tbuckley/cabot-search huggingface dataset:
614. Delivery of Micro-RNA Loaded Plasmid Through Nanoparticles Efficiently Modulate Transforming Growth Factor-Beta1 Expression in Healing Flexor Tendons: An In Vitro and In Vivo Study
Authors: You Lang Zhou, Changlai Zhu, Lu Zhong Zhang, Ya Fang Wu, Xiao Tian Wang, Paul Y. Liu, Jin Bo Tang
Journal: Molecular Therapy (2015)

Aims: Formation of adhesion around the healing tendon is a major cause of poor function of the extremities. Adhesions developed around healing digital flexor tendons are extremely harmful to active hand movement, and modulating its gene expression may be a promising approach to prevent adhesion formations. Because transforming growth factor (TGF)-beta1 is highly expressed in the adhesion tissues and is considered responsible for adhesion and scar formation, we propose to deliver micro-RNAs (miRNAs) to down-regulate expression of this key gene in order to prevent adhesions in the healing digital flexor tendon. Methods: Nanoparticles made of polylactic-co-glycolic acid were prepared and were then incorporated with plasmids expressing enhanced green fluorescence protein and miRNAs for inhibiting the transforming growth factor-beta1 gene expression. The cultured tenocytes from chicken toes were used to test efficiency of transfection of the cells by plasmid released from nanoparticles. Then 30 long toes from bilateral feet of 15 chickens were used because of their structural similarity to human digital flexor tendons. The toes were divided into 6 groups (5 tendons per group) according to injected nanoparticles and timing of harvesting samples after surgery. The 6 groups were 2-, 4- and 6-weeks after nanoparticle-plasmid (mock miRNA)-injected groups and 2-, 4- and 6-week nanoparticle-plasmid (miRNA TGF-beta1)-injected groups. Expression levels of TGF-beta1 in the tendons in different groups were evaluated with Western blotting. Tendon healing status was also evaluated. Results: In the in vitro setting, the tenocytes could be effectively transfected by the nanoparticle-plasmid complex. The expression of TGF-beta1 is significantly down-regulated in healing chicken flexor tendon treated with nanoparticle-plasmid at all three time-points after surgery (p < 0.05 or p < 0.01). Histology analysis did not demonstrate any significant inflammation or necrosis in tendons injected with nanoparticle-plasmid after surgery. The tendon healing status was not affected by use of nanoparticle-plasmid. Conclusions: Delivery of micro-RNA loaded plasmid through nanoparticles is a promising gene therapy of the injured digital flexor tendon. Our results show that this approach is a non-viral delivery method, and can efficiently modulate genes associated with adhesion formation, which may be a promising method to limit adhesion formations.
Abstract 4632: Poor survival associated with NUAK1 overexpression in serous ovarian cancer may be explained by chemotherapy resistance
Authors: Neil T. Phippen, Nicholas W. Bateman, Guisong Wang, Chad A. Hamilton, George L. Maxwell, Kathleen M. Darcy, Thomas P. Conrads
Journal: Cancer Research (2015)

Abstract Objectives: The purpose of this study was to identify and validate novel gene transcripts associated with poor prognosis ovarian cancer. Methods: Clinical, pathologic, outcomes and transcriptomics data for 22,277 probesets were downloaded for each of 1,183 eligible patients representing six datasets. Cohorts 1 (n = 638) and 2 (n = 545) were used for discovery and validation, respectively. Associations with survival were evaluated using univariate Cox modeling with Wald test and Kaplan-Meier method with log rank test. Odds ratios were evaluated using the Mantel-Haenszel test. NUAK1 expression in ovarian cancer cell lines was examined using immunoblotting. Results: There were 293 (1.3%) probesets whose expression was associated with survival in serous ovarian cancer patients in cohort 1 that passed false discovery correction, and 19 of these, including NUAK1, validated in cohort 2 (q&amp;lt;0.05). Women with high versus low transcript expression of NUAK1 had worse survival (hazard ratio = 1.4, 95% confidence interval = 1.2-1.64) and increased odds of being diagnosed at advanced age with late stage disease in addition to experiencing suboptimal debulking and earlier disease progression. Higher levels of NUAK1 protein were observed in a panel of chemoresistant versus chemosensitive ovarian cancer cells lines. Conclusions: Overexpression of NUAK1, also known as AMPK-related protein kinase 5 (ARK5) and a survival factor in nutrient starved cells with low oxygen tension, was identified and validated to predict poor prognosis in a cohort of 1,183 serous ovarian cancer patients, and to be associated with chemoresistance using in vitro models of platinum and taxane resistance in human ovarian cancer. Citation Format: Neil T. Phippen, Nicholas W. Bateman, Guisong Wang, Chad A. Hamilton, George L. Maxwell, Kathleen M. Darcy, Thomas P. Conrads. Poor survival associated with NUAK1 overexpression in serous ovarian cancer may be explained by chemotherapy resistance. [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 4632. doi:10.1158/1538-7445.AM2015-4632
144. In Vivo Targeting hTfR and EGFR Using Aptamers
Authors: Linsley Kelly, Keith Maier, Amy Yan, Matthew Levy
Journal: Molecular Therapy (2015)

Aptamers which bind cell surface receptors represent an exciting and potentially important class of ligands for the development of diagnostics and therapeutics. However, if aptamers are to be utilized in vivo, and more importantly for the targeted delivery of therapeutic cargoes, the molecular function must be robust, especially with regard to specificity and activity. Because assay formats for determining the binding specificity of aptamers to their cell surface targets vary greatly, and because some molecules have yet to be tested in vivo, it remains difficult to compare the function of these molecules and to identify which candidate molecules could be used for future development as both diagnostics and therapeutics. In order to assess this, we have chemically synthesized 15 different aptamers from the literature which target a range of human cell surface receptors associated with cancers. These include aptamers targeting EGFR, EPCAM, nucleolin, PSMA, PTK7 and hTfR, as well as some aptamers which have been derived from variations on 'whole cell SELEX' or similar approaches against cancer cells lines. Using standardized conditions, we assayed each aptamer in vitro using flow cytometry on a panel of different cancer cell lines to compare relative binding affinity and specificity. Molecules which function in vitro were subsequently assessed for tumor targeting capabilities in vivo using near-infrared imaging. Interestingly, some molecules which function robustly in vitro demonstrate little to no activity in vivo. Of the molecules tested, three demonstrate significant activity in vivo. These include an anti-EGFR aptamer, an anti-hTfR aptamer and a molecule identified via an 'internalization selection method' that is readily internalized by cancer cells, but shows little uptake by normal tissue. Taken as a whole, our data demonstrate some surprising differences in the apparent affinities and specificities of different aptamers when assayed under these standardized conditions. They also provide us with molecules which we can now think about transitioning for in vivo applications. Data on using these molecules to deliver cytotoxic drugs in vitro and in vivo will be presented.
Abstract 584: The DEK oncogene may serve as a predictive plasma biomarker in head and neck cancer patients
Authors: Trisha Wise-Draper, Lisa Privette Vinnedge, Arun Sendilnathan
Journal: Cancer Research (2015)

Abstract Head and neck cancer (HNC) remains the sixth most common cancer worldwide with almost 50,000 new diagnoses in the US each year. Although, infection with HPV has emerged as a favorable prognostic factor for head and neck squamous cell carcinoma (HNSCC) leading to de-intensifying treatment strategies, no serum biomarkers currently exist to predict tumor response and/or relapse. One candidate serum biomarker is encoded by the human DEK gene. DEK mRNA and protein is highly upregulated in tissue specimens from several tumor types including HNSCC, breast cancer and melanoma and antibodies to DEK are detected in patients with auto-immune disease (juvenile rheumatoid arthritis, systemic lupus erythematous, etc.). Our previous work has demonstrated that DEK is highly and universally expressed in HNSCC tissue specimens regardless of stage or HPV infection. Additionally, in vitro data has suggested that tumor associated macrophages secrete DEK protein leading to the hypothesis that DEK may be present in the serum of cancer patients. In fact, the detection of DEK protein in urine is currently being explored as a diagnostic biomarker for bladder cancer. Here, we sought to determine if secreted DEK protein can be detected in human plasma and if it could be used as a biomarker for HNSCC. Peripheral blood was collected from either patients with newly diagnosed, untreated, HNSCC or age-matched normal healthy controls. Plasma was separated from the samples and subjected to DEK specific ELISA (Cusabio, Wuhan, China). Plasma DEK levels were compared to tumor stage, response to therapy, and overall tumor burden in patients. Preliminary results demonstrate that DEK is indeed present in the plasma of HNSCC patients and we are currently comparing these levels to normal healthy controls. Further analyses are ongoing to determine whether DEK levels predict response to various treatment modalities, correlate with the body's immune response, and whether DEK presence in the serum will predict residual disease and/or early relapse. These data will be important to verify DEK plasma measurements as a clinically useful test and may give insight to future personalized and targeted treatment strategies for HNSCC. Citation Format: Trisha Wise-Draper, Lisa Privette Vinnedge, Arun Sendilnathan. The DEK oncogene may serve as a predictive plasma biomarker in head and neck cancer patients. [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 584. doi:10.1158/1538-7445.AM2015-584
Transglutaminase2 Expression in Acute Myeloid Leukemia: Association with Adhesion Molecule Expression and Leukemic Blast Motility
Authors: Steven M. Kornblau, Andrew Pierce, Stefan Meyer, Farhad Ravandi, Gautam Borthakur, Kevin R. Coombes, Nianxiang Zhang, Anthony Whetton
Journal: Blood (2012)
329. Using CRISPR/Cas9 as a Therapeutic Approach for Leber Congenital Amaurosis 10 (LCA10)
Authors: Guoxiang Ruan, Elizabeth Barry, Michael Lukason, Seng Cheng, Abraham Scaria
Journal: Molecular Therapy (2016)

Introduction: Leber congenital amaurosis (LCA) is the most severe form of inherited retinal diseases with early onset of symptoms in the first year of life. The most frequent genetic cause of LCA, accounting for approximately 15% of all LCA cases in western countries, is a deep-intronic mutation c. 2991+1655A>G located in the intron 26 of human CEP290 gene. LCA caused by CEP290 mutation is known as LCA10. The intronic mutation of CEP290 generates a cryptic splice donor site, resulting in the inclusion of a pseudoexon that leads to a premature stop codon and a truncated protein. The size of human CEP290 cDNA (~7.4 kb) exceeds the cargo size (~4.8 kb) of recombinant adeno-associated viral vectors (rAAVs), which makes this gene challenging for gene replacement therapy. In this regard, we tested if we can use the new genome editing technology CRISPR/Cas9 as an alternative strategy for LCA10 by removing the intronic mutation of CEP290 and preventing the cryptic splicing. Methods: CRISPR/SpCas9 was employed to introduce the intronic splice mutation c. 2991+1655 A>G into HEK 293FT cells to create a cellular model for LCA10/CEP290. In this cellular model, we used guide RNA pairs coupled with SpCas9 to delete the intronic region flanking the intronic mutation. Results: The deep-intronic mutation c. 2991+1655 A>G was successfully introduced into 293FT cells through the homology directed repair (HDR) pathway of CRISPR/spCas9. CEP290 expression levels were markedly reduced in the mutant cell line. Using this cellular model, we identified three sgRNA pairs that could efficiently (>50%) delete the intronic mutation, significantly rescue wild-type CEP290 expression levels and reduce mutant CEP290 expression. Conclusions: Our results demonstrate that the paired sgRNAs coupled with SpCas9 are capable of removing the c. 2991+1655A>G mutation and are highly efficient in preventing the splicing of the mutant cryptic exon and restoring wild-type CEP290 expression.
Levels of Uninvolved Immunoglobulin Predict Clinical Status and Progression-Free Survival for Multiple Myeloma Patients
Authors: Nika M Harutyunyan, Suzie Vardanyan, Michael Ghermezi, Jillian Gottlieb, Ariana Berenson, Claudia Andreu-Vieyra, George Tang, Eric Sanchez, Mingjie Li, Cathy Wang, Joseph Ben-Zvi, Gigi Garzio, Haiming Chen, Judith Finlay, James R Berenson
Journal: Blood (2014)
Analysis of Stem Cell Transplant Referral in a Cohort of Newly Diagnosed Chronic Lymphocytic Leukemia Patients
Authors: Wei Ding, Kari G. Rabe, Ruchi G. Sharma, Susan Schwager, Susan L Slager, William J Hogan, Saad J. Sirop, Neil E. Kay, Timothy G Call, Clive S. Zent, Deborah Bowen, Michael J. Conte, Tait D. Shanafelt
Journal: Blood (2012)
Functional Effects of the Bcl-2/Bcl-xL Inhibitor ABT-737 on Primary Cells from Smoldering Multiple Myeloma.
Authors: Maria Rosaria Ricciardi, Elisabetta Calabrese, Fabiana De Cave, Sara Santinelli, Paola Bergamo, Samantha Decandia, Chiara Gregorj, Vincenzo Federico, Michele Milella, Robert Foa, Agostino Tafuri, Maria Teresa Petrucci
Journal: Blood (2007)
Pooled analysis of clinical outcome of patients with chemorefractory metastatic colorectal cancer treated within clinical studies based on individual molecular alterations at Niguarda Cancer Center
Authors: A. Sartore-Bianchi, A. Amatu, S. Stabile, F. Tosi, E. Bonazzina, M. Maiolani, F. Rusconi, D. Galbiati, V. Orlando, L. Pietrogiovanna, A. Gambaro, S. Ghezzi, D. Mastroianni, G. Marrapese, C. Lauricella, E. Valtorta, S. Veronese, M. Truini, S. Siena
Journal: Annals of Oncology (2015)
PO13ON THE BIOLOGICAL BEHAVIOUR AND PROGNOSIS OF ANAPLASTIC OLIGODENDROGLIOMA WITH NECROSIS
Authors: M. Aizpurua, R.C. Laxton, L. Doey, I. Bodi, A. King, R. Bhangoo, R. Beaney, L. Brazil, K. Ashkan, S. Al-Sarraj
Journal: Neuro-Oncology (2015)

INTRODUCTION: Previously we have shown that glioblastomas with an oligodendroglial component (GBMO) did not differ from other glioblastomas in the frequency of 1p/19q deletion or isocitrate dehydrogenase mutation. Here we seek to determine whether anaplastic oligodendrogliomas with necrosis and very prominent endothelial cell hyperplasia (AO + N), often diagnosed as GBMO, differ in prognosis from the classic grade III counterpart (AOIII) and GBMO. METHOD: Anaplastic oligodendrogliomas with 1p/19q co-deletion and mutation to IDH1 or IDH2 were classed as either grade III or IV dependent upon the presence of the above mentioned high grade features. GBMO with neither 1p/19q co-deletion nor mutation to IDH1 or IDH2 were also selected for comparison. Statistical analyses were performed using R-Stats v2.15.2. RESULTS: AO + N (n = 16) with a median survival of 66.5 months had a worse prognosis than AOIII (n = 30) (median not reached, p = 0.04) and a better prognosis than GBMO (n = 46) (median survival 9 months, p = 1.04X10-5). The difference in survival between AO + N and GBMO remained significant when adjusted for age and gender (HR 0.17 95% CI 0.07-0.4, 6.3X10-5). CONCLUSION: The results suggest that anaplastic oligodendroglioma with necrosis and prominent endothelial cell hyperplasia behave worse than classic anaplastic oligodendroglioma and better than GBMO. Proper consideration should be given to including these neoplasms as a novel WHO grade IV classification if these results can be replicated in a larger cohort.
A Critical Appraisal of Aspirin in Secondary Prevention
Authors: Giuseppe Gargiulo, Stephan Windecker, Pascal Vranckx, Charles Michael Gibson, Roxana Mehran, Marco Valgimigli
Journal: Circulation (2016)

Aspirin represents the sine qua non for antiplatelet pharmacotherapy in patients with cardiovascular diseases because of its well-established role in secondary prevention and its widespread availability and affordability. Historical studies, conducted in an era that bears little resemblance to contemporary clinical practice, demonstrated large reductions in thrombotic risk when aspirin was compared with placebo, thus forming the evidence base promulgated in practice guidelines and recommendations. P2Y12 inhibitors have mostly been studied in addition to aspirin; dual-antiplatelet therapy proved superiority compared with aspirin monotherapy for the prevention of ischemic events, despite increased bleeding risks. An alternative approach currently under investigation includes evaluation of single-antiplatelet therapy with P2Y12 inhibitors alone versus dual-antiplatelet therapy after acute coronary syndromes or coronary stent implantation. As the availability of more effective antiplatelet agents increases, it is time to revisit the existing and long-standing paradigm supporting aspirin use for secondary prevention of atherothrombotic events. Ongoing trials will provide new evidence whether the less-is-more strategy is justified.
Abstract 361: Opposite regulation of stromelysin expression in prostate tumor and its microenvironment
Authors: Shian-Ying Sung, Chia-Ling Hsieh
Journal: Cancer Research (2015)

Abstract Crosstalk between cancer and milieu cells plays a central role during cancer progression, which includes determine the faith of increasing metalloproteinase secretion by cancer epithelial cells. Here, we showed prostate tumor and stromal fibroblasts expressed opposite levels of Stromelysin-1 and -2 in both 3D co-culture and paired patient samples. Macroarray and quantitative RT-PCR studies demonstrated significantly decreased of Stromelysin-1 expression in co-cultured HS27AC4-2 and 4 paired tumor associated fibroblasts that were collected in previous report. We noticed the Stromelysin-1 expression level was decreased in stromal region of prostate cancer. By contrast, Stromelysin-1 level was increased in malignant cancer epithelial cells in both cells and tissue staining. Canonical pathway study revealed of differentially gene expression between HS27AC4-2 and HS27ARWV including the majority of pathway enrichment in TGF-β and hydrogen peroxide as central mediators. Induction of Stromelysin-1 and -2 by TGF-β and/or hydrogen peroxide were preliminary validated in the conditioned medium of prostate cancer cells, PC3 and DU145, and paired patient stromal fibroblasts that confirmed the opposite regulation of Stromelysin-1 and -2 expression by hydrogen peroxide but not TGF-β. Our results demonstrate the differential regulation of Stromelysin-1 and -2 expression in prostate cancer cells and stromal fibroblasts through ROS, such as hydrogen peroxide, as mediator and shed the light on the potentially useful as indication for the differential regulation between cancer and stromal cells. Citation Format: Shian-Ying Sung, Chia-Ling Hsieh. Opposite regulation of stromelysin expression in prostate tumor and its microenvironment. [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 361. doi:10.1158/1538-7445.AM2015-361
Treatment Outcome and Prognostic Model for Stage IE/IIE Extranodal Natural Killer/T-Cell Lymphoma, Nasal Type: A Retrospective Study in a Cohort of 305 Patients with Long Term Follow-up
Authors: Yuankai Shi, Bo Jia, Xiaohui He, Youwu Shi, Mei Dong, Jianliang Yang, Liqiang Zhou, Shengyu Zhou, Peng Liu, Yan Qin, Sheng Yang, Hua Lin, Lin Gui, Changgong Zhang, Lin Wang, Shanshan Chen, Puyuan Xing, Hongnan Mo, Mingzhe Han
Journal: Blood (2015)
Phase I Clinical Trial of the Anti-CD22 Immunotoxin CAT-8015 (HA22) for Pediatric Acute Lymphoblastic Leukemia (ALL).
Authors: Alan S. Wayne, Deepa Bhojwani, Sima Jeha, Maryalice Stetler-Stevenson, Ching-Hon Pui, Jennifer McDevitt, David J. FitzGerald, Robert J Kreitman, Karen Kaucic, Ira Pastan
Journal: Blood (2009)
Identification of Genes with Prognostic and Therapeutic Relevance in Multiple Myeloma Using Serial Analysis of Gene Expression Technique.
Authors: Roberta S. Felix, Gisele W.B. Colleoni, Andre L. Vettore, Mihoko Yamamoto, Manuella S.S. Almeida, Valeria C.C. Andrade, Maria de Lourdes L.F. Chauffaille, Wilson A. da Silva, Otavia L. Caballero, Andrew J. Simpson, Marco Antonio Zago
Journal: Blood (2007)
541. Use of Endogenous Viral Elements to Deduce the Sequence of an Ancient Adeno-Associated Virus That Circulated Amongst Australian Marsupials ~30 Million Years Ago
Authors: Claus V. Hallwirth, Richard H. Smith, Michael Westerman, Nicola A. Hetherington, Yu-Shan Tseng, Sylvain Cecchini, Tamas Virag, Mona-Larissa Ziegler, Igor B. Rogozin, Eugene V. Koonin, Mavis Agbandje-McKenna, Ian E. Alexander, Robert M. Kotin
Journal: Molecular Therapy (2016)

Vectors based on adeno-associated viruses (AAVs) have been successfully applied in clinical trials and pre-clinical settings. AAV capsid proteins are the primary determinants of vector tropism and immunogenicity, and are continually being developed to impart desirable properties, such as immune evasion and specificity for selected target tissues in humans and those of model organisms. One approach that was recently adopted by at least two groups to generate novel capsid variants is the computational deduction of putative ancestral AAV sequences, based upon observable genetic diversity amongst closely related contemporary AAV isolates. Such inferred ancestral sequences potentially recapitulate the evolutionary history of AAVs for hundreds or possibly thousands of years. Germline endogenous viral elements (EVEs) can compensate for the lack of a viral fossil record by genetically preserving viral nucleotide sequences over a geologic time span. Here we describe an AAV-EVE (mAAV-EVE1) that is lineage-restricted to the germlines of members of the Australian marsupial suborder Macropodiformes (present-day kangaroos, wallabies, and related macropodoids), to the exclusion of other Diprotodontian marsupial lineages. Orthologous mAAV-EVE1 sequences from sixteen macropodoid species, representing a speciation history spanning an estimated 30 million years, facilitated in silico reconstruction of an inferred ancestral AAV sequence. This sequence represents the genome of an ancient marsupial AAV that circulated among Australian metatherian fauna sometime during the late Eocene to early Oligocene. The deduced ancient AAV bears remarkable resemblance to modern AAVs in its predicted structural and non-structural genes, underscoring the concept that despite their relatively rapid mutation rates, AAVs have evolved under tight constraints imposed by both form and function. Moreover, the evolutionary history of mAAV-EVE1 since its integration into the pro-macropodoid lineage reflects that of the respective host species. In addition to providing an inferred ancient AAV capsid sequence for future transduction studies, this sequence can serve as input for the generation of further novel capsids by approaches such as capsid shuffling and directed capsid engineering/evolution. Furthermore, by comparing it to contemporary AAV capsids, this sequence can inform rational capsid design approaches by providing insights into long-term capsid evolution.