tbuckley/cabot-search huggingface dataset:
Abstract 4148: Tankyrase inhibition impairs directional migration and invasion of lung cancer cells by affecting microtubule dynamics and polarity signals
Authors: Barbara Lupo, Jorge Vialard, Andrea Bertotti, Letizia Lanzetti, Livio Trusolino
Journal: Cancer Research (2015)

Abstract Tankyrases are poly(ADP)-ribose polymerases that contribute to biological processes as diverse as modulation of Wnt signaling, telomere maintenance, vesicle trafficking, and spindle pole assembly (1,2). Here we report a new function for tankyrases, namely, regulation of directional cell locomotion. Oriented migration is established by polarized reshaping of the microtubule network, which in turn is attained by phosphorylation-dependent inhibition of GSK3β at the leading edge, the ensuing association of APC with the plus end of microtubules at the cortex of cell membrane protrusions, and microtubule-based centrosome reorientation towards the migrating front (3,4). Using a panel of lung cancer cell lines as a model system, we found that pharmacologic abrogation of tankyrase activity by two different, structurally unrelated small-molecule inhibitors weakened cell migration, invasion and directional movement induced by the motogenic cytokine HGF. Mechanistically, the anti-invasive outcome of tankyrase inhibition could be ascribed to sequential deterioration of the distinct events that govern cell directional sensing. In particular, tankyrase blockade negatively impacted: i) microtubule dynamic instability; ii) HGF-triggered GSK3β phosphorylation; iii) APC plasma membrane targeting; iv) centrosome reorientation. Collectively, these findings uncover an unanticipated role for tankyrases in influencing at multiple levels the interphase dynamics of the microtubule network and the activity and localization of related polarity signals. In perspective, these results pave the way for challenging tankyrase inhibitors as therapeutic tools to oppose dissemination and metastasis of cancer cells. 1. Riffell JL, Lord CJ, Ashworth A. Tankyrase-targeted therapeutics: expanding opportunities in the PARP family. Nat Rev Drug Discov 2012;11(12):923-36. 2. Haikarainen T, Krauss S, Lehtio L. Tankyrases: structure, function and therapeutic implications in cancer. Curr Pharm Des 2014;20(41):6472-88. 3. Etienne-Manneville S. Microtubules in cell migration. Annu Rev Cell Dev Biol 2013;29:471-99. 4. Etienne-Manneville S. Polarity proteins in migration and invasion. Oncogene 2008;27(55):6970-80. Citation Format: Barbara Lupo, Jorge Vialard, Andrea Bertotti, Letizia Lanzetti, Livio Trusolino. Tankyrase inhibition impairs directional migration and invasion of lung cancer cells by affecting microtubule dynamics and polarity signals. [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 4148. doi:10.1158/1538-7445.AM2015-4148
Abstract 1630: Effects of rhBMP-2 on osteosarcoma tumorigenesis
Authors: Sajida Piperdi, David Geller, Amy Park, So Hak Chung, Richard Gorlick
Journal: Cancer Research (2015)

Abstract Introduction: Osteosarcoma (OS) is the most common primary bone malignancy in children and young adults. Complete surgical extirpation of bulk tumor is essential to successful treatment of OS. While historically ablative surgery such as amputations were the mainstay of treatment, wide excision has been shown to provide equivalent survival results, permitting for limb-salvage surgery in over 90% of cases. Following tumor resection, structural allograft bone is often employed to reconstruct the involved extremity. Bone Morphogenetic Protein-2 (BMP-2), a member of the TGF beta superfamily, possesses tremendous osteoinductive potential and could theoretically be used to promote bone healing but has been historically contraindicated due to concern it may stimulate residual tumor. To date, the role of BMP-2 in OS remains unclear and its effect on OS remains controversial. The purpose of this investigation is to evaluate the effect of exogenous recombinant human BMP-2 (rhBMP-2) on osteosarcoma. We hypothesize that exposure of osteosarcoma to rhBMP-2 will not stimulate tumor growth or development. Methods: Functional assays were performed using five standard osteosarcoma cell lines (143B, MG-63, SaOS-2, U20S, and HOS) and three patient derived xenograft cell lines (OS17, OS31, LM7). The concentration of rhBMP-2 utilized varied between 0.5 to 2 μg/ml. Motility (random migration) was measured by wound healing scratch assay. Migration (both haptotaxis and chemotaxis) was quantitatively measured using Boyden Chamber assay. Invasion was also measured using Boyden chamber over which a thin layer of extracellular matrix is applied. Comparison between different concentrations of rhBMP-2 upon different time points on osteosarcoma cell lines and characterizations are completed and underway. Results: Preliminary findings suggest that exogenous rhBMP-2 does not increase the ability of osteosarcoma cells to migrate and invade in all tested lines (143B, MG-63, OS17). Quantitative migration decreases with increasing concentration of rhBMP-2 over a 5-hour time course in all tested lines (143B, SaOS-2, MG-63, OS17). Invasion did not increase with increasing rhBMP-2 concentration in any tested line (143B, SaOS-2, OS17). Conclusions and Future Directions: Preliminary results support the contention that exposure of osteosarcoma to exogenous rhBMP-2 does not increase in vitro tumorigenesis. In fact, findings suggest that rhBMP-2 may have a protective effect in that tumor migration decreases following exposure. Continued characterization using additional tumor lines is ongoing. Citation Format: Sajida Piperdi, David Geller, Amy Park, So Hak Chung, Richard Gorlick. Effects of rhBMP-2 on osteosarcoma tumorigenesis. [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 1630. doi:10.1158/1538-7445.AM2015-1630
OC-091 Modernising the endoscopy workforce: the development of an endoscopy assistant role
Authors: J G Silcock, T A Powell
Journal: Gut (2010)

<h3>Introduction</h3> In order to meet the demands of the 2-week rule and to satisfy the 31 and 62-day cancer targets of the NHS Cancer Plan (2004), endoscopy units need to provide an effective, high quality and, above all, timely service. The rate limiting step in endoscopy service provision had been identified by the Healthcare Commission in 2005 as a shortage of suitably trained endoscopy nurses. It estimated 20% capacity lost nationally but local experience was nearer 30% (135/400 h per week of Qualified Nurse (QN) time lost through a combination of causes in Aug 2005). This led to list cancellations, often at short notice, to the detriment of patient care and waiting times while limiting staff opportunities for further career development such as specialist roles (IBD), nurse-led clinics (polyp surveillance) and improvement initiatives such as nurse-led consent and pre-assessment clinics. Within endoscopy, there are traditionally two levels of nurse support; QN and Health Care Assistants (HCAs). The latter while having developed their roles considerably to level 3 NVQ were unable to act up within the room and adopt some of the more advanced practices of the QN such as assisting with therapeutic procedures while the former could act down. We identified a need for service improvement and experienced HCAs in whom we saw potential for career development in support of the service. <h3>Methods</h3> 5 trainees (4WTE) were selected by interview (min requirement: NVQ 3 and 2 years endoscopy experience). We developed an in-house training programme and syllabus, agreed a Scope of Practice and a Clinical Governance framework with the support of our Trust Practice Development Team and funding from Aimhigher. We commissioned a module with Teesside University to address professional issues. A competency-based job description was mapped against the NHS Knowledge and Skills Framework (DOH 2005). In-house training and assessment was completed over 10 months and supported by a programme of tutorials, workshops and mentorship under supervision of nurse trainers. The university module took place over academic year 2008–2009. <h3>Results</h3> All five successfully completed in-service training, competency-based assessments and a Teesside University Certificate: Foundations in Endoscopic Practice (60 credits at level 1). In 6 months, they have assisted a QN in 60 complex procedures such as ERCP and also 55 acute upper GI bleeders at times when a second QN was unavailable. Our QNs now have the opportunity to develop their roles such as preassessment and nurse led clinics as envisaged. <h3>Conclusion</h3> This programme broadened the range of roles within the unit, with greater opportunity for career development at all levels and greater flexibility of working practices that has benefited the service and patient care.
Hemorrhagic myocardial infarction after reperfusion detected by X-ray CT. Experimental and clinical study.
Authors: Tsutomu Tamura, Takaaki Toyoki, Tomoko Ishikawa, Takashi Ogawa, Yasuro Ishikawa, Jun Odanaka, Keiichi Kusano, Yoichi Sugimura, Akihito Koizumi, Tomohide Sato, Hideo Miyashita, Yoshimichi Miyazawa, Yoshimasa Sakamoto, Hiroshi Asukochi
Journal: Circulation (1992)

The purpose of this study was to determine whether computed tomography (CT) can detect hemorrhagic infarction occuring after intracoronary thrombolytic theraphy (ICT) for acute myocardial infarction (AMI). In an experimental study, 12 dogs underwent 2-4 h of left anterior descending artery (LAD) occlusion, followed by reperfusion, and infusion of contrast material into the LAD. After CT examination, the heart was cut into transverse sections. A good correlation was obtained between the CT-enhanced area and the hemorrhagic area in the sliced heart section (r=0.895, p 0.1). The SPECT defect areas were consistently smaller than the CT enhancement areas. These results indicate that CT can detect hemorrhage into the myocardium after ICT, and that after ICT half the AMI patients showed hemorrhagic infarction. However, hemorrhage did not cause complete deterioration of the myocardium.
587. MiRNA-92a Is Involved in the Regulation of Adipose-Derived Stromal Cell (ADSC) Angiogenic Properties
Authors: Anastasia Yu Efimenko, Natalia I. Kalinina, Galina V. Klink, Evgeniy V. Gluhanyuk, Pavel I. Makarevich, Yelena V. Parfyonova, Vsevolod A. Tkachuk
Journal: Molecular Therapy (2015)

Reparative and regenerative processes after tissue damage are strongly dependent on successful restoration of vascular network. Mesenchymal stem/stromal cells (MSC) including ADSC located within the vessel wall and closely interacted with endothelial cells appear to be key regulators of angiogenesis and regeneration in adult tissues. Mechanisms of MSC ability to stimulate blood vessel growth and remodeling are extensively studying during last decades. microRNAs (miRs), small noncoding RNAs that regulate gene expression by binding to target mRNAs reducing their stability and/or inhibiting translation, play an important role in MSC regulation. It was demonstrated that miR-92a expressed in endothelial cells was induced in ischemia and involved in the regulation of angiogenesis and vessel patterning. We studied miR-92a impact in ADSC angiogenic properties regulation. ADSC were isolated from subcutaneous fat tissue of healthy young donors (n=4) and cultured up to 2-3 passages. ADSC phenotype characterized by flow cytometry was CD90+/CD73+/CD105+/CD45-/CD31- for all samples and these cells were capable of adipogenic and osteogenic differentiation. We analyzed miR profile in ADSC using Illumina microarrays and found that miR-92a was one of the highly expressed miRs in all ADSC samples. ADSC transfection by pre-miR-92a or anti-miR-92a led to the coordinated changes of miR-92a well-known target genes expression (integrin alpha 5, ITGA5, and mitogen activated protein kinase, MEK4). ADSC with over-expression of miR-92a completely lost the ability to stimulate capillary-like tube formation by endothelial cells (HUVEC) in vitro compared to ADSC transfected by the control gene. However, transfection of ADSC by anti-miR-92a did not significantly increase their stimulating effect in tube formation assay. As paracrine mechanisms are considered to be the most important for realizing of MSC angiogenic potential, we analyzed gene expression (qRT-PCR) and secretion (Bio-Plex assay and ELISA) of some key angiogenic factors in ADSC. We found that mRNA level of vascular endothelial growth factor (VEGF), angiogenin and leptin was slightly increased in ADSC transfected by anti-miR-92a and this tendency was also observed for VEGF secretion. When miR-92a was over-expressed in ADSC secretion of hepatocyte growth factor (HGF) and angiopoetin-1 by these cells significantly decreased compared to the control cells. We conclude that miR-92a might play an important role in the regulation of ADSC ability to stimulate angiogenesis and key angiogenic factors such as VEGF, HGF and angiopoetin-1 are involved in this process. The underlying mechanisms of miR-92a-mediated direct or indirect effects in ADSC need to be further investigated. Anyway, miR-92a could be considered as a promising target for the modulation of ADSC angiogenic potential.
Linking dietary patterns with gut microbial composition and function
Authors: Amy M. Sheflin, Christopher L. Melby, Franck Carbonero, Tiffany L. Weir
Journal: Gut Microbes (2016)

Emerging insights have implicated the gut microbiota as an important factor in the maintenance of human health. Although nutrition research has focused on how direct interactions between dietary components and host systems influence human health, it is becoming increasingly important to consider nutrient effects on the gut microbiome for a more complete picture. Understanding nutrient-host-microbiome interactions promises to reveal novel mechanisms of disease etiology and progression, offers new disease prevention strategies and therapeutic possibilities, and may mandate alternative criteria to evaluate the safety of food ingredients. Here we review the current literature on diet effects on the microbiome and the generation of microbial metabolites of dietary constituents that may influence human health. We conclude with a discussion of the relevance of these studies to nutrition and public health and summarize further research needs required to realize the potential of exploiting diet-microbiota interactions for improved health.
198. Adeno-Associated Viral Gene Therapy To Treat Niemann-Pick Disease, Type C1
Authors: Randy J. Chandler, Ian M. Williams, Arturo A. Incao, Forbes D. Porter, William J. Pavan, Charles P. Venditti
Journal: Molecular Therapy (2015)

Niemann-Pick disease, type C1 disease (NPC1) is a heritable lysosomal storage disease characterized by a progressive neurological degeneration that causes disability and premature death. NPC1 commonly manifests in childhood, and there are no approved treatments to delay, stop, or reverse the fatal neurodegeneration that is the hallmark of this disorder. New therapies for patients with NPC1 need to be developed. Defects in the NPC1 gene are the cause of this disease. A murine model of NPC1, Npcnih (also called BALB/(cNctr-Npc1m1N/J), arising from a spontaneous frame-shift mutation in the Npc1 gene has been described. Npcnih homozygotes (Npc1−/-) have an early, severe, and rapidly progressing disease, which is characterized by weight loss, ataxia, and lethality by 9 weeks of age. To test the potential efficacy of gene therapy with the goal of developing a new treatment for NPC patients, we constructed an adeno-associated virus (AAV) serotype 9 to deliver the human NPC1 gene under the transcriptional control of the neuronal-specific promoter, mouse calcium/calmodulin-dependent protein kinase II (CaMKII). Npc1−/- mice received 1×1012 GC of AAV9-CaMKII-NPC1 or an equivalent reporter control, AAV9-CaMKII-GFP, between 20 and 25 days of life delivered by retro-orbital injection. To achieve neuronal transduction, we relied upon the well-established property of AAV9 vectors to cross the blood-brain barrier and transduce neurons after systemic delivery. Relative to the untreated or AAV-GFP treated Npc1−/- mice (n=15, mean survival 66 days, SD=0.89), the Npc1−/- mice that received AAV9-CaMKII-NPC1 exhibited an increased life span (n=9, mean survival 105 days, SD=30; P<0.02) Although the AAV9-CaMKII-NPC1 treated Npc1−/- mice did not achieve a normal life expectancy or the same weight of wild-type mice, our results demonstrate, for the first time, the potential efficacy of systemic AAV gene therapy as a therapeutic option in patients with NPC1.
A Long-Term Follow-up Report on Autologous Hematopoetic Cell Transplant (AuHCT) for Patients with Hodgkin Lymphoma — Limited Utility of Post-Transplant Surveillance Computerized Axial Tomography (CAT scan) and/or PET Scan,
Authors: Henry C. Fung, Sunita Nathan, Neel B. Shah, John J. Maciejewski, Elizabeth Shima Rich, Jennifer Tornatta, Nancy Licciardi, Parameswaran Venugopal, Reem Karmali, Stephanie A. Gregory
Journal: Blood (2011)
Abstract 3652: Development of novel chemical inhibitors targeting the N-terminal domain (NTD) of androgen receptor variants as anti-prostate cancer agents
Authors: Jian Hui Wu
Journal: Cancer Research (2015)

Abstract The androgen receptor (AR) signaling is a driver of prostate cancer. Current therapeutic strategy for advanced prostate cancer is to suppress the AR signaling by androgen deprivation therapy (ADT) via castration and by antiandrogens to stop androgens from working. However, prostate cancer cells are very versatile in circumventing the ADT and reactivate the AR via multiple mechanisms, resulting in lethal castration-resistant prostate cancer (CRPC). An alarming problem is the emergence of AR variants that lack the ligand-binding domain (such as AR-V7) in CRPC patients, which are constitutively active without the need for androgens. Studies revealed that AR-v7 expression level was correlated with the risk of tumor recurrence after radical prostatectomy and was associated with short patient survival. In addition, mutations in full-length AR is another important mechanism of aberrant AR activation in CRPC cells. Recently, it was found that the F876L mutation is sufficient to confer enzalutamide resistance in cell lines and xenograft model. The AR F876L mutant is detected in CRPC patients treated with an enzalutamide analogue (ARN-509). The AR W741C mutant was detected in CRPC patient treated with bicalutamide and was found to be paradoxically activated by bicalutamide. In this project, we propose to develop novel AR inhibitors that target the AR N-terminal domain (NTD). The rationale for this has at least three fold: i) All of the FDA-approved antiandrogens are targeting the AR-LBD and thereby all of them are inactive against AR-v7; ii) All of the known mechanisms that could account for AR reactivation in CRPC cells are critically depending on the AR-NTD to reactivate AR; and iii) Among the NTD, DNA-binding domain (DBD) and LBD domains, the NTD is the most different domain between the AR and other members of steroid receptors. By a panel of in vitro assays, we have discovered a series of compounds that target the AR-NTD and potently inhibit all forms of the AR variants in our assays, including AR-V7, the wild-type and multiple clinically-relevant mutants of full-length ARs. Our inhibitors showed selectivity towards AR as they are inactive against the close homology proteins within the same steroid family (such as GR and PR). This project could lead to novel AR-NTD inhibitors as drug candidates for treating CRPC patients who have acquired resistance to AR-LBD-directed therapies, such as enzalutamide and abiraterone. Citation Format: Jian Hui Wu. Development of novel chemical inhibitors targeting the N-terminal domain (NTD) of androgen receptor variants as anti-prostate cancer agents. [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 3652. doi:10.1158/1538-7445.AM2015-3652
A Two Step Nonmyeloablative Allogeneic Transplantation Protocol Using In Vitro T-Cell Depleted Mobilized Stem Cells Followed by Donor Lymphocyte Infusions in Patients with Advanced CLL.
Authors: Renee M.Y. Barge, Mels Hoogendoorn, Erik W.A. Marijt, Floor Beaumont, Ingrid Starrenburg, Willem Smit, Ward Posthuma, Willem E. Fibbe, Frederik Falkenburg, Roelof Willemze
Journal: Blood (2005)
195. Comparative Analysis In Vitro of Regulatory Elements That Drive Targeted Gene Expression in Adenovirus-Associated Viral (AAV) Vectors
Authors: Pengcheng Zhou, Yanqun Shu, Dinah W.Y. Sah, Jay Hou
Journal: Molecular Therapy (2015)

Adeno-associated viral (AAV) vectors are a platform with great potential for therapeutic gene delivery. For neurodegenerative disorders such as Friedreich's ataxia, identifying a gene therapy candidate that provides clinically relevant expression of the therapeutic transgene is critical. Friedreich's ataxia is caused by the decreased expression of the mitochondria matrix protein frataxin (FXN) due to mutations in the frataxin gene. Elevation of FXN protein in the nervous system is an approach that is likely to be beneficial in addressing the neurological components of this devastating disease. However, the properties of regulatory elements that drive exogenous gene expression from AAV vectors have not been well characterized. In this study, a set of AAV vectors were generated with various combinations of different regulatory elements directing the expression of the human frataxin gene. These regulatory elements included the canonical Kozak sequence, mitochondria targeting sequences, simian virus 40 (SV40) intron, AAV inverted internal repeat (ITR), and constitutive promoters such as cytomegalovirus (CMV), chicken b-actin (CBA), human frataxin, human phosphoglycerate kinase-1 (PGK), human synapsin and human elongation factor 1α (EF-1α) promoters. For comparison in vitro, these AAV constructs were introduced into three types of human cells and primary rat DRG neurons by co-transfection with a GFP expression construct which was used as an internal control. FXN and GFP protein expression were quantitatively measured by ELISA and the relative level of FXN expression calculated by normalizing to the level of GFP in each condition. These studies demonstrated that the CMV promoter is the most potent in driving FXN expression followed by the CBA promoter. Much lower FXN expression levels were observed when the endogenous frataxin or PGK promoter was used. The canonical Kozak sequence, the SV40 intron alone and different mitochondria targeting sequences had no significant impact on FXN expression. In addition, we evaluated the effect of different optimized human codons within the frataxin transgene on FXN expression level in the context of the CBA promoter and SV40 intron. Our results demonstrated that several of these codon-optimized frataxin genes consistently increased the expression of FXN protein at least 2-fold compared to the wild type frataxin gene. Together, these results provide important information for guiding the selection and optimization of regulatory elements and codons for an AAV gene therapy for Friedreich's ataxia.
Isolated Extra-Medullary Relapse of Acute Leukemia after Allogeneic Stem-Cell Transplantation; Different Kinetics and Better Prognosis Than Systemic Relapse.
Authors: Avichai Shimoni, Avital Rand, Izhar Hardan, Noga Shem-Tov, Etai Zilbershatz, Ronit Yerushalmi, Arnon Nagler
Journal: Blood (2008)