenocarcinoma risk. It has been showed that overexpression of the genes encoded in this locus in mice increased the sensitivity to nicotine. In this report, we found that nAChR α5, but neither nAChR α7 or nAChR α9 that have been respectively shown to mediate tumorigenic alterations in lung SCC and breast cancer cells, was differentially expressed between tumor and non-tumor specimens of LAC patient specimens. Knockdown of nAChR α5 in LAC cell lines resulted in decreased cell proliferation rate as well as cell migrating and invasive capabilities. In these nAChR α5-knockdown cells, low dose (10 nM) nicotine was not able to significantly increase cell proliferation and motility, while low dose nicotine enhanced both abilities of cells when nAChR α5 expressed. Colony formation assay indicated that nAChR α5 maintained cell survival and prevent contact inhibition in LAC cells when encountering low serum stress condition. Through molecular analysis, we showed that nAChR α5 positively regulates epithelial-mesenchymal transition factors such as Snail and Slug, and negatively regulates E-cadherin. Animal experiment showed a severely suppressed tumor growth in mice transplanted with LAC cells with nAChR α5 being knocked down, in comparison to mice transplanted with parental cells. These data demonstrated a crucial role of nAChR α5 in low-dose nicotine-dependent regulation of tumorigenesis in LAC. It is, for the first time, a study of mechanism in response to low dose nicotine that implies the regulatory pathway underlying the effect of environmental nicotine. Citation Format: Mong-Lien Lotus Wang, Yi-Fan Hsu, Chih-Hsuan Liu, Cheng-Wen Wu. Nicotinic acetylcholine receptor α5 mediates low-dose nicotine-dependent regulation of tumorigenesis in lung adenocarcinoma 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 4992. doi:10.1158/1538-7445.AM2015-4992
Abstract LB-267: Role of VEGFR-1 signaling in obesity-induced tumor progression
Authors: Joao Incio, Joshua Tam, Nuh Rahbari, Priya Suboj, Daniel McManus, Shan Chin, Trupti Vardan-Kaur, Ana Batista, Suboj Babycutty, Keehoon Jung, Anna Khachatryan, Masabumi Shibuya, Raquel Soares, Dan Duda, Rakesh K. Jain, Dai Fukumura
Journal: Cancer Research (2015)

Abstract Background: Obesity associates with angiogenesis and increased macrophage infiltration in adipose tissues during weight gain. Whether these effects also occur in cancer to promote tumor progression in obese condition remains unclear. We have shown that the vascular endothelial growth factor receptor-1 (VEGFR-1) pathway can modulate tumor angiogenesis and recruitment of tumor-associated macrophages (TAMs). Here, we tested the emerging hypothesis that obesity enhances tumor progression and metastasis by augmenting angiogenesis and TAM recruitment via activation of the VEGFR-1 pathway. Methods: We used a high-fat diet-induced obesity model in either wild type (WT) or VEGFR-1 tyrosine kinase null (Flt1TK-/-) C57BL/6 mice. Then, we implanted orthotopically syngeneic pancreatic (PAN02) or breast (E0771) carcinomas. We evaluated the role of VEGFR-1 activity on systemic metabolism, tumor angiogenesis and immune environment, and tumor growth and metastasis. Results: Obesity increased p38-MAPK activation and TAM infiltration, tumor growth (p = 0.001) and metastasis (p = 0.035) in PAN02 tumors. VEGFR-1 inhibition reduced tumor growth (p = 0.007) and metastasis (p = 0.017) in obese but not lean mice. This was associated with a decreased p38-MAPK activity and a shift in TAM polarization towards the M1 phenotype with reduced secretion of pro-tumor cytokines, but no change in vascular density or number of TAMs. In the E0771 model, VEGFR-1 inhibition reduced MMP-9 expression and decreased lung metastatic burden (p = 0.026) in obese mice. In addition to these tumor effects, VEGFR-1 inhibition reduced weight gain, but caused metabolic disorder-hyperinsulinemia-during obesity. Combining metformin with VEGFR-1 inhibition not only prevented this metabolic alteration, but also by recruiting cytotoxic cells further decreased tumor growth in the PAN02 model (p = 0.047). Conclusion: Inactivation of VEGFR-1 signaling prevents weight gain and obesity-induced acceleration of tumor progression in pancreatic and breast cancer models. Targeting VEGFR-1 signaling axis in combination with an anti-diabetic drug such as metformin might be a considerable cancer therapeutic option in the obese setting. Note: This abstract was not presented at the meeting. Citation Format: Joao Incio, Joshua Tam, Nuh Rahbari, Priya Suboj, Daniel McManus, Shan Chin, Trupti Vardan-Kaur, Ana Batista, Suboj Babycutty, Keehoon Jung, Anna Khachatryan, Masabumi Shibuya, Raquel Soares, Dan Duda, Rakesh K. Jain, Dai Fukumura. Role of VEGFR-1 signaling in obesity-induced tumor progression. [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-267. doi:10.1158/1538-7445.AM2015-LB-267
720. Data-Driven Development to Deployment of Recombinagenic to Reprogramming Drives
Authors: Faisal Reza
Journal: Molecular Therapy (2016)

We consider an approach to addressing health and well-being disparities on large scales by the development and deployment of recombinagenic and reprogramming drives. Among these are, for example, "gene drives" which "drive" themselves and proximally involved genetic elements through space, i.e. (sub)populations of individuals, and time, i.e. successive generations of these (sub) populations. In doing so, they can be engineered to propagate through (sub)populations despite reducing individual fitness, since most all offspring harboring drives are affected through inheritance, rather than fractional numbers of progeny. Fitness costs are thus compensated by this inheritance advantage. This, too, has spatial, e.g. ecological, as well as temporal, e.g. evolutionary, consequences for the (sub) populations being driven, as well as the network of interactions among the (sub)populations and the shared living environment. We analyze and extend the data in our research and that of others to present technically possible types of drives, and the epidemiological contexts in which they can be applied to recombine genetic components and reprogram cellular chasses. Transient behavior during these modifications can give way to new equilibria in which, for example, disease transmission is mitigated, or disease resistance is bolstered, thus ultimately benefiting human health and agricultural well-being, respectively. We combine the aforementioned and conclude with the technological and environmentally amenable consequences of drives as applied to contexts. As a powerful synthetic technology operating in the living world as intimately and broadly as natural evolutionary drives, potential unintended and off-targeting issues as well as safeguards and optimization of the development to deployment of drives are discussed. Simultaneously, as a technology dependent on its successful interplay with the environment, natural and man-made, drives are limited in their applicability due to their own inherent requirements, e.g. suitable for mating organisms, and brief generational timespans, as well as those external to them, e.g. ethics and safety for the target for the drive and others in the ecosystem, and immediate and long-term effects on other interactions in the network.
Protamine nanocapsules as carriers for oral peptide delivery
Authors: Lungile Nomcebo Thwala, Diego Pan Delgado, Kevin Leone, Ilaria Marigo, Federico Benetti, Miguel Chenlo, Clara V. Alvarez, Sulay Tovar, Carlos Dieguez, Noemi Stefania Csaba, Maria Jose Alonso
Journal: Journal of Controlled Release (2018)
PO60USE OF DSC-MRI IN DIFFERENTIATING BETWEEN TRUE AND PSEUDO-PROGRESSION IN PATIENTS WITH GLIOBLASTOMA
Authors: S. B. Withey, N.P. Davies, R.B. Flintham, J. Herbert, P. Sanghera, G. Cruickshank, V. Sawlani
Journal: Neuro-Oncology (2015)

INTRODUCTION: MRI is used routinely to assess response to chemo-radiotherapy for glioblastoma (GBM). However, distinguishing between treatment effects and disease progression using published criteria based on contrast-enhancement on T1-weighted images is difficult. The phenomenon of pseudo-progression (psP) mimicking true progression (tP) is well known in this context. Early accurate diagnosis of tP versus psP is essential to optimise treatment strategies and improve outcome. This pilot study aims to evaluate the use of dynamic susceptibility (DSC-) MRI for differentiating between tP and psP by measuring cerebral blood volume (CBV). METHOD: Data were analysed from 5 patients who underwent MRI scans on a Siemens 3T scanner, including DSC-MRI (temporal resolution 2.1 s; injection of 0.1 mmol/kg Gadovist at 6 ml/s) and post-contrast T1-weighted scans at short intervals following surgery and chemo-radiotherapy for GBM. CE marked software (Olea Sphere) was used to obtain CBV maps with correction for T1 effects. Regions of interest were defined to calculate rCBV, the ratio of CBV in the lesion to that in normal contralateral tissue. RESULTS: Maximum rCBV varied widely across patients (mean ± standard deviation: 2.7 ± 2.0). Using a threshold of 1.8 from the literature 2 patients had hypo-perfused lesions suggesting psP and 3 patients had hyper-perfused lesions indicating tP. These findings will be correlated with follow-up scans and clinical data. CONCLUSION: This study confirms feasibility of measuring rCBV in patients undergoing treatment for GBM within a clinical workflow. Follow-up analysis will test the hypothesis that values of rCBV greater than 1.8 are indicative of tP.